SNPMiner Trials by Shray Alag


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Report for Mutation G551D

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 42 clinical trials

Clinical Trials


1 A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study of VX-770 to Evaluate Safety, Pharmacokinetics, and Biomarkers of CFTR Activity in Cystic Fibrosis (CF) Subjects With Genotype G551D

The purpose of this study was to evaluate the safety and tolerability of ivacaftor in patients with cystic fibrosis (CF) who were aged 18 years or older and have a G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ivacaftor is a potent and selective CFTR potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. Potentiators are pharmacological agents that increase the chloride ion transport properties of the channel in the presence of cyclic AMP-dependent protein kinase A (PKA) activation.

NCT00457821 Cystic Fibrosis Drug: Ivacaftor 25 mg/75 mg Drug: Ivacaftor 75 mg/150 mg Drug: Ivacaftor 150 mg or 250 mg Drug: Placebo
MeSH:Cystic Fibrosis Fibrosis

A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study of VX-770 to Evaluate Safety, Pharmacokinetics, and Biomarkers of CFTR Activity in Cystic Fibrosis (CF) Subjects With Genotype G551D. --- G551D ---

Safety Study of Ivacaftor in Subjects With Cystic Fibrosis The purpose of this study was to evaluate the safety and tolerability of ivacaftor in patients with cystic fibrosis (CF) who were aged 18 years or older and have a G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. --- G551D ---

Ivacaftor is a potent and selective CFTR potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. --- G551D ---

The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity.. Inclusion Criteria: - Weighing at least 40 kg - Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele - Forced expiratory volume in 1 second (FEV1) of at least 40% of predicted normal for age, gender, and height - Willing to remain on stable medication regimen for the duration of study participation - No significant clinical laboratory abnormalities, not pregnant, and willing to use at least 2 highly effective birth control methods during Part 1 and 1 highly effective birth control method during Part 2 of the study - No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator Exclusion Criteria: - History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject - Ongoing acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 14 days of Day 1 of the study - History of alcohol, medication or illicit drug abuse within one year prior to Day 1 - Abnormal liver function ≥ 3x the upper limit of normal - History of abnormal renal function (creatinine clearance < 50 mL/min using Cockcroft-Gault equation) - History of solid organ or hematological transplantation - Pregnant or breast-feeding (for women) - Ongoing participation in another therapeutic clinical trial, or prior participation in an investigational drug study without appropriate washout - Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) Inclusion Criteria: - Weighing at least 40 kg - Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele - Forced expiratory volume in 1 second (FEV1) of at least 40% of predicted normal for age, gender, and height - Willing to remain on stable medication regimen for the duration of study participation - No significant clinical laboratory abnormalities, not pregnant, and willing to use at least 2 highly effective birth control methods during Part 1 and 1 highly effective birth control method during Part 2 of the study - No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator Exclusion Criteria: - History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject - Ongoing acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 14 days of Day 1 of the study - History of alcohol, medication or illicit drug abuse within one year prior to Day 1 - Abnormal liver function ≥ 3x the upper limit of normal - History of abnormal renal function (creatinine clearance < 50 mL/min using Cockcroft-Gault equation) - History of solid organ or hematological transplantation - Pregnant or breast-feeding (for women) - Ongoing participation in another therapeutic clinical trial, or prior participation in an investigational drug study without appropriate washout - Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) Cystic Fibrosis Cystic Fibrosis Fibrosis This was a double-blind, placebo-controlled, cross-over, multiple dose study of up to 28 days of dosing, in subjects with cystic fibrosis (CF) who have a G551D-CTFR gene mutation. --- G551D ---

The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity.. Inclusion Criteria: - Weighing at least 40 kg - Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele - Forced expiratory volume in 1 second (FEV1) of at least 40% of predicted normal for age, gender, and height - Willing to remain on stable medication regimen for the duration of study participation - No significant clinical laboratory abnormalities, not pregnant, and willing to use at least 2 highly effective birth control methods during Part 1 and 1 highly effective birth control method during Part 2 of the study - No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator Exclusion Criteria: - History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject - Ongoing acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 14 days of Day 1 of the study - History of alcohol, medication or illicit drug abuse within one year prior to Day 1 - Abnormal liver function ≥ 3x the upper limit of normal - History of abnormal renal function (creatinine clearance < 50 mL/min using Cockcroft-Gault equation) - History of solid organ or hematological transplantation - Pregnant or breast-feeding (for women) - Ongoing participation in another therapeutic clinical trial, or prior participation in an investigational drug study without appropriate washout - Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) Inclusion Criteria: - Weighing at least 40 kg - Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele - Forced expiratory volume in 1 second (FEV1) of at least 40% of predicted normal for age, gender, and height - Willing to remain on stable medication regimen for the duration of study participation - No significant clinical laboratory abnormalities, not pregnant, and willing to use at least 2 highly effective birth control methods during Part 1 and 1 highly effective birth control method during Part 2 of the study - No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator Exclusion Criteria: - History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject - Ongoing acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 14 days of Day 1 of the study - History of alcohol, medication or illicit drug abuse within one year prior to Day 1 - Abnormal liver function ≥ 3x the upper limit of normal - History of abnormal renal function (creatinine clearance < 50 mL/min using Cockcroft-Gault equation) - History of solid organ or hematological transplantation - Pregnant or breast-feeding (for women) - Ongoing participation in another therapeutic clinical trial, or prior participation in an investigational drug study without appropriate washout - Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) Cystic Fibrosis Cystic Fibrosis Fibrosis This was a double-blind, placebo-controlled, cross-over, multiple dose study of up to 28 days of dosing, in subjects with cystic fibrosis (CF) who have a G551D-CTFR gene mutation. --- G551D --- --- G551D ---

The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity.. Inclusion Criteria: - Weighing at least 40 kg - Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele - Forced expiratory volume in 1 second (FEV1) of at least 40% of predicted normal for age, gender, and height - Willing to remain on stable medication regimen for the duration of study participation - No significant clinical laboratory abnormalities, not pregnant, and willing to use at least 2 highly effective birth control methods during Part 1 and 1 highly effective birth control method during Part 2 of the study - No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator Exclusion Criteria: - History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject - Ongoing acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 14 days of Day 1 of the study - History of alcohol, medication or illicit drug abuse within one year prior to Day 1 - Abnormal liver function ≥ 3x the upper limit of normal - History of abnormal renal function (creatinine clearance < 50 mL/min using Cockcroft-Gault equation) - History of solid organ or hematological transplantation - Pregnant or breast-feeding (for women) - Ongoing participation in another therapeutic clinical trial, or prior participation in an investigational drug study without appropriate washout - Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) Inclusion Criteria: - Weighing at least 40 kg - Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele - Forced expiratory volume in 1 second (FEV1) of at least 40% of predicted normal for age, gender, and height - Willing to remain on stable medication regimen for the duration of study participation - No significant clinical laboratory abnormalities, not pregnant, and willing to use at least 2 highly effective birth control methods during Part 1 and 1 highly effective birth control method during Part 2 of the study - No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator Exclusion Criteria: - History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject - Ongoing acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 14 days of Day 1 of the study - History of alcohol, medication or illicit drug abuse within one year prior to Day 1 - Abnormal liver function ≥ 3x the upper limit of normal - History of abnormal renal function (creatinine clearance < 50 mL/min using Cockcroft-Gault equation) - History of solid organ or hematological transplantation - Pregnant or breast-feeding (for women) - Ongoing participation in another therapeutic clinical trial, or prior participation in an investigational drug study without appropriate washout - Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) Cystic Fibrosis Cystic Fibrosis Fibrosis This was a double-blind, placebo-controlled, cross-over, multiple dose study of up to 28 days of dosing, in subjects with cystic fibrosis (CF) who have a G551D-CTFR gene mutation. --- G551D --- --- G551D --- --- G551D ---

Primary Outcomes

Description: Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug). Serious adverse events that were ongoing at the follow-up visit were followed until the event resolved, returned to baseline, or was determined to be a stable or chronic condition.

Measure: Number of Subjects With Adverse Events (Combined Part 1 and Part 2)

Time: Baseline to Follow-up

Description: Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug). Serious adverse events that were ongoing at the follow-up visit were followed until the event resolved, returned to baseline, or was determined to be a stable or chronic condition.

Measure: Number of Adverse Events (Combined Part 1 and Part 2)

Time: Baseline to Follow-up

Secondary Outcomes

Description: The transepithelial nasal potential difference (NPD) is a direct measure of transepithelial ion transport. NPD under conditions of zero chloride concentration perfusion solution in the presence of isoproterenol was of primary interest.

Measure: Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2)

Time: 14 days and 28 days

Description: Spirometry is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. Relative change reflects the percent change from the baseline values [100% * (X-Y)/Y], where X and Y are post-baseline and baseline values, respectively.

Measure: Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2)

Time: 14 days and 28 days

Description: The CFQ-R is a health-related quality of life measure for subjects with cystic fibrosis. Each domain is scored from 0 (worst) to 100 (best). A difference of at least 4 points in the respiratory domain score of the CFQ-R is considered a minimal clinically important difference (MCID).

Measure: Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score)

Time: 14 days and 28 days

Description: The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity.

Measure: Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2)

Time: 14 days and 28 days

2 A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of VX-770 in Subjects With Cystic Fibrosis and the G551D Mutation

The purpose of this study was to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis aged 12 years and older who have the G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ivacaftor is a potent and selective CFTR potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. Potentiators are pharmacological agents that increase the chloride ion transport properties of the channel in the presence of cyclic AMP-dependent protein kinase A (PKA) activation.

NCT00909532 Cystic Fibrosis Drug: Ivacaftor Drug: Placebo
MeSH:Cystic Fibrosis Fibrosis

A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of VX-770 in Subjects With Cystic Fibrosis and the G551D Mutation. --- G551D ---

Study of Ivacaftor in Cystic Fibrosis Subjects Aged 12 Years and Older With the G551D Mutation The purpose of this study was to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis aged 12 years and older who have the G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. --- G551D ---

Study of Ivacaftor in Cystic Fibrosis Subjects Aged 12 Years and Older With the G551D Mutation The purpose of this study was to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis aged 12 years and older who have the G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. --- G551D --- --- G551D ---

Ivacaftor is a potent and selective CFTR potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. --- G551D ---

As malnutrition is common in patients with cystic fibrosis (CF) because of increased energy expenditures due to lung disease and fat malabsorption, body weight is an important clinical measure of nutritional status.. Inclusion Criteria: - Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele - Forced expiratory volume in 1 second (FEV1) of 40% to 90% (inclusive) of predicted normal for age, gender, and height at Screening. --- G551D ---

- No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator - Willing to use highly effective birth control methods during the study Exclusion Criteria: - History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject - Acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 4 weeks of Day 1 of the study - History of alcohol, medication or illicit drug abuse within one year prior to Day 1 - Abnormal liver function ≥ 3x the upper limit of normal - Abnormal renal function at Screening - History of solid organ or hematological transplantation - Pregnant, planning a pregnancy, breast-feeding, or unwilling to follow contraception requirements - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days prior to Screening - Use of inhaled hypertonic saline treatment - Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP 3A4) Inclusion Criteria: - Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele - Forced expiratory volume in 1 second (FEV1) of 40% to 90% (inclusive) of predicted normal for age, gender, and height at Screening. --- G551D ---

- No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator - Willing to use highly effective birth control methods during the study Exclusion Criteria: - History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject - Acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 4 weeks of Day 1 of the study - History of alcohol, medication or illicit drug abuse within one year prior to Day 1 - Abnormal liver function ≥ 3x the upper limit of normal - Abnormal renal function at Screening - History of solid organ or hematological transplantation - Pregnant, planning a pregnancy, breast-feeding, or unwilling to follow contraception requirements - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days prior to Screening - Use of inhaled hypertonic saline treatment - Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP 3A4) Cystic Fibrosis Cystic Fibrosis Fibrosis This was a phase 3 study in subjects with cystic fibrosis (CF) age 12 years and older who have a G551D-CFTR mutation and percent predicted forced expiratory volumn in 1 second (FEV1) between 40% and 90%. --- G551D ---

Patients with the G551D mutation were the targeted population for this study because ivacaftor is a potentiator of the gating function of the CFTR protein, and the most prevalent mutation with a gating defect in CF is the G551D mutation. --- G551D ---

Patients with the G551D mutation were the targeted population for this study because ivacaftor is a potentiator of the gating function of the CFTR protein, and the most prevalent mutation with a gating defect in CF is the G551D mutation. --- G551D --- --- G551D ---

This study was designed to further evaluate the efficacy of ivacaftor in subjects with CF who have a G551D-CFTR gene mutation and to evaluate safety in this population over a longer period than previously studied. --- G551D ---

Primary Outcomes

Description: Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.

Measure: Absolute Mean Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24

Time: baseline through 24 weeks

Secondary Outcomes

Description: Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.

Measure: Absolute Mean Change From Baseline in Percent Predicted FEV1 Through Week 48

Time: baseline through 48 weeks

Description: The CFQ-R is a health-related quality of life measure for subjects with cystic fibrosis. Each domain is scored from 0 (worst) to 100 (best). A difference of at least 4 points in the respiratory domain score of the CFQ-R is considered a minimal clinically important difference (MCID).

Measure: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled)

Time: baseline through 24 weeks and 48 weeks

Description: The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity.

Measure: Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48

Time: baseline through 24 weeks and 48 weeks

Description: Pulmonary exacerbation was defined as a change in antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of signs/symptoms such as change in sputum; new or increased hemoptysis; increased cough or dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees C; anorexia or weight loss; sinus pain/tenderness and discharge; change in physical examination of the chest; decreased pulmonary function by 10%; and radiographic changes indicative of pulmonary infection.

Measure: Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48

Time: baseline through 24 weeks and 48 weeks

Description: As malnutrition is common in patients with cystic fibrosis (CF) because of increased energy expenditures due to lung disease and fat malabsorption, body weight is an important clinical measure of nutritional status.

Measure: Absolute Change From Baseline in Weight at Week 24 and Week 48

Time: baseline to 24 weeks and 48 weeks

3 A Phase 3, 2-Part, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Pharmacokinetics, Efficacy and Safety of VX-770 in Subjects Aged 6 to 11 Years With Cystic Fibrosis and the G551D Mutation

The purpose of this study was to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis aged 6 to 11 years who have the G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ivacaftor is a potent and selective potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. Potentiators are pharmacological agents that increase the chloride ion transport properties of the channel in the presence of cyclic adenosine monophosphate (AMP)-dependent protein kinase A (PKA) activation.

NCT00909727 Cystic Fibrosis Drug: Ivacaftor Drug: Placebo
MeSH:Cystic Fibrosis Fibrosis

A Phase 3, 2-Part, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Pharmacokinetics, Efficacy and Safety of VX-770 in Subjects Aged 6 to 11 Years With Cystic Fibrosis and the G551D Mutation. --- G551D ---

Study of Ivacaftor in Cystic Fibrosis Subjects Aged 6 to 11 Years With the G551D Mutation The purpose of this study was to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis aged 6 to 11 years who have the G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. --- G551D ---

Study of Ivacaftor in Cystic Fibrosis Subjects Aged 6 to 11 Years With the G551D Mutation The purpose of this study was to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis aged 6 to 11 years who have the G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. --- G551D --- --- G551D ---

Ivacaftor is a potent and selective potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. --- G551D ---

As malnutrition is common in patients with cystic fibrosis (CF) because of increased energy expenditures due to lung disease and fat malabsorption, body weight is an important clinical measure of nutritional status.. Inclusion Criteria: - Weighing at least 15 kg - Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele - Forced expiratory volume in 1 second (FEV1) of 40% to 105% (inclusive) of predicted normal for age, gender, and height (Knudson standards) at Screening - Able to swallow tablets - As judged by the investigator, parent or legal guardian and subject must have been able to understand protocol requirements, restrictions, and instructions, and the parent or legal guardian should have been able to ensure that the subject complied with, and was likely to complete, the study as planned - Parent or legal guardian must have signed the informed consent form and corresponding assent must be obtained from the subject - Willing to use at least 1 highly effective birth control method during the study - No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator Exclusion Criteria: - History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject - Acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 4 weeks of Day 1 of the study - Abnormal liver function ≥ 3x the upper limit of normal - Abnormal renal function at Screening - History of solid organ or hematological transplantation - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days prior to Screening - Use of inhaled hypertonic saline treatment - Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP 3A4) Inclusion Criteria: - Weighing at least 15 kg - Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele - Forced expiratory volume in 1 second (FEV1) of 40% to 105% (inclusive) of predicted normal for age, gender, and height (Knudson standards) at Screening - Able to swallow tablets - As judged by the investigator, parent or legal guardian and subject must have been able to understand protocol requirements, restrictions, and instructions, and the parent or legal guardian should have been able to ensure that the subject complied with, and was likely to complete, the study as planned - Parent or legal guardian must have signed the informed consent form and corresponding assent must be obtained from the subject - Willing to use at least 1 highly effective birth control method during the study - No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator Exclusion Criteria: - History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject - Acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 4 weeks of Day 1 of the study - Abnormal liver function ≥ 3x the upper limit of normal - Abnormal renal function at Screening - History of solid organ or hematological transplantation - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days prior to Screening - Use of inhaled hypertonic saline treatment - Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP 3A4) Cystic Fibrosis Cystic Fibrosis Fibrosis This is a Phase 3, 2-part, randomized, double-blind, placebo-controlled, parallel group multicenter study of orally administered ivacaftor in subjects with cystic fibrosis (CF) 6 to 11 years of age who have the G551D-CFTR mutation and a forced expiratory volume in 1 second (FEV1) between 90% and 105% predicted (using Knudson standards). --- G551D ---

As malnutrition is common in patients with cystic fibrosis (CF) because of increased energy expenditures due to lung disease and fat malabsorption, body weight is an important clinical measure of nutritional status.. Inclusion Criteria: - Weighing at least 15 kg - Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele - Forced expiratory volume in 1 second (FEV1) of 40% to 105% (inclusive) of predicted normal for age, gender, and height (Knudson standards) at Screening - Able to swallow tablets - As judged by the investigator, parent or legal guardian and subject must have been able to understand protocol requirements, restrictions, and instructions, and the parent or legal guardian should have been able to ensure that the subject complied with, and was likely to complete, the study as planned - Parent or legal guardian must have signed the informed consent form and corresponding assent must be obtained from the subject - Willing to use at least 1 highly effective birth control method during the study - No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator Exclusion Criteria: - History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject - Acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 4 weeks of Day 1 of the study - Abnormal liver function ≥ 3x the upper limit of normal - Abnormal renal function at Screening - History of solid organ or hematological transplantation - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days prior to Screening - Use of inhaled hypertonic saline treatment - Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP 3A4) Inclusion Criteria: - Weighing at least 15 kg - Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele - Forced expiratory volume in 1 second (FEV1) of 40% to 105% (inclusive) of predicted normal for age, gender, and height (Knudson standards) at Screening - Able to swallow tablets - As judged by the investigator, parent or legal guardian and subject must have been able to understand protocol requirements, restrictions, and instructions, and the parent or legal guardian should have been able to ensure that the subject complied with, and was likely to complete, the study as planned - Parent or legal guardian must have signed the informed consent form and corresponding assent must be obtained from the subject - Willing to use at least 1 highly effective birth control method during the study - No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator Exclusion Criteria: - History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject - Acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 4 weeks of Day 1 of the study - Abnormal liver function ≥ 3x the upper limit of normal - Abnormal renal function at Screening - History of solid organ or hematological transplantation - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days prior to Screening - Use of inhaled hypertonic saline treatment - Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP 3A4) Cystic Fibrosis Cystic Fibrosis Fibrosis This is a Phase 3, 2-part, randomized, double-blind, placebo-controlled, parallel group multicenter study of orally administered ivacaftor in subjects with cystic fibrosis (CF) 6 to 11 years of age who have the G551D-CFTR mutation and a forced expiratory volume in 1 second (FEV1) between 90% and 105% predicted (using Knudson standards). --- G551D --- --- G551D ---

As malnutrition is common in patients with cystic fibrosis (CF) because of increased energy expenditures due to lung disease and fat malabsorption, body weight is an important clinical measure of nutritional status.. Inclusion Criteria: - Weighing at least 15 kg - Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele - Forced expiratory volume in 1 second (FEV1) of 40% to 105% (inclusive) of predicted normal for age, gender, and height (Knudson standards) at Screening - Able to swallow tablets - As judged by the investigator, parent or legal guardian and subject must have been able to understand protocol requirements, restrictions, and instructions, and the parent or legal guardian should have been able to ensure that the subject complied with, and was likely to complete, the study as planned - Parent or legal guardian must have signed the informed consent form and corresponding assent must be obtained from the subject - Willing to use at least 1 highly effective birth control method during the study - No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator Exclusion Criteria: - History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject - Acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 4 weeks of Day 1 of the study - Abnormal liver function ≥ 3x the upper limit of normal - Abnormal renal function at Screening - History of solid organ or hematological transplantation - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days prior to Screening - Use of inhaled hypertonic saline treatment - Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP 3A4) Inclusion Criteria: - Weighing at least 15 kg - Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele - Forced expiratory volume in 1 second (FEV1) of 40% to 105% (inclusive) of predicted normal for age, gender, and height (Knudson standards) at Screening - Able to swallow tablets - As judged by the investigator, parent or legal guardian and subject must have been able to understand protocol requirements, restrictions, and instructions, and the parent or legal guardian should have been able to ensure that the subject complied with, and was likely to complete, the study as planned - Parent or legal guardian must have signed the informed consent form and corresponding assent must be obtained from the subject - Willing to use at least 1 highly effective birth control method during the study - No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator Exclusion Criteria: - History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject - Acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 4 weeks of Day 1 of the study - Abnormal liver function ≥ 3x the upper limit of normal - Abnormal renal function at Screening - History of solid organ or hematological transplantation - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days prior to Screening - Use of inhaled hypertonic saline treatment - Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP 3A4) Cystic Fibrosis Cystic Fibrosis Fibrosis This is a Phase 3, 2-part, randomized, double-blind, placebo-controlled, parallel group multicenter study of orally administered ivacaftor in subjects with cystic fibrosis (CF) 6 to 11 years of age who have the G551D-CFTR mutation and a forced expiratory volume in 1 second (FEV1) between 90% and 105% predicted (using Knudson standards). --- G551D --- --- G551D --- --- G551D ---

Patients with the G551D mutation were the targeted population for this study because ivacaftor is a potentiator of the gating effect of the CFTR protein, and the most prevalent mutation with a gating defect in CF is the G551D mutation. --- G551D ---

Patients with the G551D mutation were the targeted population for this study because ivacaftor is a potentiator of the gating effect of the CFTR protein, and the most prevalent mutation with a gating defect in CF is the G551D mutation. --- G551D --- --- G551D ---

Primary Outcomes

Description: Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.

Measure: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24

Time: baseline through 24 weeks

Secondary Outcomes

Description: Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.

Measure: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 48

Time: baseline through 48 weeks

Description: The CFQ-R is a health-related quality of life measure for subjects with cystic fibrosis. Each domain is scored from 0 (worst) to 100 (best). A difference of at least 4 points in the respiratory domain score of the CFQ-R is considered a minimal clinically important difference (MCID).

Measure: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Through Week 24 and Week 48 (Respiratory Domain Score, Children)

Time: baseline through 24 weeks and 48 weeks

Description: The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity.

Measure: Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48

Time: baseline through 24 weeks and 48 weeks

Description: As malnutrition is common in patients with cystic fibrosis (CF) because of increased energy expenditures due to lung disease and fat malabsorption, body weight is an important clinical measure of nutritional status.

Measure: Absolute Change From Baseline in Weight at Week 24 and Week 48

Time: baseline to 24 weeks and 48 weeks

4 A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Safety and Efficacy of VX-770 in Subjects Aged 12 Years and Older With Cystic Fibrosis Who Are Homozygous for the F508del-CFTR Mutation

The purpose of this study was to evaluate the safety and efficacy of ivacaftor in participants with cystic fibrosis (CF) who were aged 12 years or older and were homozygous for the F508del-CF transmembrane conductance regulator (CFTR) mutation. Ivacaftor is a potent and selective CFTR potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. Potentiators are pharmacological agents that increase the chloride ion transport properties of the channel in the presence of cyclic adenosine monophosphate (AMP)-dependent protein kinase A (PKA) activation.

NCT00953706 Cystic Fibrosis Drug: Ivacaftor Drug: Placebo
MeSH:Cystic Fibrosis Fibrosis

Ivacaftor is a potent and selective CFTR potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. --- G551D ---

Primary Outcomes

Description: Spirometry (as measured by ppFEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. ppFEV1 (predicted for age, gender, and height) was calculated using the Knudson method.

Measure: Part A : Absolute Change From Part A Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 16

Time: Part A baseline through Week 16

Secondary Outcomes

Description: The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; Higher scores indicating fewer symptoms and better health-related quality of life.

Measure: Part A : Absolute Change From Part A Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 16

Time: Part A baseline through Week 16

Description: The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity.

Measure: Part A : Absolute Change From Part A Baseline in Sweat Chloride Concentration Through Week 16

Time: Part A baseline through Week 16

Description: As malnutrition is common in participants with cystic fibrosis (CF) because of increased energy expenditures due to lung disease and fat malabsorption, body weight is an important clinical measure of nutritional status.

Measure: Part A : Rate of Change From Baseline in Weight Through Week 16

Time: Part A baseline through Week 16

Description: ppFEV1 is defined in Outcome Measure 1.

Measure: Part B : Absolute Change From Part A and Part B Baseline in ppFEV1 Through Week 64

Time: Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64

Description: ppFEV1 is defined in Outcome Measure 1.

Measure: Part B : Rate of Change From Part A Baseline in ppFEV1 Through Week 64

Time: Part A baseline through Week 64

Description: ppFEV1 is defined in Outcome Measure 1.

Measure: Part B : Rate of Change From Part B Baseline in ppFEV1 Through Week 64

Time: Part B baseline through Week 64

Description: The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; Higher scores indicating fewer symptoms and better health-related quality of life.

Measure: Part B : Absolute Change From Part A and Part B Baseline in CFQ-R Respiratory Domain Score Through Week 64

Time: Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64

Description: The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity.

Measure: Part B : Absolute Change From Part A and Part B Baseline in Sweat Chloride Concentration Through Week 64

Time: Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64

Description: As malnutrition is common in patients with cystic fibrosis (CF) because of increased energy expenditures due to lung disease and fat malabsorption, body weight is an important clinical measure of nutritional status.

Measure: Part B : Absolute Change From Part A and Part B Baseline in Weight Through Week 64

Time: Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64

Description: Pulmonary exacerbation was defined as new, or changed, antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of the following signs/symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees Celsius; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent (%); and radiographic changes indicative of pulmonary infection.

Measure: Part B : Number of Participants With Pulmonary Exacerbations

Time: Part B baseline through Week 64

Description: Pulmonary exacerbation was defined as new, or changed, antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of the following signs/symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees Celsius; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent (%); and radiographic changes indicative of pulmonary infection.

Measure: Part B : Number of Pulmonary Exacerbation Events

Time: Part B baseline through Week 64

Description: Pulmonary exacerbation was defined as new, or changed, antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of the following signs/symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees Celsius; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent (%); and radiographic changes indicative of pulmonary infection.

Measure: Part B : Number of Pulmonary Exacerbation Events Per Participant Per Year

Time: Part B baseline through Week 64

5 A Phase 2, Single-Blind, Placebo-Controlled Study to Evaluate the Effect of VX-770 on Hyperpolarized Helium-3 Magnetic Resonance Imaging in Subjects With Cystic Fibrosis, the G551D Mutation, and FEV1 ≥40% Predicted

Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The encoded protein, CFTR, is an epithelial chloride ion channel responsible for aiding in the regulation of salt and water absorption and secretion in various tissues. Although the disease affects multiple organs, the leading cause of mortality is the progressive loss of lung function. Obstruction of airways with thick mucus, chronic bacterial infection of the airways, and inflammatory response are all thought to play a role in causing lung damage. Through its function as a chloride channel, CFTR is believed to be integral in epithelial ion and water transport and hence, maintaining the normal hydration of lung secretions. VX-770 (ivacaftor) is a potent and selective potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR. Based on in vitro studies and pharmacologic, pharmacokinetic (PK), and safety profiles, VX-770 has been selected for clinical development as a possible treatment for patients with CF. Hyperpolarized noble gas magnetic resonance imaging (HG-MRI) is a promising new means of assessing lung function by direct imaging of certain non-radioactive isotopes of an inert noble gas, such as helium or xenon. Through this technique, high-resolution 3-dimensional images of lung ventilation can be obtained in both pediatric and adult patients during a single short breath-hold following inhalation of the gas. This is a 2-part study to evaluate the effect of VX-770 on hyperpolarized helium-3 magnetic resonance imaging (3He-MRI), and to evaluate the safety and efficacy of VX-770 in subjects aged 12 years and older with CF who have the G551D-CFTR mutation. Part A is a single-blind, placebo-controlled study that includes 4 weeks of VX-770 treatment and 4 weeks of placebo treatment. Part B is an open-label, 48 week study of long-term effect of VX 770 on hyperpolarized 3He-MRI.

NCT01161537 Cystic Fibrosis Drug: VX-770 Drug: Placebo
MeSH:Cystic Fibrosis Fibrosis

A Phase 2, Single-Blind, Placebo-Controlled Study to Evaluate the Effect of VX-770 on Hyperpolarized Helium-3 Magnetic Resonance Imaging in Subjects With Cystic Fibrosis, the G551D Mutation, and FEV1 ≥40% Predicted. --- G551D ---

Study of the Effect of VX-770 on Hyperpolarized Helium-3 Magnetic Resonance Imaging in Subjects With Cystic Fibrosis and the G551D Mutation Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. --- G551D ---

VX-770 (ivacaftor) is a potent and selective potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR. --- G551D ---

This is a 2-part study to evaluate the effect of VX-770 on hyperpolarized helium-3 magnetic resonance imaging (3He-MRI), and to evaluate the safety and efficacy of VX-770 in subjects aged 12 years and older with CF who have the G551D-CFTR mutation. --- G551D ---

Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in Part B (48 weeks).. Inclusion Criteria: - Male or female with Cystic Fibrosis - Must have the G551D-CFTR mutation on at least 1 allele - FEV1 ≥40% of predicted normal for age, gender, and height at Screening - 12 years of age or older - Must be able to swallow tablets Exclusion Criteria: - History of solid organ or hematological transplantation - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening - Use of inhaled hypertonic saline treatment within 14 days prior to the Screening Visit - Extensive body tattoos or other physical features that will confound MRI Inclusion Criteria: - Male or female with Cystic Fibrosis - Must have the G551D-CFTR mutation on at least 1 allele - FEV1 ≥40% of predicted normal for age, gender, and height at Screening - 12 years of age or older - Must be able to swallow tablets Exclusion Criteria: - History of solid organ or hematological transplantation - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening - Use of inhaled hypertonic saline treatment within 14 days prior to the Screening Visit - Extensive body tattoos or other physical features that will confound MRI Cystic Fibrosis Cystic Fibrosis Fibrosis null --- G551D ---

Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in Part B (48 weeks).. Inclusion Criteria: - Male or female with Cystic Fibrosis - Must have the G551D-CFTR mutation on at least 1 allele - FEV1 ≥40% of predicted normal for age, gender, and height at Screening - 12 years of age or older - Must be able to swallow tablets Exclusion Criteria: - History of solid organ or hematological transplantation - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening - Use of inhaled hypertonic saline treatment within 14 days prior to the Screening Visit - Extensive body tattoos or other physical features that will confound MRI Inclusion Criteria: - Male or female with Cystic Fibrosis - Must have the G551D-CFTR mutation on at least 1 allele - FEV1 ≥40% of predicted normal for age, gender, and height at Screening - 12 years of age or older - Must be able to swallow tablets Exclusion Criteria: - History of solid organ or hematological transplantation - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening - Use of inhaled hypertonic saline treatment within 14 days prior to the Screening Visit - Extensive body tattoos or other physical features that will confound MRI Cystic Fibrosis Cystic Fibrosis Fibrosis null --- G551D --- --- G551D ---

Primary Outcomes

Description: Subjects inhaled hyperpolarized helium-3 (3He) gas mixed with nitrogen to make a total volume of approximately one-third forced vital capacity (FVC) to a maximum of 1 liter and hold their breath for 20 seconds or less. Rapid magnetic resonance imaging (MRI) was performed during inhalation/exhalation and/or breath-hold. Areas of decreased ventilation were observed as ventilation defects that are visualized as decreased (and/or absent) 3He intensity in 3He-MRI. The total ventilation defect was defined as the ratio of total ventilation defect volume (L) to total lung volume (L), expressed as a percentage. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in VX-770 treatment phase (Day 15 to 42).

Measure: Part A: Change From Baseline in Total Ventilation Defect Defined by Hyperpolarized Helium 3 Magnetic Resonance Imaging (3He-MRI) at Day 43

Time: Part A: Baseline (pre-dose Day 15), Day 43

Description: Subjects were asked to inhale hyperpolarized 3 He gas mixed with nitrogen to make a total volume of approximately one-third forced vital capacity (FVC) to a maximum of 1 liter and hold their breath for 20 seconds or less. Rapid MRI was performed during inhalation/exhalation and/or breath-hold. Areas of decreased ventilation were observed as ventilation defects that are visualized as decreased (and/or absent) 3He intensity in 3He MRI. The total ventilation defect was defined as the ratio of total ventilation defect volume (L) to total lung volume (L), expressed as a percentage. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in Part B (48 weeks).

Measure: Part B: Change From Baseline in Total Ventilation Defect Defined by Hyperpolarized Helium 3 Magnetic Resonance Imaging (3He-MRI) at Week 48

Time: Part B: Baseline (Day -1), Week 48

Secondary Outcomes

Description: AE: any adverse change from subject's baseline (pre-treatment) condition, including any adverse experience, abnormal recording/clinical laboratory assessment which occurs during course of study, whether it is considered related to study drug or not. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event. Related AEs includes all AEs for which the causality was either related to study drug or possibly related to study drug.

Measure: Part A: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Related AEs

Time: Part A: Day 1 up to Day 57

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Predicted FEV1 (for age, gender, and height) was calculated using the Knudson method. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in VX-770 treatment phase (Day 15 to 42).

Measure: Part A: Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Day 43

Time: Part A: Baseline (pre-dose Day 15), Day 43

Description: Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in VX-770 treatment phase (Day 15 to 42).

Measure: Part A: Absolute Change From Baseline in Sweat Chloride at Day 43

Time: Part A: Baseline (pre-dose Day 15), Day 43

Description: The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in VX-770 treatment phase (Day 15 to 42).

Measure: Part A: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score At Day 43

Time: Baseline (pre-dose Day 15), Day 43

Description: AE: any adverse change from subject's baseline (pre-treatment) condition, including any adverse experience, abnormal recording/clinical laboratory assessment which occurs during course of study, whether it is considered related to study drug or not. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event. Related AEs includes all AEs for which the causality was either related to study drug or possibly related to study drug.

Measure: Part B: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Related AEs

Time: Part B: Day 1 up to Week 48

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Predicted FEV1 (for age, gender, and height) was calculated using the Knudson method. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in Part B (48 weeks).

Measure: Part B: Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 48

Time: Part B: Baseline (Day -1), Week 48

Description: Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in Part B (48 weeks).

Measure: Part B: Absolute Change From Baseline in Sweat Chloride at Week 48

Time: Part B: Baseline (Day -1), Week 48

Description: The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in Part B (48 weeks).

Measure: Part B: Absolute Change From Baseline in in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score At Week 48

Time: Part B: Baseline (Day -1), Week 48

6 A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Effect of VX-770 on Lung Clearance Index in Subjects With Cystic Fibrosis, the G551D Mutation, and FEV1 >90% Predicted

The purpose of this study is to evaluate the effect of ivacaftor (VX-770) on lung clearance index (LCI) in subjects aged 6 years and older with cystic fibrosis (CF) who have the G551D-CFTR mutation on at least 1 allele.

NCT01262352 Cystic Fibrosis Drug: Ivacaftor Drug: Placebo
MeSH:Cystic Fibrosis Fibrosis

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Effect of VX-770 on Lung Clearance Index in Subjects With Cystic Fibrosis, the G551D Mutation, and FEV1 >90% Predicted. --- G551D ---

Study of the Effect of Ivacaftor on Lung Clearance Index in Subjects With Cystic Fibrosis and the G551D Mutation The purpose of this study is to evaluate the effect of ivacaftor (VX-770) on lung clearance index (LCI) in subjects aged 6 years and older with cystic fibrosis (CF) who have the G551D-CFTR mutation on at least 1 allele. --- G551D ---

Study of the Effect of Ivacaftor on Lung Clearance Index in Subjects With Cystic Fibrosis and the G551D Mutation The purpose of this study is to evaluate the effect of ivacaftor (VX-770) on lung clearance index (LCI) in subjects aged 6 years and older with cystic fibrosis (CF) who have the G551D-CFTR mutation on at least 1 allele. --- G551D --- --- G551D ---

The primary analytical focus was the respiratory health domain, which was analyzed by combining all self-response questionnaire versions from different age groups (e.g., Adult/Adolescent and Child versions).. Inclusion Criteria: - Male or female subjects with confirmed diagnosis of CF - Must have the G551D-CFTR mutation in at least 1 allele - FEV1 >90% of predicted normal for age, gender, and height Exclusion Criteria: - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening - Use of inhaled hypertonic saline treatment within 2 weeks of the Period 1, Day 1 visit Inclusion Criteria: - Male or female subjects with confirmed diagnosis of CF - Must have the G551D-CFTR mutation in at least 1 allele - FEV1 >90% of predicted normal for age, gender, and height Exclusion Criteria: - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening - Use of inhaled hypertonic saline treatment within 2 weeks of the Period 1, Day 1 visit Cystic Fibrosis Cystic Fibrosis Fibrosis Currently, limited objective measures are available to quantify lung function in CF patients with mild lung disease. --- G551D ---

The primary analytical focus was the respiratory health domain, which was analyzed by combining all self-response questionnaire versions from different age groups (e.g., Adult/Adolescent and Child versions).. Inclusion Criteria: - Male or female subjects with confirmed diagnosis of CF - Must have the G551D-CFTR mutation in at least 1 allele - FEV1 >90% of predicted normal for age, gender, and height Exclusion Criteria: - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening - Use of inhaled hypertonic saline treatment within 2 weeks of the Period 1, Day 1 visit Inclusion Criteria: - Male or female subjects with confirmed diagnosis of CF - Must have the G551D-CFTR mutation in at least 1 allele - FEV1 >90% of predicted normal for age, gender, and height Exclusion Criteria: - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening - Use of inhaled hypertonic saline treatment within 2 weeks of the Period 1, Day 1 visit Cystic Fibrosis Cystic Fibrosis Fibrosis Currently, limited objective measures are available to quantify lung function in CF patients with mild lung disease. --- G551D --- --- G551D ---

This study explored the effect of ivacaftor on LCI and the efficacy of ivacaftor on other clinical and biomarker endpoints of CF lung disease in subjects aged 6 years and older with CF who have the G551D-CFTR mutation on at least 1 allele. --- G551D ---

Primary Outcomes

Description: Lung clearance index (LCI) is a measure of ventilation inhomogeneity that is derived from a multiple-breath washout test. The LCI was calculated as the number of lung volume turnovers (cumulative expired volume divided by the functional residual capacity [FRC]) required to reduce end-tidal SF6 concentration to 1/40th of the starting value.

Measure: Absolute Change From Baseline in Lung Clearance Index (LCI)

Time: Baseline through Day 29

Secondary Outcomes

Description: Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.

Measure: Absolute Change From Baseline in Percent Predicted FEV1

Time: Baseline through Day 29

Description: The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity.

Measure: Change From Baseline in Sweat Chloride

Time: Baseline through Day 29

Description: The CFQ-R is a health-related quality of life measure for subjects with cystic fibrosis. Each domain is scored from 0 (worst) to 100 (best). A difference of at least 4 points in the respiratory domain score of the CFQ-R is considered a minimal clinically important difference (MCID). The primary analytical focus was the respiratory health domain, which was analyzed by combining all self-response questionnaire versions from different age groups (e.g., Adult/Adolescent and Child versions).

Measure: Change From Baseline in CF Questionnaire-Revised (CFQ-R) Score (Respiratory Domain Score, Pooled)

Time: Baseline through Day 29

7 VX-770 Expanded Access Program (EAP)

The purpose of this expanded access program is to provide VX-770 prior to its commercial availability to people with cystic fibrosis (CF) who have at least one copy of the G551D-CFTR mutation and who are in critical medical need and who are not eligible for participation in other Vertex-sponsored studies.

NCT01381289 Cystic Fibrosis Drug: VX-770
MeSH:Cystic Fibrosis

VX-770 Expanded Access Program The purpose of this expanded access program is to provide VX-770 prior to its commercial availability to people with cystic fibrosis (CF) who have at least one copy of the G551D-CFTR mutation and who are in critical medical need and who are not eligible for participation in other Vertex-sponsored studies. --- G551D ---

- Have the G551D-CFTR mutation in at least 1 allele - Will be aged 6 years or older on the date of signed informed consent form - Highest FEV1 in the 6 months prior to screening is ≤ 40% predicted value or patient is documented to be active on the lung transplant wait list Exclusion Criteria: - If female, currently pregnant - Abnormal liver function, at screening on recent clinical laboratory testing, defined as >3 × upper limit of normal (ULN), of any 3 or more of the following: AST, ALT, GGT, serum alkaline phosphatase, total bilirubin - Is currently requiring invasive mechanical ventilation - Is currently participating, or has participated in the past 30 days in another therapeutic or clinical study Inclusion Criteria: - Male or female with confirmed diagnosis of CF, with a sweat chloride >60 mmol/L OR 2 CF-causing mutations AND chronic sinopulmonary disease OR gastrointestinal/nutritional abnormalities. --- G551D ---

- Have the G551D-CFTR mutation in at least 1 allele - Will be aged 6 years or older on the date of signed informed consent form - Highest FEV1 in the 6 months prior to screening is ≤ 40% predicted value or patient is documented to be active on the lung transplant wait list Exclusion Criteria: - If female, currently pregnant - Abnormal liver function, at screening on recent clinical laboratory testing, defined as >3 × upper limit of normal (ULN), of any 3 or more of the following: AST, ALT, GGT, serum alkaline phosphatase, total bilirubin - Is currently requiring invasive mechanical ventilation - Is currently participating, or has participated in the past 30 days in another therapeutic or clinical study Cystic Fibrosis Cystic Fibrosis VX-770, a compound being developed by Vertex Pharmaceuticals Incorporated (Vertex) for the treatment of CF, is an orally bioavailable small molecule that targets the underlying defect in CF, the dysfunctional CFTR protein. --- G551D ---

In Phase 3 studies of VX-770 in patients with CF and a G551D CFTR mutation, improvements in CFTR function (measured by reduction in sweat chloride concentration) and improvements in lung function were observed. --- G551D ---


8 G551D Observational Study (GOAL)-Expanded to Additional Genotypes and Extended for Long Term Follow up (GOAL-e2)

The goal of this research study is to collect blood and urine samples from people who have either the R117H type of CF or the non-G551D gating type of CF to be kept for future research.We will also use some of the collected blood to measure the number of neutrophils.

NCT01521338 Cystic Fibrosis
MeSH:Cystic Fibrosis Fibrosis

G551D Observational Study (GOAL)-Expanded to Additional Genotypes and Extended for Long Term Follow up (GOAL-e2). --- G551D ---

G551D Observational Study- Expanded to Additional Genotypes and Extended for Long Therm Follow up (GOAL-e2) The goal of this research study is to collect blood and urine samples from people who have either the R117H type of CF or the non-G551D gating type of CF to be kept for future research.We will also use some of the collected blood to measure the number of neutrophils. --- G551D ---

G551D Observational Study- Expanded to Additional Genotypes and Extended for Long Therm Follow up (GOAL-e2) The goal of this research study is to collect blood and urine samples from people who have either the R117H type of CF or the non-G551D gating type of CF to be kept for future research.We will also use some of the collected blood to measure the number of neutrophils. --- G551D --- --- R117H --- --- G551D ---

For Cohort 1 (Closed to enrollment June 30, 2012): G551D on at least 1 allele Any known or unknown mutations allowed on second allele. --- G551D ---

2. For Cohort 2: R117H on at least 1 allele Any known or unknown mutation on the second allele except G551D 3. --- R117H --- --- G551D ---

For Cohort 3: A Non-G551D gating mutation on one allele: (G178R, S549N, S549R, G551S,G970R, G1244E, S1251N, S1255P, G1349D) Any known or unknown mutation on the second allele except G551D OR R117H 3. Enrolled in the Cystic Fibrosis Foundation Patient Registry (with the exception of Canadian sites). --- G551D ---

For Cohort 3: A Non-G551D gating mutation on one allele: (G178R, S549N, S549R, G551S,G970R, G1244E, S1251N, S1255P, G1349D) Any known or unknown mutation on the second allele except G551D OR R117H 3. Enrolled in the Cystic Fibrosis Foundation Patient Registry (with the exception of Canadian sites). --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G970R --- --- G1244E --- --- S1251N --- --- S1255P --- --- G1349D --- --- G551D ---

Primary Outcomes

Description: Change in FEV1% predicted between Visit 1 and visit 5

Measure: Primary Endpoint for the Core Study

Time: Change in FEV1% predicted between Visit 1 and Visit 5

Secondary Outcomes

Description: Change in sweat chloride between Visit 1 and Visit 5.

Measure: Change in sweat chloride between Visit 1 and Visit 5.

Time: VISIT 1 AND VISIT 5

Description: Change in body weight between Visit 1 and Visit 5.

Measure: Change in body weight between Visit 1 and Visit 5.

Time: VISIT 1 AND VISIT 5

Other Outcomes

Description: The core and sub-studies will be linked so that associations between primary and secondary endpoints from each sub-study and clinical parameters (e.g., spirometry, weight, and sweat chloride) collected as part of the Core Study may be explored.

Measure: ASSOCIATION BETWEEN PRIMARY AND SECONDARY ENDPOINTS

Time: 1 YEAR

9 A Phase 2, Multicenter, Double-Blinded, Placebo Controlled Study to Evaluate Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of VX-661 Monotherapy and VX-661/Ivacaftor Cotherapy in Subjects With Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation

The purpose of this study is to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) effects of VX-661 alone and when coadministered with ivacaftor in participants with cystic fibrosis (CF) who are homozygous or heterozygous for the F508del-CFTR mutation.

NCT01531673 Cystic Fibrosis Drug: VX-661 Drug: Ivacaftor Drug: Placebo matched to VX-661 Drug: Placebo matched to ivacaftor
MeSH:Cystic Fibrosis Fibrosis

Group 7 participants must have the F508del-CFTR mutation on 1 allele, and gating mutation G551D on the second allele and have been on their physician prescribed 150 mg KalydecoTM q12h (commercially available ivacaftor) for at least 28 days at the Screening Visit. --- G551D ---

Primary Outcomes

Description: An AE is defined as any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the Informed Consent Form is signed. AE includes serious as well as non-serious AEs. Serious Adverse Event (SAE) is any AE that results in any of the following: death; life-threatening condition; inpatient hospitalization or prolongation of hospitalization; persistent or significant disability or incapacity; congenital anomaly or birth defect; or other important medical event. Treatment-emergent adverse events are defined as adverse events that were reported or worsened on or after start of study drug through the Follow-up Visit (28 days after last dose of study drug) or premature discontinuation.

Measure: Safety as Determined by Adverse Events (AEs)

Time: Start of study drug through the Follow-up Visit (Up to Day 56)

Description: Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug.

Measure: Change in Sweat Chloride From Baseline Through Study Day 28 for Group 1-5b

Time: Baseline through Day 28

Description: Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.

Measure: Change in Sweat Chloride From Baseline Through Study Day 28 for Group 6

Time: Baseline through Day 28

Description: Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug.

Measure: Change in Sweat Chloride From Baseline Through Study Day 28 for Group 7

Time: Baseline through Day 28

Secondary Outcomes

Description: Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug.

Measure: Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 1-5b

Time: Baseline, Day 7, Day 14, Day 21, Day 28

Description: Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.

Measure: Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 6

Time: Baseline, Day 7, Day 14, Day 21, Day 28

Description: Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug.

Measure: Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 7

Time: Baseline, Day 7, Day 14, Day 21, Day 28

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

Measure: Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 1-5b

Time: Baseline, Day 7, Day 14, Day 21, Day 28

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.

Measure: Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6

Time: Baseline, Day 7, Day 14, Day 21, Day 28

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

Measure: Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7

Time: Baseline, Day 7, Day 14, Day 21, Day 28

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

Measure: Change in FEV1 (Liter [L]) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 1-5b

Time: Baseline, Day 7, Day 14, Day 21, Day 28

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.

Measure: Change in FEV1 (L) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6

Time: Baseline, Day 7, Day 14, Day 21, Day 28

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

Measure: Change in FEV1 (L) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7

Time: Baseline, Day 7, Day 14, Day 21, Day 28

Description: The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.

Measure: Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 1-5b

Time: Baseline, Day 14, Day 28

Description: The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.

Measure: Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6

Time: Baseline, Day 14, Day 28

Description: The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.

Measure: Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7

Time: Baseline, Day 14, Day 28

Description: Participants who received VX-661 monotherapy (Group 1, 2a, 3a and 5a) were analyzed for this outcome measure. PK analysis (AUC0-24h) was not planned for placebo reporting arms.

Measure: Area Under the Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24h) of VX-661 After Administration of VX-661 Monotherapy

Time: Day 28

Description: Participants who received VX-661 in combination with Ivacaftor (Group 2b, 3b, 4, 5b, 6a, 6d and 7) were analyzed for this outcome measure. PK analysis was not planned for placebo reporting arms.

Measure: AUC0-24h of VX-661 and AUC0-12h of Ivacaftor After Administration of VX-661 in Combination With Ivacaftor

Time: Day 28

10 Cystic Fibrosis Related Bone Disease: the Role of CFTR

The purpose of this study is to determine whether ivacaftor, a recently FDA-approved CFTR potentiator, improves bone micro-architecture and strength in patients with cystic fibrosis with at least one G551D CFTR mutation.

NCT01549314 Cystic Fibrosis Related Bone Disease
MeSH:Bone Diseases Cyst Cystic Fibrosis Fibrosis

Cystic Fibrosis Related Bone Disease: the Role of CFTR The purpose of this study is to determine whether ivacaftor, a recently FDA-approved CFTR potentiator, improves bone micro-architecture and strength in patients with cystic fibrosis with at least one G551D CFTR mutation. --- G551D ---

COHORT 1 Inclusion Criteria: - Age 6 to 75 years old - Established diagnosis of CF with at least one abnormal G551D-CFTR allele - Eligibility for and intent to start treatment with ivacaftor or started treatment with ivacaftor within previous 6 months Exclusion Criteria: - Psychiatric or mental incapacity that would preclude subject from assenting to study participation - Current pregnancy - History of organ transplantation - History of Burkholderia dolosa infection COHORT 2: Subjects will be grouped by gender, age and race to match subjects in Cohort 1 within two years. --- G551D ---

- Any medical or psychiatric condition or situation that would compromise subject safety, informed consent/assent, treatment compliance, follow-up measurements, or data quality COHORT 1 Inclusion Criteria: - Age 6 to 75 years old - Established diagnosis of CF with at least one abnormal G551D-CFTR allele - Eligibility for and intent to start treatment with ivacaftor or started treatment with ivacaftor within previous 6 months Exclusion Criteria: - Psychiatric or mental incapacity that would preclude subject from assenting to study participation - Current pregnancy - History of organ transplantation - History of Burkholderia dolosa infection COHORT 2: Subjects will be grouped by gender, age and race to match subjects in Cohort 1 within two years. --- G551D ---

- Any medical or psychiatric condition or situation that would compromise subject safety, informed consent/assent, treatment compliance, follow-up measurements, or data quality Cystic Fibrosis Related Bone Disease Bone Diseases Cyst Cystic Fibrosis Fibrosis Ivacaftor, a CFTR potentiator, has recently been FDA approved for the treatment of cystic fibrosis in patients with at least one G551D CFTR mutation. --- G551D ---

Primary Outcomes

Description: Change in cortical volumetric bone mineral density at the radius

Measure: Bone Microarchitecture and Strength Measures of the Radius and Tibia

Time: Baseline and 24 months

Secondary Outcomes

Description: Change in PA spine bone mineral density

Measure: Areal Bone Mineral Density as Measured by DXA

Time: Baseline and 24 months

Description: Change in osteocalcin

Measure: Bone Turnover Markers

Time: Baseline and 24 months

11 A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Ivacaftor in Subjects With Cystic Fibrosis Who Have the R117H-CFTR Mutation

The purpose of this study is to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis (CF) who have the R117H-CFTR mutation.

NCT01614457 Cystic Fibrosis Drug: Ivacaftor Drug: Placebo
MeSH:Cystic Fibrosis Fibrosis

SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event.. Inclusion Criteria: - Male or female with confirmed diagnosis of CF - Must have at least 1 allele of the R117H CFTR mutation - Percent predicted forced expiratory volume in 1 second (FEV1) 40 percent (%) to 90% (for subjects aged 12 years or older) or 40% to 105% (for subjects aged 6 to 11 years) predicted normal for age, sex, and height - 6 years of age or older - Minimum weight of 15 kilogram (kg) at screening - Females of childbearing potential must not be pregnant - Willing to comply with contraception requirements Exclusion Criteria: - CFTR gene mutation leading to CFTR channel with gating defect (that is, any 1 of the following mutations: G551D, G178R, G551S, S549N, S549R, G970R, G1244E, S1251N, S1255P, or G1349D) - History of any illness or condition that might confound the results of the study or pose an additional risk in administering ivacaftor to the subject - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before the first dose of study drug - Abnormal liver function, at screening, defined as greater than or equal to (>=) 3 time upper limit of normal (ULN), of any 3 or more of the following: serum aspartate transaminase (AST), serum alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), serum alkaline phosphatase (ALP), total bilirubin - Colonization with organisms associated with a more rapid decline in pulmonary status (for example, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus) at screening - History of solid organ or hematological transplantation - History of alcohol, medication or illicit drug abuse within 1 year before the first dose of study drug - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days before screening - Any "non-CF-related" illness within 2 weeks before Day 1 (first dose of study drug). --- R117H --- --- G551D ---

"Illness" was defined as an acute (serious or non-serious) condition (for example, gastroenteritis) - Use of any inhibitors or inducers of cytochrome (CYP) P450 3A Inclusion Criteria: - Male or female with confirmed diagnosis of CF - Must have at least 1 allele of the R117H CFTR mutation - Percent predicted forced expiratory volume in 1 second (FEV1) 40 percent (%) to 90% (for subjects aged 12 years or older) or 40% to 105% (for subjects aged 6 to 11 years) predicted normal for age, sex, and height - 6 years of age or older - Minimum weight of 15 kilogram (kg) at screening - Females of childbearing potential must not be pregnant - Willing to comply with contraception requirements Exclusion Criteria: - CFTR gene mutation leading to CFTR channel with gating defect (that is, any 1 of the following mutations: G551D, G178R, G551S, S549N, S549R, G970R, G1244E, S1251N, S1255P, or G1349D) - History of any illness or condition that might confound the results of the study or pose an additional risk in administering ivacaftor to the subject - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before the first dose of study drug - Abnormal liver function, at screening, defined as greater than or equal to (>=) 3 time upper limit of normal (ULN), of any 3 or more of the following: serum aspartate transaminase (AST), serum alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), serum alkaline phosphatase (ALP), total bilirubin - Colonization with organisms associated with a more rapid decline in pulmonary status (for example, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus) at screening - History of solid organ or hematological transplantation - History of alcohol, medication or illicit drug abuse within 1 year before the first dose of study drug - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days before screening - Any "non-CF-related" illness within 2 weeks before Day 1 (first dose of study drug). --- R117H --- --- G551D ---

"Illness" was defined as an acute (serious or non-serious) condition (for example, gastroenteritis) - Use of any inhibitors or inducers of cytochrome (CYP) P450 3A Cystic Fibrosis Cystic Fibrosis Fibrosis Ivacaftor is the first CFTR modulator to show an improvement in CFTR function and clinical benefit in subjects with CF. Results from Phase 3 studies (VX08-770-102 [Study 102] [NCT00909532] and VX08-770-103 [Study 103] [NCT00909727]) showed that ivacaftor is effective in the treatment of subjects with CF who have the G551D-CFTR mutation, as evidenced by sustained improvements in CFTR channel function (measured by reduction in sweat chloride concentration) and corresponding substantial, durable improvements in lung function, pulmonary exacerbations, respiratory symptoms, and weight gain. --- G551D ---

Ivacaftor (Trade Name Kalydeco; 150 mg tablets) was initially approved in the United States for the treatment of CF in subjects 6 years of age and older who have a G551D mutation in the CFTR gene. --- G551D ---

Primary Outcomes

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male subjects 18 years and older and female subjects 16 years and older. The Wang standard was used for male subjects aged 6 to 17 years and for female subjects aged 6 to 15 years.

Measure: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24

Time: Baseline, Week 24

Secondary Outcomes

Description: BMI was defined as weight in kilogram (kg) divided by height in square meter (m^2).

Measure: Change From Baseline in Body Mass Index (BMI) at Week 24

Time: Baseline, Week 24

Description: Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride.

Measure: Change From Baseline in Sweat Chloride Through Week 24

Time: Baseline, Week 24

Description: The CFQ-R is a validated subject-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life

Measure: Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 24

Time: Baseline, Week 24

Description: Number of events (pulmonary exacerbation) during the pre-specified time intervals were reported. A subject without an exacerbation before withdrawal from the study was considered censored at the time of withdrawal, and a subject without an exacerbation who completes the study period was considered censored at the end of the analysis period.

Measure: Time to First Pulmonary Exacerbation

Time: Day 0 to 15, Day 16 to 56, Day 57 to 112, Day 113 to 168

Description: AE: any untoward medical occurrence, including clinically significant clinical laboratory assessments which occurs during course of study, whether it is considered related to study drug or not. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event.

Measure: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time: Baseline up to follow-up (3 to 4 weeks after last dose [last dose = Week 24])

12 A Phase 3, Two-Part, Randomized, Double-Blind, Placebo-Controlled, Crossover Study With an Open-Label Period to Evaluate the Efficacy and Safety of Ivacaftor in Subjects With Cystic Fibrosis Who Have a Non-G551D CFTR Gating Mutation

The purpose of this study is to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis (CF) who have a non-G551D cystic fibrosis transmembrane regulator (CFTR) gating mutation (any one of the following CFTR mutations: G178R, G551S, S549N, S549R, G970R, G1244E, S1251N, S1255P, or G1349D).

NCT01614470 Cystic Fibrosis Drug: Ivacaftor Drug: Placebo
MeSH:Cystic Fibrosis Fibrosis

A Phase 3, Two-Part, Randomized, Double-Blind, Placebo-Controlled, Crossover Study With an Open-Label Period to Evaluate the Efficacy and Safety of Ivacaftor in Subjects With Cystic Fibrosis Who Have a Non-G551D CFTR Gating Mutation. --- G551D ---

Study of Ivacaftor in Subjects With Cystic Fibrosis (CF) Who Have a Non-G551D CF Transmembrane Conductance Regulator (CFTR) Gating Mutation The purpose of this study is to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis (CF) who have a non-G551D cystic fibrosis transmembrane regulator (CFTR) gating mutation (any one of the following CFTR mutations: G178R, G551S, S549N, S549R, G970R, G1244E, S1251N, S1255P, or G1349D). --- G551D ---

Study of Ivacaftor in Subjects With Cystic Fibrosis (CF) Who Have a Non-G551D CF Transmembrane Conductance Regulator (CFTR) Gating Mutation The purpose of this study is to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis (CF) who have a non-G551D cystic fibrosis transmembrane regulator (CFTR) gating mutation (any one of the following CFTR mutations: G178R, G551S, S549N, S549R, G970R, G1244E, S1251N, S1255P, or G1349D). --- G551D --- --- G551D ---

SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event.. Inclusion Criteria: - Male or female with confirmed diagnosis of CF - At least 1 allele of the following CFTR gating mutations: G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, G1349D - Percent predicted forced expiratory volume in 1 second (FEV1) greater than or equal to (>=) 40 percent (%) predicted normal for age, sex, and height - 6 years of age or older - Minimum weight of 15 kilogram (kg) at screening - Females of childbearing potential must not be pregnant - Willing to comply with contraception requirements Exclusion Criteria: - G551D-CFTR mutation on at least 1 allele - History of any illness or condition that might confound the results of the study or pose an additional risk in administering ivacaftor to the subject - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before the first dose of study drug - History of solid organ or hematological transplantation - History of alcohol, medication or illicit drug abuse within 1 year before the first dose of study drug - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days before screening - Use of inhaled hypertonic saline treatment - Use of any inhibitors or inducers of cytochrome (CYP) P450 3A - Evidence of cataract or lens opacity at screening Inclusion Criteria: - Male or female with confirmed diagnosis of CF - At least 1 allele of the following CFTR gating mutations: G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, G1349D - Percent predicted forced expiratory volume in 1 second (FEV1) greater than or equal to (>=) 40 percent (%) predicted normal for age, sex, and height - 6 years of age or older - Minimum weight of 15 kilogram (kg) at screening - Females of childbearing potential must not be pregnant - Willing to comply with contraception requirements Exclusion Criteria: - G551D-CFTR mutation on at least 1 allele - History of any illness or condition that might confound the results of the study or pose an additional risk in administering ivacaftor to the subject - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before the first dose of study drug - History of solid organ or hematological transplantation - History of alcohol, medication or illicit drug abuse within 1 year before the first dose of study drug - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days before screening - Use of inhaled hypertonic saline treatment - Use of any inhibitors or inducers of cytochrome (CYP) P450 3A - Evidence of cataract or lens opacity at screening Cystic Fibrosis Cystic Fibrosis Fibrosis Ivacaftor is the first CFTR modulator to show an improvement in CFTR function and clinical benefit in subjects with CF. Results from Phase 3 studies (VX08-770-102 [Study 102] [NCT00909532] and VX08-770-103 [Study 103] [NCT00909727]) showed that ivacaftor is effective in the treatment of subjects with CF who have the G551D-CFTR mutation, as evidenced by sustained improvements in CFTR channel function (measured by reduction in sweat chloride concentration) and corresponding substantial, durable improvements in lung function, pulmonary exacerbations, respiratory symptoms, and weight gain. --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G970R --- --- G1244E --- --- S1251N --- --- S1255P --- --- G1349D --- --- G551D ---

SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event.. Inclusion Criteria: - Male or female with confirmed diagnosis of CF - At least 1 allele of the following CFTR gating mutations: G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, G1349D - Percent predicted forced expiratory volume in 1 second (FEV1) greater than or equal to (>=) 40 percent (%) predicted normal for age, sex, and height - 6 years of age or older - Minimum weight of 15 kilogram (kg) at screening - Females of childbearing potential must not be pregnant - Willing to comply with contraception requirements Exclusion Criteria: - G551D-CFTR mutation on at least 1 allele - History of any illness or condition that might confound the results of the study or pose an additional risk in administering ivacaftor to the subject - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before the first dose of study drug - History of solid organ or hematological transplantation - History of alcohol, medication or illicit drug abuse within 1 year before the first dose of study drug - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days before screening - Use of inhaled hypertonic saline treatment - Use of any inhibitors or inducers of cytochrome (CYP) P450 3A - Evidence of cataract or lens opacity at screening Inclusion Criteria: - Male or female with confirmed diagnosis of CF - At least 1 allele of the following CFTR gating mutations: G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, G1349D - Percent predicted forced expiratory volume in 1 second (FEV1) greater than or equal to (>=) 40 percent (%) predicted normal for age, sex, and height - 6 years of age or older - Minimum weight of 15 kilogram (kg) at screening - Females of childbearing potential must not be pregnant - Willing to comply with contraception requirements Exclusion Criteria: - G551D-CFTR mutation on at least 1 allele - History of any illness or condition that might confound the results of the study or pose an additional risk in administering ivacaftor to the subject - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before the first dose of study drug - History of solid organ or hematological transplantation - History of alcohol, medication or illicit drug abuse within 1 year before the first dose of study drug - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days before screening - Use of inhaled hypertonic saline treatment - Use of any inhibitors or inducers of cytochrome (CYP) P450 3A - Evidence of cataract or lens opacity at screening Cystic Fibrosis Cystic Fibrosis Fibrosis Ivacaftor is the first CFTR modulator to show an improvement in CFTR function and clinical benefit in subjects with CF. Results from Phase 3 studies (VX08-770-102 [Study 102] [NCT00909532] and VX08-770-103 [Study 103] [NCT00909727]) showed that ivacaftor is effective in the treatment of subjects with CF who have the G551D-CFTR mutation, as evidenced by sustained improvements in CFTR channel function (measured by reduction in sweat chloride concentration) and corresponding substantial, durable improvements in lung function, pulmonary exacerbations, respiratory symptoms, and weight gain. --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G970R --- --- G1244E --- --- S1251N --- --- S1255P --- --- G1349D --- --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G970R --- --- G1244E --- --- S1251N --- --- S1255P --- --- G1349D --- --- G551D ---

SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event.. Inclusion Criteria: - Male or female with confirmed diagnosis of CF - At least 1 allele of the following CFTR gating mutations: G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, G1349D - Percent predicted forced expiratory volume in 1 second (FEV1) greater than or equal to (>=) 40 percent (%) predicted normal for age, sex, and height - 6 years of age or older - Minimum weight of 15 kilogram (kg) at screening - Females of childbearing potential must not be pregnant - Willing to comply with contraception requirements Exclusion Criteria: - G551D-CFTR mutation on at least 1 allele - History of any illness or condition that might confound the results of the study or pose an additional risk in administering ivacaftor to the subject - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before the first dose of study drug - History of solid organ or hematological transplantation - History of alcohol, medication or illicit drug abuse within 1 year before the first dose of study drug - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days before screening - Use of inhaled hypertonic saline treatment - Use of any inhibitors or inducers of cytochrome (CYP) P450 3A - Evidence of cataract or lens opacity at screening Inclusion Criteria: - Male or female with confirmed diagnosis of CF - At least 1 allele of the following CFTR gating mutations: G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, G1349D - Percent predicted forced expiratory volume in 1 second (FEV1) greater than or equal to (>=) 40 percent (%) predicted normal for age, sex, and height - 6 years of age or older - Minimum weight of 15 kilogram (kg) at screening - Females of childbearing potential must not be pregnant - Willing to comply with contraception requirements Exclusion Criteria: - G551D-CFTR mutation on at least 1 allele - History of any illness or condition that might confound the results of the study or pose an additional risk in administering ivacaftor to the subject - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before the first dose of study drug - History of solid organ or hematological transplantation - History of alcohol, medication or illicit drug abuse within 1 year before the first dose of study drug - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days before screening - Use of inhaled hypertonic saline treatment - Use of any inhibitors or inducers of cytochrome (CYP) P450 3A - Evidence of cataract or lens opacity at screening Cystic Fibrosis Cystic Fibrosis Fibrosis Ivacaftor is the first CFTR modulator to show an improvement in CFTR function and clinical benefit in subjects with CF. Results from Phase 3 studies (VX08-770-102 [Study 102] [NCT00909532] and VX08-770-103 [Study 103] [NCT00909727]) showed that ivacaftor is effective in the treatment of subjects with CF who have the G551D-CFTR mutation, as evidenced by sustained improvements in CFTR channel function (measured by reduction in sweat chloride concentration) and corresponding substantial, durable improvements in lung function, pulmonary exacerbations, respiratory symptoms, and weight gain. --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G970R --- --- G1244E --- --- S1251N --- --- S1255P --- --- G1349D --- --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G970R --- --- G1244E --- --- S1251N --- --- S1255P --- --- G1349D --- --- G551D --- --- G551D ---

Ivacaftor (Trade Name Kalydeco; 150 mg tablets) was initially approved in the United States for the treatment of CF in subjects 6 years of age and older who have a G551D mutation in the CFTR gene. --- G551D ---

Primary Outcomes

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male subjects 18 years and older and female subjects 16 years and older. The Wang standard was used for male subjects aged 6 to 17 years and for female subjects aged 6 to 15 years. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during study Part 1.

Measure: Part 1: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8

Time: Part 1: Baseline (pre-dose Day 1), Week 8

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male subjects 18 years and older and female subjects 16 years and older. The Wang standard was used for male subjects aged 6 to 17 years and for female subjects aged 6 to 15 years. Absolute change in percent predicted FEV1 over 24 weeks of ivacaftor treatment (from Week 12 [Part 1: Treatment Period 2] through Week 36 [Part 2]) was reported for subjects who received ivacaftor in Part 1: Treatment Period 2, as per planned analysis. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during Part 1: Treatment Period 2.

Measure: Part 2: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through 24 Weeks of Treatment (Week 36 Visit)

Time: Baseline (pre-dose Week 12), Week 36

Secondary Outcomes

Description: BMI was defined as weight in kilogram (kg) divided by height in meters^2 (m^2). Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during study Part 1.

Measure: Part 1: Change From Baseline in Body Mass Index (BMI) at Week 8

Time: Part 1: Baseline (pre-dose Day 1), Week 8

Description: BMI was defined as weight in kg divided by height in m^2. Change in BMI over 24 weeks of ivacaftor treatment (from Week 12 [Part 1: Treatment Period 2] through Week 36 [Part 2]) was reported for subjects who received ivacaftor in Part 1: Treatment Period 2 as per planned analysis. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during Part 1: Treatment Period 2.

Measure: Part 2: Change From Baseline in Body Mass Index (BMI) at 24 Weeks of Treatment (Week 36 Visit)

Time: Baseline (pre-dose Week 12), Week 36

Description: Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during study Part 1.

Measure: Part 1: Change From Baseline in Sweat Chloride Through Week 8

Time: Part 1: Baseline (pre-dose Day 1), Week 8

Description: Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride. Change in sweat chloride over 24 weeks of ivacaftor treatment (from Week 12 [Part 1: Treatment Period 2] through Week 36 [Part 2]) was reported for subjects who received ivacaftor in Part 1: Treatment Period 2 as per planned analysis. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during Part 1: Treatment Period 2.

Measure: Part 2: Change From Baseline in Sweat Chloride Through 24 Weeks of Treatment (Week 36 Visit)

Time: Baseline (pre-dose Week 12), Week 36

Description: The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during study Part 1.

Measure: Part 1: Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 8

Time: Part 1: Baseline (pre-dose Day 1), Week 8

Description: The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Change in CFQ-R respiratory domain score over 24 weeks of ivacaftor treatment (from Week 12 [Part 1: Treatment Period 2] through Week 36 [Part 2]) was reported for subjects who received ivacaftor in Part 1: Treatment Period 2 as per planned analysis. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during Part 1: Treatment Period 2.

Measure: Part 2: Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through 24 Weeks of Treatment (Week 36 Visit)

Time: Baseline (pre-dose Week 12), Week 36

Description: AE: any adverse change from subject's baseline (pre-treatment) condition, including any adverse experience, abnormal recording/clinical laboratory assessment which occurs during course of study, whether it is considered related to study drug or not. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event.

Measure: Part 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time: Part 1: From signing of informed consent up to Week 20

Description: AE: any adverse change from subject's baseline (pre-treatment) condition, including any adverse experience, abnormal recording/clinical laboratory assessment which occurs during course of study, whether it is considered related to study drug or not. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event.

Measure: Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time: Part 2: Week 20 up to Week 40

13 A Pilot Study Testing the Effect of Ivacaftor on Lung Function in Subjects With Cystic Fibrosis, Residual CFTR Function, and FEV1 ≥40% Predicted

This study is a multiple within participant crossover study to evaluate the effect of ivacaftor on lung function in participants aged 12 years and older with cystic fibrosis (CF) who have phenotypic or molecular evidence of residual CF transmembrane conductance regulator (CFTR) function.

NCT01685801 Cystic Fibrosis Drug: Ivacaftor Drug: Placebo-matched-to-ivacaftor tablet
MeSH:Cystic Fibrosis Fibrosis

Data was to be reported by drug treatment for double-blind crossover period (Cycle 1 up to Washout Period 2) and open-label period.. Inclusion Criteria: - Male or female participants with confirmed diagnosis of CF - Clinical evidence of residual CFTR function based on any 1 of the following: 1) Clinically documented residual exocrine pancreatic function, 2) Sweat chloride value less than equal to (<=) 80 millimole per liter (mmol/L) at screening, or 3) Age of diagnosis greater than equal to (>=) 12 years and at least 1 copy of a CFTR mutation associated with residual CFTR function or defective mRNA splicing - FEV1 >= 40 percent (%) - 12 years of age or older - Willing to agree to meet the contraception requirements - Able to swallow tablets Exclusion Criteria: - A copy of any of the following CFTR mutations: G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, or G1349D - Unable to perform spirometry - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before Day 1 - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening Inclusion Criteria: - Male or female participants with confirmed diagnosis of CF - Clinical evidence of residual CFTR function based on any 1 of the following: 1) Clinically documented residual exocrine pancreatic function, 2) Sweat chloride value less than equal to (<=) 80 millimole per liter (mmol/L) at screening, or 3) Age of diagnosis greater than equal to (>=) 12 years and at least 1 copy of a CFTR mutation associated with residual CFTR function or defective mRNA splicing - FEV1 >= 40 percent (%) - 12 years of age or older - Willing to agree to meet the contraception requirements - Able to swallow tablets Exclusion Criteria: - A copy of any of the following CFTR mutations: G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, or G1349D - Unable to perform spirometry - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before Day 1 - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening Cystic Fibrosis Cystic Fibrosis Fibrosis CFTR Mutations associated with residual function or defective messenger ribonucleic acid (mRNA) splicing include the following: R117H, E56K, P67L, D110E, D110H, R117C, R347H, R352Q, A455E, D579G, S945L, L206W, R1070W, F1074L, D1152H, S1235R, D1270N, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, --- G551D ---

Data was to be reported by drug treatment for double-blind crossover period (Cycle 1 up to Washout Period 2) and open-label period.. Inclusion Criteria: - Male or female participants with confirmed diagnosis of CF - Clinical evidence of residual CFTR function based on any 1 of the following: 1) Clinically documented residual exocrine pancreatic function, 2) Sweat chloride value less than equal to (<=) 80 millimole per liter (mmol/L) at screening, or 3) Age of diagnosis greater than equal to (>=) 12 years and at least 1 copy of a CFTR mutation associated with residual CFTR function or defective mRNA splicing - FEV1 >= 40 percent (%) - 12 years of age or older - Willing to agree to meet the contraception requirements - Able to swallow tablets Exclusion Criteria: - A copy of any of the following CFTR mutations: G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, or G1349D - Unable to perform spirometry - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before Day 1 - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening Inclusion Criteria: - Male or female participants with confirmed diagnosis of CF - Clinical evidence of residual CFTR function based on any 1 of the following: 1) Clinically documented residual exocrine pancreatic function, 2) Sweat chloride value less than equal to (<=) 80 millimole per liter (mmol/L) at screening, or 3) Age of diagnosis greater than equal to (>=) 12 years and at least 1 copy of a CFTR mutation associated with residual CFTR function or defective mRNA splicing - FEV1 >= 40 percent (%) - 12 years of age or older - Willing to agree to meet the contraception requirements - Able to swallow tablets Exclusion Criteria: - A copy of any of the following CFTR mutations: G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, or G1349D - Unable to perform spirometry - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before Day 1 - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening Cystic Fibrosis Cystic Fibrosis Fibrosis CFTR Mutations associated with residual function or defective messenger ribonucleic acid (mRNA) splicing include the following: R117H, E56K, P67L, D110E, D110H, R117C, R347H, R352Q, A455E, D579G, S945L, L206W, R1070W, F1074L, D1152H, S1235R, D1270N, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G970R --- --- G1244E --- --- S1251N --- --- S1255P --- --- G1349D --- --- G551D ---

Primary Outcomes

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Data was to be reported for each cycle (Cycle 1 and Cycle 2) and as per drug treatment, for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).

Measure: Cycle 1 and Cycle 2: Absolute Change From Cycle Baseline In Percent Predicted Forced Expiratory Volume In 1 Second (FEV1) After 2 Weeks of Treatment

Time: Cycle 1 baseline, Cycle 1 Day 15 (for Cycle 1 reporting arms); Cycle 2 baseline, Cycle 2 Day 15 (for Cycle 2 reporting arms)

Secondary Outcomes

Description: LCI is a measure of ventilation inhomogeneity that is derived from a multiple-breath washout test. The LCI was calculated as the number of lung volume turnovers (cumulative expired volume divided by the functional residual capacity [FRC]) required to reduce end-tidal concentration of an inert gas to 1/40th of the starting value. Data was to be reported for each cycle (Cycle 1 and Cycle 2) and as per drug treatment. Data was to be reported for each cycle (Cycle 1 and Cycle 2) and as per drug treatment, for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).

Measure: Cycle 1 and Cycle 2: Absolute Change From Cycle Baseline In Lung Clearance Index (LCI) After 2 Weeks of Treatment

Time: Cycle 1 baseline, Cycle 1 Day 15 (for Cycle 1 reporting arms); Cycle 2 baseline, Cycle 2 Day 15 (for Cycle 2 reporting arms)

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Data was to be reported for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).

Measure: Open-label Period: Absolute Change From Open-label Baseline In Percent Predicted Forced Expiratory Volume In 1 Second (FEV1) at Day 57

Time: Open-label Baseline, Open-label Day 57

Description: LCI is a measure of ventilation inhomogeneity that is derived from a multiple-breath washout test. The LCI was calculated as the number of lung volume turnovers (cumulative expired volume divided by the functional residual capacity [FRC]) required to reduce end-tidal concentration of an inert gas to 1/40th of the starting value. Data was to be reported for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).

Measure: Open-label Period: Absolute Change From Open-label Baseline In Lung Clearance Index (LCI) at Day 57

Time: Open-label Baseline, Open-label Day 57

Description: Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride. Data was to be reported for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).

Measure: Open-label Period: Absolute Change From Study Baseline In Sweat Chloride at Day 57

Time: Study Baseline, Open-label Day 57

Description: Data was to be reported for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).

Measure: Open-label Period: Absolute Change From Open-label Baseline In Weight at Day 57

Time: Open-label Baseline, Open-label Day 57

Description: Adverse events (AEs) that started (or increased in severity) from first dose of study drug through completion of Follow-up were considered TEAEs, with exception that if an AE started during a Washout Period and was beyond 14 days from last dose date of preceding cycle, AE was considered as a "Washout Period" AE, and hence not TEAE. A TEAE was attributed to treatment in which it started or to the treatment in second cycling period of previous Crossover Period if it started during a Washout Period. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Data was to be reported by drug treatment for double-blind crossover period (Cycle 1 up to Washout Period 2) and open-label period.

Measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Time: From first dose of study drug through completion of follow-up visit (up to 26 weeks)

14 A Phase 3, Two-Arm, Rollover Study to Evaluate the Safety of Long Term Ivacaftor Treatment in Subjects 6 Years of Age and Older With Cystic Fibrosis and a Non-G551D CFTR Mutation

The purpose of this study is to evaluate the safety of long-term ivacaftor treatment in participants with cystic fibrosis (CF) from Studies 110 (NCT01614457), 111 (NCT01614470), and 113 (NCT01685801).

NCT01707290 Cystic Fibrosis Drug: Ivacaftor
MeSH:Cystic Fibrosis Fibrosis

A Phase 3, Two-Arm, Rollover Study to Evaluate the Safety of Long Term Ivacaftor Treatment in Subjects 6 Years of Age and Older With Cystic Fibrosis and a Non-G551D CFTR Mutation. --- G551D ---

Rollover Study of Ivacaftor in Subjects With Cystic Fibrosis and a Non G551D CFTR Mutation The purpose of this study is to evaluate the safety of long-term ivacaftor treatment in participants with cystic fibrosis (CF) from Studies 110 (NCT01614457), 111 (NCT01614470), and 113 (NCT01685801). --- G551D ---

Cystic Fibrosis Cystic Fibrosis Fibrosis Ivacaftor is the first Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator to show an improvement in CFTR function and clinical benefit in participants with CF. Results from Phase 3 studies (NCT00909532 [Study 102] and NCT00909727 [Study 103]) showed that ivacaftor is effective in the treatment of participants with CF who have the G551D-CFTR mutation, as evidenced by sustained improvements in CFTR channel function (measured by reduction in sweat chloride concentration) and corresponding substantial, durable improvements in lung function, pulmonary exacerbations, respiratory symptoms, and weight gain. --- G551D ---

Ivacaftor (Trade Name Kalydeco; 150 mg tablets) was initially approved in the United States for the treatment of CF in participants 6 years of age and older who have a G551D mutation in the CFTR gene. --- G551D ---

Primary Outcomes

Description: AE: any untoward medical occurrence in a participants during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, In-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. TEAEs were defined as adverse events with start date or increased severity on and after the first dose of study drug through Week 108.

Measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs) in Ivacaftor Arm

Time: Day 1 up to Week 108 (Study 112)

Secondary Outcomes

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 6 to 17 years and for female participants aged 6 to 15 years. Baseline was defined as the most recent measurement before intake of the first dose of study drug (Ivacaftor) in Study 112. Results were planned to be reported for Ivacaftor arm and were stratified by parent study 110, 111 and 113.

Measure: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 2, 12, 24, 36, 48, 60, 72, 84, 96, and 104

Time: Baseline, Week 2, 12, 24, 36, 48, 60, 72, 84, 96 and 104 (Study 112)

Description: BMI was defined as weight in kg divided by height in m^2. Baseline was defined as the most recent measurement before intake of the first dose of study drug (Ivacaftor) in Study 112. Results were planned to be reported for Ivacaftor arm and were stratified by parent study 110, 111 and 113.

Measure: Absolute Change From Baseline in Body Mass Index (BMI) at Week 2,12, 24, 36, 48, 60, 72, 84, 96 and 104

Time: Baseline, Week 2, 12, 24, 36, 48, 60, 72, 84, 96 and 104 (Study 112)

Description: Sweat samples were collected using an approved collection device. Baseline was defined as the most recent measurement before intake of the first dose of study drug (Ivacaftor) in Study 112. Results were planned to be reported for Ivacaftor arm and were stratified by parent study 110, 111 and 113.

Measure: Absolute Change From Baseline in Sweat Chloride at Week 2, 24, 48 and 104

Time: Baseline, Week 2, 24, 48 and 104 (Study 112)

Description: The CFQ-R is a validated participant reported outcome measuring health related quality of life for participants with CF. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health related quality of life. Baseline was defined as the most recent measurement before intake of the first dose of study drug (ivacaftor) in Study 112. Results were planned to be reported for Ivacaftor arm and were stratified by parent study 110, 111 and 113.

Measure: Absolute Change From Baseline in Respiratory Domain of the Cystic Fibrosis Questionnaire Revised (CFQ-R) at Week 2, 12, 24, 36, 48, 60, 72, 84, 96 and 104

Time: Baseline, Week 2, 12, 24, 36, 48, 60, 72, 84, 96 and 104 (Study 112)

Description: Pulmonary exacerbation events include those events which require treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. The number of events were reported. Results were planned to be reported for Ivacaftor arm and were stratified by parent study 110, 111 and 113.

Measure: Number of Pulmonary Exacerbations Events

Time: Through Week 104 (Study 112)

Description: SAE was defined as a medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, In-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event.

Measure: Number of Participants With Serious Adverse Events (SAEs) in Observational Arm

Time: up to 2 years (Study 112)

15 Effects of a Partially Supervised Conditioning Program in CF: an International Multi-centre, Randomized Controlled Trial

Physical activity and exercise have become an accepted and valued component of Cystic Fibrosis care. Regular physical activity and exercise can slow the rate of decline of pulmonary function, improve physical fitness, and enhance quality of life. However, motivating people to be more active is challenging. Supervised exercise programs are expensive and labor intensive, and adherence falls off significantly once supervision ends. Unsupervised or partially supervised programs are less costly and more flexible, but compliance can be more problematic. The primary objective of this study is to evaluate the effects of a 12-months partially supervised exercise intervention along with regular motivation on forced expiratory volume in 1 second (FEV1) in a large international group of cystic fibrosis patients. Secondary endpoints include patient reported quality of life, as well as levels of anxiety and depression, and control of blood sugar. A total of 292 patients with cystic fibrosis 12 years and older with a FEV1 ≥35% predicted will be recruited. Following baseline assessments (2 visits) patients will be randomized into an intervention and a control group. Thereafter, they will be seen every 3 months for assessments in their centre for one year (4 follow-up visits). Along with individual counseling to increase vigorous physical activity by at least 3 hours per week on each clinic visit, the intervention group will document daily exercise and inactivity time and will receive a step counter and they will record their progress with a web-based program. They will also receive monthly phone calls from the study staff. After 6 months, they will continue with the step counter and web-based program for a further 6 months. The control group will receive access to this intervention after 12 months of standardized care. Should this relatively simple program prove successful, this will be made available on a wider scale internationally.

NCT01744561 Cystic Fibrosis Behavioral: Exercise Intervention
MeSH:Cystic Fibrosis

- Unstable condition precluding exercise (major hemoptysis or pneumothorax within the last 3 months, acute exacerbation and iv-antibiotics during the last 4 weeks, planned surgery, listed for lung transplantation, major musculoskeletal injuries such as fractures or sprains during the last 2 months, others according to the impression of the doctor) - Cardiac arrhythmias with exercise - Requiring additional oxygen with exercise - Recent diagnosis of diabetes 3 months prior to screening or at screening - Recent changes in medication 1 month or less prior to screening (systemic steroids, ibuprofen, inhaled antibiotics, mannitol, DNAse, hypertonic saline) - At least one G551D mutation and not on ivacaftor (VX770) yet but planned start or planned stop of ivacaftor during the trial - Colonization with Burkholderia cenocepacia Inclusion Criteria: - Confirmed diagnosis of Cystic Fibrosis - Age ≥12 years - Forced expiratory volume in 1 second (FEV1) ≥ 35% predicted - Access to the internet Exclusion Criteria: - Participation in another clinical trial up to 4 weeks prior to the first baseline visit - Pregnancy/Breastfeeding - Inability to exercise - More than 4 hours of reported strenuous physical activities per week currently or up to 3 months prior to baseline measurements and not already planned within the coming 6 months. --- G551D ---

- Unstable condition precluding exercise (major hemoptysis or pneumothorax within the last 3 months, acute exacerbation and iv-antibiotics during the last 4 weeks, planned surgery, listed for lung transplantation, major musculoskeletal injuries such as fractures or sprains during the last 2 months, others according to the impression of the doctor) - Cardiac arrhythmias with exercise - Requiring additional oxygen with exercise - Recent diagnosis of diabetes 3 months prior to screening or at screening - Recent changes in medication 1 month or less prior to screening (systemic steroids, ibuprofen, inhaled antibiotics, mannitol, DNAse, hypertonic saline) - At least one G551D mutation and not on ivacaftor (VX770) yet but planned start or planned stop of ivacaftor during the trial - Colonization with Burkholderia cenocepacia Cystic Fibrosis Cystic Fibrosis null --- G551D ---

Primary Outcomes

Measure: Change in forced expiratory volume in 1 second (FEV1; in % predicted using the average of two baseline measurements) from baseline to 6 months in the intervention group compared to controls.

Time: baseline and 6 months

Secondary Outcomes

Measure: Change in peak oxygen uptake (%predicted)

Time: baseline to 6 months and baseline to 12 months

Measure: Change in maximal aerobic power (%predicted)

Time: baseline to 6 months and baseline to 12 months

Measure: Change in measured steps per day

Time: baseline to 6 months and baseline to 12 months

Measure: Change in exercise steps per day

Time: baseline to 6 months and baseline to 12 months

Measure: Change in reported physical activity

Time: baseline to 6 months and baseline to 12 months

Measure: Change in forced expiratory volume in 1 second (FEV1; %predicted)

Time: baseline to 6 months and baseline to 12 months

Measure: Change in forced vital capacity (FVC; % predicted)

Time: baseline to 6 months and baseline to 12 months

Measure: Change in residual volume in percent of total lung capacity (RV/TLC; %)

Time: baseline to 6 months and baseline to 12 months

Measure: Time to first exacerbation

Time: baseline to 6 months and baseline to 12 months

Description: from diary

Measure: Number of upper respiratory tract infections

Time: baseline to 6 months and baseline to 12 months

Description: from questionnaire

Measure: Days on additional oral / intravenous antibiotics

Time: baseline to 6 months and baseline to 12 months

Measure: Change in body mass index (kg/m2)

Time: baseline to 6 months and baseline to 12 months

Description: estimated from skinfold thickness

Measure: Change in muscle mass (kg)

Time: baseline to 6 months and baseline to 12 months

Description: estimated from skinfold thickness

Measure: Change in percent body fat

Time: baseline to 6 months and baseline to 12 months

Description: from the revised Cystic Fibrosis health-related quality of life Questionnaire (CFQ-R questionnaire)

Measure: Change in Quality of Life scales

Time: baseline to 6 months and baseline to 12 months

Description: from Depression Anxiety Stress Scales

Measure: Change in depression, anxiety and stress scores

Time: baseline to 6 months and baseline to 12 months

Description: standardized oral glucose tolerance test only patients without diabetes mellitus

Measure: Change in plasma glucose concentrations 1 and 2 hours after a standardized glucose load

Time: baseline to 9 months

Description: causality as judged by investigator

Measure: Adverse events possibly or likely related to exercise

Time: baseline to 6 months and baseline to 12 months

Measure: Severe adverse events

Time: baseline to 6 months and baseline to 12 months

Measure: Serious adverse events

Time: baseline to 6 months and baseline to 12 months

Other Outcomes

Description: based on questionnaire and diary

Measure: Compliance with the exercise goal

Time: baseline to 6 months and baseline to 12 months

Description: based on nitrogen multiple breath washout, in selected centres only

Measure: Change in lung clearance index

Time: baseline to 6 months and baseline to 12 months

Description: based on accelerometry, in selected centres only

Measure: Change in time spent in moderate-and-vigorous physical activity

Time: baseline to 6 months and baseline to 12 months

Description: based on dual energy x-ray absorptiometry, in selected centres only

Measure: Change in bone mineral density and body composition

Time: baseline to 6 months and baseline to 12 months

Description: based on nuclear medicine scans, US centres only

Measure: Change in mucociliary clearance with exercise

Time: baseline to 6 months

16 Short Term Effects of Ivacaftor in Non-G551D Cystic Fibrosis Patients

This is a study of the short-term effects of ivacaftor on sweat chloride concentration and lung function in cystic fibrosis (CF) patients who fall outside current FDA approval. This new, first of its kind drug is approved for use only in CF patients with the G551D mutation in whom it safely confers considerable benefits. However, it is highly likely that CF patients with many other mutations can benefit similarly from this drug, some of whom can be identified by phenotype or genotype. We will enroll up to 30 CF subjects with clinical presentations in which there is one or more signs of residual CF channel function. The signs of residual function include: normal digestion, concentration of chloride in sweat between 55 and 85, or milder than expected CF disease in a CF patient with severe gene mutations. The primary outcome measure will be the difference in sweat chloride concentration measured in subjects on placebo and on ivacaftor. Secondary outcome measured will be lung function.

NCT01784419 Cystic Fibrosis Drug: ivacaftor
MeSH:Cystic Fibrosis Fibrosis

Short Term Effects of Ivacaftor in Non-G551D Cystic Fibrosis Patients. --- G551D ---

Short Term Effects of Ivacaftor in Non-G551D Cystic Fibrosis Patients This is a study of the short-term effects of ivacaftor on sweat chloride concentration and lung function in cystic fibrosis (CF) patients who fall outside current FDA approval. --- G551D ---

This new, first of its kind drug is approved for use only in CF patients with the G551D mutation in whom it safely confers considerable benefits. --- G551D ---

It is currently FDA approved for use only in CF patients with the G551D gating mutation. --- G551D ---

Based on results from previous studies, we hypothesize that non-G551D patients with signs of residual CF channel activity might respond favorably to treatment with ivacaftor. --- G551D ---

This includes patients with any of the non-G551D gating mutations, that are pancreatic sufficient, that have a sweat chloride concentration between 55 and 85 mmol, or that are much healthier than expected. --- G551D ---

Primary Outcomes

Description: Sweat chloride concentration measured by pilocarpine iontophoresis, a standard clinical laboratory technique. Sweat collection accomplished with the Wescor Macroduct system. Sweat chloride is measured at the start and end of each study period. There are two study periods during which subjects take either ivacaftor or placebo.

Measure: Sweat chloride concentration

Time: 14 +/- 2 days

Secondary Outcomes

Description: Standard spirometry will be performed at the start and end of each 2 week study period. Subjects will take study drug (ivacaftor or placebo during each study period.

Measure: Spirometry

Time: 14 +/- 2 days

Description: Subjects will perform multibreath washout testing using standard techniques to measure functional residual capacity and lung clearance index at the beginning and end of each study period.

Measure: Multibreath washout testing

Time: 14 +/- 2 days

17 Airway Infection, Inflammatory Markers and Exercise Capacity in Patients With Cystic Fibrosis and at Least One G551D Mutation Taking VX770 (Ivacaftor)

Ivacaftor will restore CFTR function in treated CF patients with the G551D mutation. Improvement in ventilation, salt balance and well-being will contribute to better exercise capacity at all levels of lung function. While potential improvements may be variable across the spectrum of lung function, even small gains at low levels of FEV1 may have significant benefit for some subjects.

NCT01937325 Cystic Fibrosis Drug: ivacaftor Drug: placebo
MeSH:Cystic Fibrosis Fibrosis

Airway Infection, Inflammatory Markers and Exercise Capacity in Patients With Cystic Fibrosis and at Least One G551D Mutation Taking VX770 (Ivacaftor). --- G551D ---

CPET in CF Patients With One G551D Mutation Taking VX770 Ivacaftor will restore CFTR function in treated CF patients with the G551D mutation. --- G551D ---

CPET in CF Patients With One G551D Mutation Taking VX770 Ivacaftor will restore CFTR function in treated CF patients with the G551D mutation. --- G551D --- --- G551D ---

- All participants will have at least one copy of the G551D mutation. --- G551D ---

Primary Outcomes

Description: Respiratory exercise testing, including spirometry and V02 max.

Measure: exercise capacity

Time: one month, 3 months

Secondary Outcomes

Description: Cytokine levels (IL-1β, IL-6, TNFα, IL-8, VEGF & Activin A) determined using cytometric bead analysis and / or ELISA

Measure: Inflammatory profile

Time: One month, 3 months

18 The Role of IL-17 Neutrophils in CF Lung Inflammation

The purpose of this study is to determine whether IL-17 polymorphonuclear leukocytes (PMNs) are central to the disease pathology in CF. This will be determined by demonstrating that IL-17 PMNs are present in the CF airway, correlate with lung function measures, and decrease in patients being treated with IV antibiotics for a pulmonary exacerbation.

NCT02025829 Cystic Fibrosis
MeSH:Cystic Fibrosis Pneumonia Inflammation Fibrosis
HPO:Pneumonia

Inclusion Criteria: - For Both Cohorts: ≥ 18 < 50 years of age - For Both Cohorts: Must have a documented diagnosis of CF (positive sweat chloride ≥60 milliequivalents (mEq)/liter, by pilocarpine iontophoresis) and/or a genotype with two identifiable mutations consistent with CF accompanied by one or more clinical features with the CF) phenotype - For Both Cohorts: Chronically infected with P. aeruginosa defined by 2 positive cultures in the past year or 3 in the last two years - For Both Cohorts: Ability to expectorate mucus - For Both Cohorts: Ability to provide written informed consent - For Clinically Stable Cohort: 4 subjects with one copy of G551D - For Clinically Stable Cohort: 10 subjects who do not have G551D, they must have one copy of F508del - For Clinically Stable Cohort: CF subjects must have a baseline FEV1 percent predicted > 50% (in the last year, obtained from medical record) - For Clinically Stable Cohort: Clinically stable: free of any acute illness for >14 days - For Clinically Stable Cohort: Must have performed spirometry for clinical purposes at that clinical visit - For Clinically Stable Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes at the time of the study visit - For Clinically Stable Cohort: Have not been prescribed any new systemic antibiotics for the 14 days prior to enrollment - For Exacerbation/IV Antibiotics Cohort: One copy of F508del - For Exacerbation/IV Antibiotics Cohort: Must have a doctor defined pulmonary exacerbation requiring treatment with IV antibiotics - For Exacerbation/IV Antibiotics Cohort: Must have performed spirometry for clinical purposes within 72 hours of initiating IV antibiotics and within 72 hours of completing IV antibiotics - For Exacerbation/IV Antibiotics Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes within 72 hours of admission Exclusion Criteria: - For Both Cohorts: Pregnancy (based on self-report) - For Both Cohorts: Co-infection with Burkholderia cepacia complex organisms - For Both Cohorts: Any condition that in the opinion of the subject or the subject's managing physician that would compromise that individuals ability to participate in these studies - For Both Cohorts: Inability to tolerate the study procedures Inclusion Criteria: - For Both Cohorts: ≥ 18 < 50 years of age - For Both Cohorts: Must have a documented diagnosis of CF (positive sweat chloride ≥60 milliequivalents (mEq)/liter, by pilocarpine iontophoresis) and/or a genotype with two identifiable mutations consistent with CF accompanied by one or more clinical features with the CF) phenotype - For Both Cohorts: Chronically infected with P. aeruginosa defined by 2 positive cultures in the past year or 3 in the last two years - For Both Cohorts: Ability to expectorate mucus - For Both Cohorts: Ability to provide written informed consent - For Clinically Stable Cohort: 4 subjects with one copy of G551D - For Clinically Stable Cohort: 10 subjects who do not have G551D, they must have one copy of F508del - For Clinically Stable Cohort: CF subjects must have a baseline FEV1 percent predicted > 50% (in the last year, obtained from medical record) - For Clinically Stable Cohort: Clinically stable: free of any acute illness for >14 days - For Clinically Stable Cohort: Must have performed spirometry for clinical purposes at that clinical visit - For Clinically Stable Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes at the time of the study visit - For Clinically Stable Cohort: Have not been prescribed any new systemic antibiotics for the 14 days prior to enrollment - For Exacerbation/IV Antibiotics Cohort: One copy of F508del - For Exacerbation/IV Antibiotics Cohort: Must have a doctor defined pulmonary exacerbation requiring treatment with IV antibiotics - For Exacerbation/IV Antibiotics Cohort: Must have performed spirometry for clinical purposes within 72 hours of initiating IV antibiotics and within 72 hours of completing IV antibiotics - For Exacerbation/IV Antibiotics Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes within 72 hours of admission Exclusion Criteria: - For Both Cohorts: Pregnancy (based on self-report) - For Both Cohorts: Co-infection with Burkholderia cepacia complex organisms - For Both Cohorts: Any condition that in the opinion of the subject or the subject's managing physician that would compromise that individuals ability to participate in these studies - For Both Cohorts: Inability to tolerate the study procedures Cystic Fibrosis Cystic Fibrosis Pneumonia Inflammation Fibrosis This study consists of two parts which will be conducted in parallel. --- G551D ---

Inclusion Criteria: - For Both Cohorts: ≥ 18 < 50 years of age - For Both Cohorts: Must have a documented diagnosis of CF (positive sweat chloride ≥60 milliequivalents (mEq)/liter, by pilocarpine iontophoresis) and/or a genotype with two identifiable mutations consistent with CF accompanied by one or more clinical features with the CF) phenotype - For Both Cohorts: Chronically infected with P. aeruginosa defined by 2 positive cultures in the past year or 3 in the last two years - For Both Cohorts: Ability to expectorate mucus - For Both Cohorts: Ability to provide written informed consent - For Clinically Stable Cohort: 4 subjects with one copy of G551D - For Clinically Stable Cohort: 10 subjects who do not have G551D, they must have one copy of F508del - For Clinically Stable Cohort: CF subjects must have a baseline FEV1 percent predicted > 50% (in the last year, obtained from medical record) - For Clinically Stable Cohort: Clinically stable: free of any acute illness for >14 days - For Clinically Stable Cohort: Must have performed spirometry for clinical purposes at that clinical visit - For Clinically Stable Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes at the time of the study visit - For Clinically Stable Cohort: Have not been prescribed any new systemic antibiotics for the 14 days prior to enrollment - For Exacerbation/IV Antibiotics Cohort: One copy of F508del - For Exacerbation/IV Antibiotics Cohort: Must have a doctor defined pulmonary exacerbation requiring treatment with IV antibiotics - For Exacerbation/IV Antibiotics Cohort: Must have performed spirometry for clinical purposes within 72 hours of initiating IV antibiotics and within 72 hours of completing IV antibiotics - For Exacerbation/IV Antibiotics Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes within 72 hours of admission Exclusion Criteria: - For Both Cohorts: Pregnancy (based on self-report) - For Both Cohorts: Co-infection with Burkholderia cepacia complex organisms - For Both Cohorts: Any condition that in the opinion of the subject or the subject's managing physician that would compromise that individuals ability to participate in these studies - For Both Cohorts: Inability to tolerate the study procedures Inclusion Criteria: - For Both Cohorts: ≥ 18 < 50 years of age - For Both Cohorts: Must have a documented diagnosis of CF (positive sweat chloride ≥60 milliequivalents (mEq)/liter, by pilocarpine iontophoresis) and/or a genotype with two identifiable mutations consistent with CF accompanied by one or more clinical features with the CF) phenotype - For Both Cohorts: Chronically infected with P. aeruginosa defined by 2 positive cultures in the past year or 3 in the last two years - For Both Cohorts: Ability to expectorate mucus - For Both Cohorts: Ability to provide written informed consent - For Clinically Stable Cohort: 4 subjects with one copy of G551D - For Clinically Stable Cohort: 10 subjects who do not have G551D, they must have one copy of F508del - For Clinically Stable Cohort: CF subjects must have a baseline FEV1 percent predicted > 50% (in the last year, obtained from medical record) - For Clinically Stable Cohort: Clinically stable: free of any acute illness for >14 days - For Clinically Stable Cohort: Must have performed spirometry for clinical purposes at that clinical visit - For Clinically Stable Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes at the time of the study visit - For Clinically Stable Cohort: Have not been prescribed any new systemic antibiotics for the 14 days prior to enrollment - For Exacerbation/IV Antibiotics Cohort: One copy of F508del - For Exacerbation/IV Antibiotics Cohort: Must have a doctor defined pulmonary exacerbation requiring treatment with IV antibiotics - For Exacerbation/IV Antibiotics Cohort: Must have performed spirometry for clinical purposes within 72 hours of initiating IV antibiotics and within 72 hours of completing IV antibiotics - For Exacerbation/IV Antibiotics Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes within 72 hours of admission Exclusion Criteria: - For Both Cohorts: Pregnancy (based on self-report) - For Both Cohorts: Co-infection with Burkholderia cepacia complex organisms - For Both Cohorts: Any condition that in the opinion of the subject or the subject's managing physician that would compromise that individuals ability to participate in these studies - For Both Cohorts: Inability to tolerate the study procedures Cystic Fibrosis Cystic Fibrosis Pneumonia Inflammation Fibrosis This study consists of two parts which will be conducted in parallel. --- G551D --- --- G551D ---

Inclusion Criteria: - For Both Cohorts: ≥ 18 < 50 years of age - For Both Cohorts: Must have a documented diagnosis of CF (positive sweat chloride ≥60 milliequivalents (mEq)/liter, by pilocarpine iontophoresis) and/or a genotype with two identifiable mutations consistent with CF accompanied by one or more clinical features with the CF) phenotype - For Both Cohorts: Chronically infected with P. aeruginosa defined by 2 positive cultures in the past year or 3 in the last two years - For Both Cohorts: Ability to expectorate mucus - For Both Cohorts: Ability to provide written informed consent - For Clinically Stable Cohort: 4 subjects with one copy of G551D - For Clinically Stable Cohort: 10 subjects who do not have G551D, they must have one copy of F508del - For Clinically Stable Cohort: CF subjects must have a baseline FEV1 percent predicted > 50% (in the last year, obtained from medical record) - For Clinically Stable Cohort: Clinically stable: free of any acute illness for >14 days - For Clinically Stable Cohort: Must have performed spirometry for clinical purposes at that clinical visit - For Clinically Stable Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes at the time of the study visit - For Clinically Stable Cohort: Have not been prescribed any new systemic antibiotics for the 14 days prior to enrollment - For Exacerbation/IV Antibiotics Cohort: One copy of F508del - For Exacerbation/IV Antibiotics Cohort: Must have a doctor defined pulmonary exacerbation requiring treatment with IV antibiotics - For Exacerbation/IV Antibiotics Cohort: Must have performed spirometry for clinical purposes within 72 hours of initiating IV antibiotics and within 72 hours of completing IV antibiotics - For Exacerbation/IV Antibiotics Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes within 72 hours of admission Exclusion Criteria: - For Both Cohorts: Pregnancy (based on self-report) - For Both Cohorts: Co-infection with Burkholderia cepacia complex organisms - For Both Cohorts: Any condition that in the opinion of the subject or the subject's managing physician that would compromise that individuals ability to participate in these studies - For Both Cohorts: Inability to tolerate the study procedures Inclusion Criteria: - For Both Cohorts: ≥ 18 < 50 years of age - For Both Cohorts: Must have a documented diagnosis of CF (positive sweat chloride ≥60 milliequivalents (mEq)/liter, by pilocarpine iontophoresis) and/or a genotype with two identifiable mutations consistent with CF accompanied by one or more clinical features with the CF) phenotype - For Both Cohorts: Chronically infected with P. aeruginosa defined by 2 positive cultures in the past year or 3 in the last two years - For Both Cohorts: Ability to expectorate mucus - For Both Cohorts: Ability to provide written informed consent - For Clinically Stable Cohort: 4 subjects with one copy of G551D - For Clinically Stable Cohort: 10 subjects who do not have G551D, they must have one copy of F508del - For Clinically Stable Cohort: CF subjects must have a baseline FEV1 percent predicted > 50% (in the last year, obtained from medical record) - For Clinically Stable Cohort: Clinically stable: free of any acute illness for >14 days - For Clinically Stable Cohort: Must have performed spirometry for clinical purposes at that clinical visit - For Clinically Stable Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes at the time of the study visit - For Clinically Stable Cohort: Have not been prescribed any new systemic antibiotics for the 14 days prior to enrollment - For Exacerbation/IV Antibiotics Cohort: One copy of F508del - For Exacerbation/IV Antibiotics Cohort: Must have a doctor defined pulmonary exacerbation requiring treatment with IV antibiotics - For Exacerbation/IV Antibiotics Cohort: Must have performed spirometry for clinical purposes within 72 hours of initiating IV antibiotics and within 72 hours of completing IV antibiotics - For Exacerbation/IV Antibiotics Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes within 72 hours of admission Exclusion Criteria: - For Both Cohorts: Pregnancy (based on self-report) - For Both Cohorts: Co-infection with Burkholderia cepacia complex organisms - For Both Cohorts: Any condition that in the opinion of the subject or the subject's managing physician that would compromise that individuals ability to participate in these studies - For Both Cohorts: Inability to tolerate the study procedures Cystic Fibrosis Cystic Fibrosis Pneumonia Inflammation Fibrosis This study consists of two parts which will be conducted in parallel. --- G551D --- --- G551D --- --- G551D ---

Inclusion Criteria: - For Both Cohorts: ≥ 18 < 50 years of age - For Both Cohorts: Must have a documented diagnosis of CF (positive sweat chloride ≥60 milliequivalents (mEq)/liter, by pilocarpine iontophoresis) and/or a genotype with two identifiable mutations consistent with CF accompanied by one or more clinical features with the CF) phenotype - For Both Cohorts: Chronically infected with P. aeruginosa defined by 2 positive cultures in the past year or 3 in the last two years - For Both Cohorts: Ability to expectorate mucus - For Both Cohorts: Ability to provide written informed consent - For Clinically Stable Cohort: 4 subjects with one copy of G551D - For Clinically Stable Cohort: 10 subjects who do not have G551D, they must have one copy of F508del - For Clinically Stable Cohort: CF subjects must have a baseline FEV1 percent predicted > 50% (in the last year, obtained from medical record) - For Clinically Stable Cohort: Clinically stable: free of any acute illness for >14 days - For Clinically Stable Cohort: Must have performed spirometry for clinical purposes at that clinical visit - For Clinically Stable Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes at the time of the study visit - For Clinically Stable Cohort: Have not been prescribed any new systemic antibiotics for the 14 days prior to enrollment - For Exacerbation/IV Antibiotics Cohort: One copy of F508del - For Exacerbation/IV Antibiotics Cohort: Must have a doctor defined pulmonary exacerbation requiring treatment with IV antibiotics - For Exacerbation/IV Antibiotics Cohort: Must have performed spirometry for clinical purposes within 72 hours of initiating IV antibiotics and within 72 hours of completing IV antibiotics - For Exacerbation/IV Antibiotics Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes within 72 hours of admission Exclusion Criteria: - For Both Cohorts: Pregnancy (based on self-report) - For Both Cohorts: Co-infection with Burkholderia cepacia complex organisms - For Both Cohorts: Any condition that in the opinion of the subject or the subject's managing physician that would compromise that individuals ability to participate in these studies - For Both Cohorts: Inability to tolerate the study procedures Inclusion Criteria: - For Both Cohorts: ≥ 18 < 50 years of age - For Both Cohorts: Must have a documented diagnosis of CF (positive sweat chloride ≥60 milliequivalents (mEq)/liter, by pilocarpine iontophoresis) and/or a genotype with two identifiable mutations consistent with CF accompanied by one or more clinical features with the CF) phenotype - For Both Cohorts: Chronically infected with P. aeruginosa defined by 2 positive cultures in the past year or 3 in the last two years - For Both Cohorts: Ability to expectorate mucus - For Both Cohorts: Ability to provide written informed consent - For Clinically Stable Cohort: 4 subjects with one copy of G551D - For Clinically Stable Cohort: 10 subjects who do not have G551D, they must have one copy of F508del - For Clinically Stable Cohort: CF subjects must have a baseline FEV1 percent predicted > 50% (in the last year, obtained from medical record) - For Clinically Stable Cohort: Clinically stable: free of any acute illness for >14 days - For Clinically Stable Cohort: Must have performed spirometry for clinical purposes at that clinical visit - For Clinically Stable Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes at the time of the study visit - For Clinically Stable Cohort: Have not been prescribed any new systemic antibiotics for the 14 days prior to enrollment - For Exacerbation/IV Antibiotics Cohort: One copy of F508del - For Exacerbation/IV Antibiotics Cohort: Must have a doctor defined pulmonary exacerbation requiring treatment with IV antibiotics - For Exacerbation/IV Antibiotics Cohort: Must have performed spirometry for clinical purposes within 72 hours of initiating IV antibiotics and within 72 hours of completing IV antibiotics - For Exacerbation/IV Antibiotics Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes within 72 hours of admission Exclusion Criteria: - For Both Cohorts: Pregnancy (based on self-report) - For Both Cohorts: Co-infection with Burkholderia cepacia complex organisms - For Both Cohorts: Any condition that in the opinion of the subject or the subject's managing physician that would compromise that individuals ability to participate in these studies - For Both Cohorts: Inability to tolerate the study procedures Cystic Fibrosis Cystic Fibrosis Pneumonia Inflammation Fibrosis This study consists of two parts which will be conducted in parallel. --- G551D --- --- G551D --- --- G551D --- --- G551D ---

Primary Outcomes

Description: In the Exacerbation/IV Antibiotics Cohort--Subjects will serve as their own controls. The percentage of neutrophils (in sputum) positive for IL-17 was determined by flow cytometry for each subject at the beginning and end of treatment for a pulmonary exacerbation. Sputum IL-17 neutrophil counts will be compared to the change in lung function (FEV1) as determined by spirometry (American Thoracic Society standards).

Measure: Change in Sputum IL-17 Neutrophils

Time: End of Treatment, two weeks. Samples will be obtained from each study volunteer at the beginning of IV antibiotic treatment and at the completion of antibiotic treatment for a pulmonary exacerbation

Secondary Outcomes

Description: In the Clinically Stable Cohort--Measurement of sputum inflammatory mediators: IL-1β, IL-6, IL-8, IL-17A, TGF-β, TNF-α, and neutrophil elastase

Measure: Sputum Inflammatory Mediators: IL-1β, IL-6, IL-8, IL-17A, TGF-β, TNF-α, and Neutrophil Elastase

Time: Samples will be obtained at one outpatient clinic visit during the next calendar year

Description: In the Exacerbation/IV Antibiotics Cohort--Measurement of sputum inflammatory mediators by multiplex assay for IL-1β, IL-6, IL-8, and IL-17A. Neutrophil elastase determined by colorimetric assay. Measurements at the beginning of IV antibiotic treatment and after 2 weeks antibiotic treatment for a pulmonary exacerbation

Measure: Sputum Inflammatory Mediators: IL-1β, IL-6, IL-8, IL-17A, and Neutrophil Elastase

Time: End of Treatment, two weeks. Samples will be obtained from each study volunteer at the beginning of IV antibiotic treatment and at the completion of antibiotic treatment for a pulmonary exacerbation

19 Effects of Ivacaftor (Kalydeco) Treatment Upon Insulin and Incretin Secretion in Patients With Cystic Fibrosis

This study is aimed at better understanding the impact of ivacaftor upon insulin and incretin secretion and glucose tolerance in patients with Cystic Fibrosis with a glycine (G551D) mutation. Investigators hypothesize that treatment with ivacaftor improves insulin secretion in individuals with CF.

NCT02039986 Cystic Fibrosis Related Diabetes Cystic Fibrosis
MeSH:Cystic Fibrosis Fibrosis

Ivacaftor (Kalydeco) and Insulin in Cystic Fibrosis (CF) This study is aimed at better understanding the impact of ivacaftor upon insulin and incretin secretion and glucose tolerance in patients with Cystic Fibrosis with a glycine (G551D) mutation. --- G551D ---

To compare insulin secretion and maximal insulin secretory capacity prior to initiation of ivacaftor and after 16 weeks of ivacaftor treatment in subjects with CF and at least one G551D CFTR mutation, or other CFTR gating mutation, and to explore the impact of ivacaftor upon incretin secretion, incretin regulation of insulin secretion, and glucose excursion during a mixed meal tolerance test in CF.. Composite change from baseline in relationships of insulin secretion and protein and interleukin levels at 16 weeks. --- G551D ---

To explore the composite relationships of insulin secretion, maximal insulin secretory capacity, and incretin secretion with secreted frizzled protein-4 levels and interleukin 1β levels.. Inclusion Criteria: - 6 yrs or older with cystic fibrosis - at least one G551D CFTR mutation or other non-G551D gating mutation, or residual function CFTR mutation such as, but not limited to, R117H mutation, for which ivacaftor is to be initiated. --- G551D ---

To explore the composite relationships of insulin secretion, maximal insulin secretory capacity, and incretin secretion with secreted frizzled protein-4 levels and interleukin 1β levels.. Inclusion Criteria: - 6 yrs or older with cystic fibrosis - at least one G551D CFTR mutation or other non-G551D gating mutation, or residual function CFTR mutation such as, but not limited to, R117H mutation, for which ivacaftor is to be initiated. --- G551D --- --- G551D ---

Inclusion Criteria: - 6 yrs or older with cystic fibrosis - at least one G551D CFTR mutation or other non-G551D gating mutation, or residual function CFTR mutation such as, but not limited to, R117H mutation, for which ivacaftor is to be initiated. --- G551D ---

Inclusion Criteria: - 6 yrs or older with cystic fibrosis - at least one G551D CFTR mutation or other non-G551D gating mutation, or residual function CFTR mutation such as, but not limited to, R117H mutation, for which ivacaftor is to be initiated. --- G551D --- --- G551D ---

Primary Outcomes

Description: To compare insulin secretion and maximal insulin secretory capacity prior to initiation of ivacaftor and after 16 weeks of ivacaftor treatment in subjects with CF and at least one G551D CFTR mutation, or other CFTR gating mutation, and to explore the impact of ivacaftor upon incretin secretion, incretin regulation of insulin secretion, and glucose excursion during a mixed meal tolerance test in CF.

Measure: Change from baseline in insulin secretion capacity at 16 weeks

Time: baseline and 16 weeks

Secondary Outcomes

Description: To explore the composite relationships of insulin secretion, maximal insulin secretory capacity, and incretin secretion with secreted frizzled protein-4 levels and interleukin 1β levels.

Measure: Composite change from baseline in relationships of insulin secretion and protein and interleukin levels at 16 weeks

Time: baseline and 16 weeks

20 Energy Balance and Weight Gain With Ivacaftor Treatment of CFTR Gating Mutations

Ivacaftor is a novel, FDA approved new therapy that addresses Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunctions in subjects with Cystic fibrosis (CF) and "gating mutations". The primary aim is to determine the mechanism(s) for weight gain in participants whom Ivacaftor treatment was initiated based on clinical indications by CF Care Team. This longitudinal study will assess in detail energy expenditure, weight gain, body composition, and lung function in 24 subjects ≥6 years old with CF with a gating mutation before treatment and after three months treatment with Ivacaftor. All subjects will be seen at the Children's Hospital of Philadelphia's Clinical Translational Research Center.

NCT02141464 Cystic Fibrosis
MeSH:Cystic Fibrosis Weight Gain
HPO:Increased body weight

For mutations like G551D that permit CFTR expression at the cell membrane but compromise its activity, Ivacaftor increases the probability that the channel is open and active. --- G551D ---

Primary Outcomes

Measure: Reduction in resting energy expenditure

Time: 3 months

21 A Double-blind, Randomized, Placebo-controlled Cross Over Study of Inhaled Alginate Oligosaccharide (OligoG) Administered for 28 Days in Subjects With Cystic Fibrosis

The purpose of the study is assessment of efficacy and safety of OligoG as a dry powder formulation, in adult subjects with cystic fibrosis.

NCT02157922 Cystic Fibrosis Drug: alginate oligosaccharide
MeSH:Cystic Fibrosis Fibrosis

- Diagnosed with the G551D-mutation, and currently on concomitant treatment with Ivacaftor (Kalydeco). --- G551D ---

Primary Outcomes

Description: An improvement in FEV1 during treatment with OligoG as compared to placebo is the primary endpoint of the study.

Measure: FEV1 (Forced Expiratory Volume in 1 second)

Time: 28 days, i.e. start and end of treatment periods

Secondary Outcomes

Description: Mucociliary clearance is assessed by measuring the movement of an inhaled radiotracer up the airways.

Measure: Mucociliary and cough clearance

Time: 28 days, i.e. start and end of treatment periods

Other Outcomes

Description: Measurement of vital signs, ECG, blood oxygen saturation and pulmonary function tests. Adverse events and concomitant medications will be recorded, and blood samples will be collected for hematology, clinical chemistry and OligoG concentration.

Measure: Safety

Time: Screening, day 0, 14, 28, 56, 70, 84 and follow up

22 Ivacaftor in French Patients With Cystic Fibrosis and a G551D Mutation - Efficacy and Safety Results After the First Year of Treatment in the Real Life Setting.

The purpose of this study is to determine whether the treatment with Ivacaftor remains effective and safe in the patients with cystic fibrosis (and at least one G551D CFTR mutation) in the real life setting, after the drug has been approved by the Health authorities.

NCT02194881 Cystic Fibrosis Drug: CF patients with a G551D mutation and treated with Ivacaftor
MeSH:Cystic Fibrosis Fibrosis

Ivacaftor in French Patients With Cystic Fibrosis and a G551D Mutation - Efficacy and Safety Results After the First Year of Treatment in the Real Life Setting.. Ivacaftor in French Patients With Cystic Fibrosis and a G551D Mutation The purpose of this study is to determine whether the treatment with Ivacaftor remains effective and safe in the patients with cystic fibrosis (and at least one G551D CFTR mutation) in the real life setting, after the drug has been approved by the Health authorities. --- G551D ---

Ivacaftor in French Patients With Cystic Fibrosis and a G551D Mutation - Efficacy and Safety Results After the First Year of Treatment in the Real Life Setting.. Ivacaftor in French Patients With Cystic Fibrosis and a G551D Mutation The purpose of this study is to determine whether the treatment with Ivacaftor remains effective and safe in the patients with cystic fibrosis (and at least one G551D CFTR mutation) in the real life setting, after the drug has been approved by the Health authorities. --- G551D --- --- G551D ---

Ivacaftor in French Patients With Cystic Fibrosis and a G551D Mutation - Efficacy and Safety Results After the First Year of Treatment in the Real Life Setting.. Ivacaftor in French Patients With Cystic Fibrosis and a G551D Mutation The purpose of this study is to determine whether the treatment with Ivacaftor remains effective and safe in the patients with cystic fibrosis (and at least one G551D CFTR mutation) in the real life setting, after the drug has been approved by the Health authorities. --- G551D --- --- G551D --- --- G551D ---

Inclusion Criteria: - French patients with CF aged 6 or older who are homozygous or heterozygous for the G551D mutation - Treated with Ivacaftor - First prescription of Ivacaftor before June 1st 2013 (including patients randomized in the VX770 clinical trials) Exclusion Criteria: - CF patients younger than 6 years old - CF patients who have received lung transplantation - CF patients without a G551D mutation. --- G551D ---

Inclusion Criteria: - French patients with CF aged 6 or older who are homozygous or heterozygous for the G551D mutation - Treated with Ivacaftor - First prescription of Ivacaftor before June 1st 2013 (including patients randomized in the VX770 clinical trials) Exclusion Criteria: - CF patients younger than 6 years old - CF patients who have received lung transplantation - CF patients without a G551D mutation. --- G551D --- --- G551D ---

Primary Outcomes

Description: pulmonary function

Measure: FEV1 (in liters and in % predicted)

Time: until one years after initiation of treatment

Secondary Outcomes

Measure: pulmonary exacerbations

Time: until one years after initiation of treatment

Measure: number of hospitalizations and number of days of hospitalization per year

Time: until one year after initiation of treatment

Description: number of oral antibiotic treatments and number of days of oral antibiotic treatments, number of IV courses and days of IV antibiotics per year

Measure: number of antibiotic treatments and number of days of antibiotic treatments

Time: until one year after initiation of treatment

Description: Evolution of bacteria and fungi in sputum

Measure: respiratory colonization

Time: until least one year after initiation of treatment

Description: Weight (and BMI-Zscore for children)

Measure: nutritional status

Time: until one year after initiation of treatment

Description: Dates and reasons for interruption and discontinuation of treatment with Ivacaftor Adverse events, indicating what in the physician's opinion might be due to Ivacaftor

Measure: Adverse events

Time: until one year after initiation of treatment

23 Effects of Kalydeco on Upper Airway and Paranasal Sinus Inflammation Measured by Nasal Lavage and on Symptoms

The aim of the proposed trial in assessment of effects of Kalydeco™ treatment on sinonasal involvement in CF patients with at least one mutation of G551D receiving a new therapy with the CFTR potentiator. The focus will be given on changes in epithelial lining fluid inflammatory markers from CF upper airways sampled by nasal lavage. The program is subdivided into a part A assessing inflammatory markers in NL and sinonasal symptoms longitudinally from pre-treatment to months with the new therapy. Part B will only be performed in a smaller subgroup and assess inflammatory markers in NL every second day in the first month of treatment and then every week until the end of month 3 with Kalydeco™ therapy.

NCT02311140 Inflammatory Changes in Epithelial Lining Fluid Sampled Non-invasively by Nasal Lavage in CF Patients With G551D Receiving Kalydeco Other: nasal lavage (routine diagnostic procedure in our centre), assessment of symptoms
MeSH:Sinusitis Inflammation
HPO:Sinusitis

Effects of Kalydeco on Upper Airway and Paranasal Sinus Inflammation Measured by Nasal Lavage and on Symptoms The aim of the proposed trial in assessment of effects of Kalydeco™ treatment on sinonasal involvement in CF patients with at least one mutation of G551D receiving a new therapy with the CFTR potentiator. --- G551D ---

Inclusion Criteria: - G551D and Kalydeco therapy Exclusion Criteria: - no G551D Inclusion Criteria: - G551D and Kalydeco therapy Exclusion Criteria: - no G551D Inflammatory Changes in Epithelial Lining Fluid Sampled Non-invasively by Nasal Lavage in CF Patients With G551D Receiving Kalydeco Sinusitis Inflammation null --- G551D ---

Inclusion Criteria: - G551D and Kalydeco therapy Exclusion Criteria: - no G551D Inclusion Criteria: - G551D and Kalydeco therapy Exclusion Criteria: - no G551D Inflammatory Changes in Epithelial Lining Fluid Sampled Non-invasively by Nasal Lavage in CF Patients With G551D Receiving Kalydeco Sinusitis Inflammation null --- G551D --- --- G551D ---

Inclusion Criteria: - G551D and Kalydeco therapy Exclusion Criteria: - no G551D Inclusion Criteria: - G551D and Kalydeco therapy Exclusion Criteria: - no G551D Inflammatory Changes in Epithelial Lining Fluid Sampled Non-invasively by Nasal Lavage in CF Patients With G551D Receiving Kalydeco Sinusitis Inflammation null --- G551D --- --- G551D --- --- G551D ---

Inclusion Criteria: - G551D and Kalydeco therapy Exclusion Criteria: - no G551D Inclusion Criteria: - G551D and Kalydeco therapy Exclusion Criteria: - no G551D Inflammatory Changes in Epithelial Lining Fluid Sampled Non-invasively by Nasal Lavage in CF Patients With G551D Receiving Kalydeco Sinusitis Inflammation null --- G551D --- --- G551D --- --- G551D --- --- G551D ---

Inclusion Criteria: - G551D and Kalydeco therapy Exclusion Criteria: - no G551D Inclusion Criteria: - G551D and Kalydeco therapy Exclusion Criteria: - no G551D Inflammatory Changes in Epithelial Lining Fluid Sampled Non-invasively by Nasal Lavage in CF Patients With G551D Receiving Kalydeco Sinusitis Inflammation null --- G551D --- --- G551D --- --- G551D --- --- G551D --- --- G551D ---

Primary Outcomes

Measure: Changes in concentration of inflammatory markers

Time: 3 yrs

24 A Double Blind, Placebo Controlled, Dose Escalation Trial of Glycerol Phenylbutyrate Corrector Therapy for Cystic Fibrosis

We propose to test the effectiveness of the combination of CF pancreatic enzyme replacement therapy (PERT) on absorption of Ravicti® and subsequent restoration of nasal epithelial cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride transport during the nasal potential difference (NPD) test. Funding source FDA Office of Orphan Products Development.

NCT02323100 Cystic Fibrosis Drug: Ravicti low dose Drug: Ravicti high dose Drug: Placebo
MeSH:Cystic Fibrosis Fibrosis

In the ensuing years, Vertex Pharmaceuticals, Inc. has had success with the development of ivacaftor3;3;4 (VX-770) as a potentiator of G551D CFTR and has studied the drug alone and in combination with their corrector lumacaftor5 (VX-809) and VX-661. --- G551D ---

Primary Outcomes

Description: chloride and sodium transport in nasal epithelium

Measure: The primary biological endpoint will be the change in average measurement of nasal potential difference between day 7 and baseline.

Time: 7 days

Secondary Outcomes

Description: change between date and baseline in sodium and chloride transport

Measure: Change in other NPD measures from baseline and Days 4, 7, and 14 to include baseline PD, change in amiloride, low chloride, and low chloride plus isoproterenol.

Time: 14 days

Description: change between study time point and baseline in sweat chloride

Measure: Change in average sweat chloride measurement between days 4, 7, 14 and baseline.

Time: 14 days

Description: standard safety and tolerability lab values

Measure: Safety and tolerability.

Time: 14 days

Description: quantification of exogenous pancreatic enzyme effects on release of active drug from the pro-drug triglyceride form

Measure: Efficacy of PERT on absorption of Ravicti®.

Time: 14 days

Other Outcomes

Description: blood pharmacokinetics

Measure: Plasma will be sampled for pharmacokinetics (PK) studies

Time: 14 days

Description: blood counts, metabolic measures, CRP

Measure: Safety labs: hematology, complete metabolic panel (CMP), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), uric acid. Sputum microbiology and spirometry will be performed.

Time: 14 days

25 Observational Study of Outcomes in Cystic Fibrosis Patients With Selected Gating Mutations on a CFTR Allele (The VOCAL Study)

To describe the effectiveness of Kalydeco® treatment in patients with cystic fibrosis (CF) who have 1 of 8 non G551D gating CFTR mutations (G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D).

NCT02445053 Cystic Fibrosis Drug: ivacaftor
MeSH:Cystic Fibrosis Fibrosis

Observational Study of Outcomes in Cystic Fibrosis Patients With Selected Gating Mutations on a CFTR Allele (The VOCAL Study) To describe the effectiveness of Kalydeco® treatment in patients with cystic fibrosis (CF) who have 1 of 8 non G551D gating CFTR mutations (G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D). --- G551D ---

Primary Outcomes

Measure: Pulmonary exacerbations - Number of pulmonary exacerbations and duration of treatment for pulmonary exacerbations during Kalydeco treatment compared to the period before Kalydeco treatment

Time: 48 Months

Measure: Respiratory Microbiology - Percentage of patients with cultures positive for Pseudomonas aeruginosa during Kalydeco treatment compared to the period before Kalydeco treatment

Time: 48 Months

Measure: Respiratory Microbiology - Percentage of patients with cultures positive for bacteria other than Pseudomonas aeruginosa and for fungi during Kalydeco treatment compared to the period before Kalydeco treatment

Time: 48 Months

Measure: FEV1: Absolute change in percent predicted FEV1 during Kalydeco treatment

Time: 48 Months

Measure: Measures of nutritional status: Absolute change in weight, weight-for-age Z score, body mass index (BMI), and BMI-for-age Z-score during Kalydeco treatment

Time: 48 Months

Measure: Comorbidities: Incidence and prevalence of comorbidities during Kalydeco treatment compared to the period before Kalydeco treatment

Time: 48 Months

Measure: Mortality: Incidence and cause of deaths

Time: 48 Months

Measure: Organ transplantation: Incidence and reason for organ transplantations

Time: 48 Months

Other Outcomes

Measure: To explore the effect of Kalydeco treatment on Health-Related Quality of Life (HRQoL) in patients with CF and in caregivers of pediatric patients enrolled in the study.

Time: 48 Months

26 A Phase IIa, Open-label Study of Multiple Doses of GLPG1837 in Subjects With Cystic Fibrosis and the G551D Mutation

32 cystic fibrosis patients with the G551D mutation will be treated for 4 weeks, consisting of three consecutive treatment periods: two 1-week periods followed by one 2-week period, evaluating one dose of GLPG1837 each. After the treatment period, there is a 7-10 days follow-up period. During the course of the study, subjects will be examined for any side effects that may occur (safety and tolerability). Changes in sweat chloride will be assessed as biomarker from baseline onwards, and changes in pulmonary function (efficacy) will be explored throughout the study. The amount of GLPG1837 present in the blood (pharmacokinetics) will also be determined.

NCT02707562 Cystic Fibrosis Drug: GLPG1837 dose 1 Drug: GLPG1837 dose 2 Drug: GLPG1837 dose 3
MeSH:Cystic Fibrosis Fibrosis

A Phase IIa, Open-label Study of Multiple Doses of GLPG1837 in Subjects With Cystic Fibrosis and the G551D Mutation. --- G551D ---

Study of GLPG1837 in Subjects With Cystic Fibrosis (G551D Mutation) 32 cystic fibrosis patients with the G551D mutation will be treated for 4 weeks, consisting of three consecutive treatment periods: two 1-week periods followed by one 2-week period, evaluating one dose of GLPG1837 each. --- G551D ---

Study of GLPG1837 in Subjects With Cystic Fibrosis (G551D Mutation) 32 cystic fibrosis patients with the G551D mutation will be treated for 4 weeks, consisting of three consecutive treatment periods: two 1-week periods followed by one 2-week period, evaluating one dose of GLPG1837 each. --- G551D --- --- G551D ---

Inclusion Criteria: - Male or female subjects ≥ 18 years of age, with a confirmed diagnosis of cystic fibrosis - Subjects with gating G551D CFTR mutation on at least one allele in the CFTR gene - Subjects currently receiving treatment with ivacaftor on a stable regimen or not on a treatment regimen with ivacaftor, for at least 2 weeks prior to screening - Weight ≥ 40.0 kg - Subjects on stable concomitant treatment regimen for at least 4 weeks prior to baseline (excluding ivacaftor) - Pre- or post-bronchodilator FEV1 ≥ 40% of predicted normal - Subject will have to use highly effective contraceptive methods Exclusion Criteria: - On an ivacaftor-containing treatment regimen and unable or unwilling to discontinue ivacaftor for the washout and treatment periods of the study - Concomitant use of antifungal drugs within 4 weeks of baseline - A history of a clinically meaningful unstable or uncontrolled chronic disease - Liver cirrhosis and portal hypertension - Any significant change in the medical regimen for pulmonary health within 4 weeks of baseline - Unstable pulmonary status or respiratory tract infection or changes in therapy for pulmonary disease within 4 weeks of baseline - Abnormal liver function - Clinically significant abnormalities on ECG - History of malignancy, solid organ/haematological transplantation - Abnormal renal function - Participation in another experimental therapy study within 30 days or 5 times halflife Inclusion Criteria: - Male or female subjects ≥ 18 years of age, with a confirmed diagnosis of cystic fibrosis - Subjects with gating G551D CFTR mutation on at least one allele in the CFTR gene - Subjects currently receiving treatment with ivacaftor on a stable regimen or not on a treatment regimen with ivacaftor, for at least 2 weeks prior to screening - Weight ≥ 40.0 kg - Subjects on stable concomitant treatment regimen for at least 4 weeks prior to baseline (excluding ivacaftor) - Pre- or post-bronchodilator FEV1 ≥ 40% of predicted normal - Subject will have to use highly effective contraceptive methods Exclusion Criteria: - On an ivacaftor-containing treatment regimen and unable or unwilling to discontinue ivacaftor for the washout and treatment periods of the study - Concomitant use of antifungal drugs within 4 weeks of baseline - A history of a clinically meaningful unstable or uncontrolled chronic disease - Liver cirrhosis and portal hypertension - Any significant change in the medical regimen for pulmonary health within 4 weeks of baseline - Unstable pulmonary status or respiratory tract infection or changes in therapy for pulmonary disease within 4 weeks of baseline - Abnormal liver function - Clinically significant abnormalities on ECG - History of malignancy, solid organ/haematological transplantation - Abnormal renal function - Participation in another experimental therapy study within 30 days or 5 times halflife Cystic Fibrosis Cystic Fibrosis Fibrosis null --- G551D ---

Inclusion Criteria: - Male or female subjects ≥ 18 years of age, with a confirmed diagnosis of cystic fibrosis - Subjects with gating G551D CFTR mutation on at least one allele in the CFTR gene - Subjects currently receiving treatment with ivacaftor on a stable regimen or not on a treatment regimen with ivacaftor, for at least 2 weeks prior to screening - Weight ≥ 40.0 kg - Subjects on stable concomitant treatment regimen for at least 4 weeks prior to baseline (excluding ivacaftor) - Pre- or post-bronchodilator FEV1 ≥ 40% of predicted normal - Subject will have to use highly effective contraceptive methods Exclusion Criteria: - On an ivacaftor-containing treatment regimen and unable or unwilling to discontinue ivacaftor for the washout and treatment periods of the study - Concomitant use of antifungal drugs within 4 weeks of baseline - A history of a clinically meaningful unstable or uncontrolled chronic disease - Liver cirrhosis and portal hypertension - Any significant change in the medical regimen for pulmonary health within 4 weeks of baseline - Unstable pulmonary status or respiratory tract infection or changes in therapy for pulmonary disease within 4 weeks of baseline - Abnormal liver function - Clinically significant abnormalities on ECG - History of malignancy, solid organ/haematological transplantation - Abnormal renal function - Participation in another experimental therapy study within 30 days or 5 times halflife Inclusion Criteria: - Male or female subjects ≥ 18 years of age, with a confirmed diagnosis of cystic fibrosis - Subjects with gating G551D CFTR mutation on at least one allele in the CFTR gene - Subjects currently receiving treatment with ivacaftor on a stable regimen or not on a treatment regimen with ivacaftor, for at least 2 weeks prior to screening - Weight ≥ 40.0 kg - Subjects on stable concomitant treatment regimen for at least 4 weeks prior to baseline (excluding ivacaftor) - Pre- or post-bronchodilator FEV1 ≥ 40% of predicted normal - Subject will have to use highly effective contraceptive methods Exclusion Criteria: - On an ivacaftor-containing treatment regimen and unable or unwilling to discontinue ivacaftor for the washout and treatment periods of the study - Concomitant use of antifungal drugs within 4 weeks of baseline - A history of a clinically meaningful unstable or uncontrolled chronic disease - Liver cirrhosis and portal hypertension - Any significant change in the medical regimen for pulmonary health within 4 weeks of baseline - Unstable pulmonary status or respiratory tract infection or changes in therapy for pulmonary disease within 4 weeks of baseline - Abnormal liver function - Clinically significant abnormalities on ECG - History of malignancy, solid organ/haematological transplantation - Abnormal renal function - Participation in another experimental therapy study within 30 days or 5 times halflife Cystic Fibrosis Cystic Fibrosis Fibrosis null --- G551D --- --- G551D ---

Primary Outcomes

Description: To evaluate the safety and tolerability of GLPG1837 in terms of adverse events at every visit

Measure: Changes in adverse events

Time: Up to 9 weeks

Description: To evaluate the safety and tolerability of GLPG1837 in terms of abnormal laboratory parameters at every visit

Measure: Changes in laboratory parameters

Time: Up to 7 weeks

Description: To evaluate the safety and tolerability of GLPG1837 in terms of abnormal vital signs as measured by temperature, blood pressure, heart rate and respiratory rate, at every visit

Measure: Changes in vital signs - composite outcome measure

Time: Up to 9 weeks

Description: To evaluate the safety and tolerability of GLPG1837 in terms of abnormalities during physical examination at every visit

Measure: Changes in physical examination - composite outcome measure

Time: Up to 9 weeks

Description: To evaluate the safety and tolerability of GLPG1837 in terms of abnormal electrocardiogram at every visit

Measure: Changes in electrocardiogram

Time: Up to 7 weeks

Secondary Outcomes

Description: To evaluate the effect of GLPG1837 in terms of change in sweat chloride concentration, a biomarker to measure cystic fibrosis transmembrane conductance regulator (CFTR) ion channel function at every visit

Measure: Changes in sweat chloride concentration

Time: Up to 9 weeks

Description: To explore the effect of GLPG1837 in terms of change in pulmonary function (forced expiratory volume in 1 second, FEV1) assessed by spirometry at every visit

Measure: Changes in pulmonary function (forced expiratory volume in 1 second, FEV1) assessed by spirometry

Time: Up to 9 weeks

Description: To characterize the pharmacokinetics (PK) of GLPG1837 by measuring the amount in plasma between Day 8 and Day 29 at every visit; On Day 29, an 8-hour profile will determine the Cmax, the maximum observed plasma concentration

Measure: Plasma levels of GLPG1837: Cmax, the maximum observed plasma concentration

Time: Up to 3 weeks

Description: To characterize the pharmacokinetics (PK) of GLPG1837 by measuring the amount in plasma between Day 8 and Day 29 at every visit; On Day 29, an 8-hour profile will determine the tmax, the time of occurrence of Cmax

Measure: Plasma levels of GLPG1837: tmax, the time of occurrence of Cmax

Time: Up to 3 weeks

Description: To characterize the pharmacokinetics (PK) of GLPG1837 by measuring the amount in plasma between Day 8 and Day 29 at every visit; On Day 29, an 8-hour profile will determine the AUC, the area under the plasma concentration-time curve

Measure: Plasma levels of GLPG1837: AUC, the area under the plasma concentration-time curve

Time: Up to 3 weeks

27 A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of N91115 for Efficacy and Safety in Patients With CF Heterozygous for F508del-CFTR + Gating Mutation Being Treated With Ivacaftor

Cavosonstat (N91115) is being studied as a potential novel therapy for cystic fibrosis (CF), and this study assesses a target population of patients who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R).

NCT02724527 Cystic Fibrosis Drug: Cavosonstat Drug: Placebo
MeSH:Cystic Fibrosis Fibrosis

Study of Cavosonstat (N91115) in CF Patients Who Are Heterozygous for F508del-CFTR and a Gating Mutation and Being Treated With Ivacaftor Cavosonstat (N91115) is being studied as a potential novel therapy for cystic fibrosis (CF), and this study assesses a target population of patients who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D ---

Primary Outcomes

Description: Forced Expiratory Volume (FEV) absolute measurements comparing baseline to after 4 and 8 weeks of N91115 treatment. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. ppFEV1 (predicted for age, gender, and height) is calculated using the Hankinson method.

Measure: The absolute change in ppFEV1 in the N91115 treated group

Time: Baseline, week 4 and 8 assessments

Secondary Outcomes

Description: Forced Expiratory Volume relative measurements comparing baseline to after 4 and 8 weeks of N91115 treatment. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. ppFEV1 (predicted for age, gender, and height) is calculated using the Hankinson method.

Measure: The relative change from study baseline within the active treatment group in ppFEV1 values

Time: Baseline, week 4 and 8 assessments

Description: Sweat chloride concentration measured by pilocarpine iontophoresis, a standard clinical laboratory technique. Sweat collection accomplished with the Wescor Macroduct System.

Measure: Absolute change from study baseline within the active treatment group in sweat chloride

Time: Baseline, week 4 and 8 assessments

Description: Patient questionnaires will compare baseline scores on their respiratory symptoms to weeks 4 and 8

Measure: Changes in the respiratory domain of the Cystic Fibrosis Questionnaire - Revised, (CFQ-R)

Time: Baseline, week 4 and 8 assessments

Description: Patient questionnaires will compare baseline global impression of changes in health from baseline to weeks 4 and 8

Measure: Absolute change from baseline within the active treatment group in Patient Global Impression of Change

Time: Baseline, week 4 and 8 assessments

Description: Assessments of clinical laboratory values, electrocardiogram (ECG), pulmonary exacerbations, and vital signs

Measure: Safety as determined by adverse events assessment

Time: Baseline to 8 weeks treatment with a 28-day follow up period

Description: Plasma collection for assessment of N91115 and ivacaftor Cmax

Measure: Pharmacokinetic Assessment of Maximum Plasma Concentration [Cmax] for N91115 & ivacaftor

Time: Weeks 1, 4 and 8

Description: Plasma collection for assessment of N91115 and ivacaftor AUC

Measure: Pharmacokinetic Assessment of area under the plasma concentration verse time curve [AUC] for N91115 & ivacaftor

Time: Weeks 1, 4 and 8

28 A Phase 3, 2 Part, Open-Label Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Ivacaftor in Subjects With Cystic Fibrosis Who Are Less Than 24 Months of Age and Have a CFTR Gating Mutation

The purpose of this study is to evaluate the safety of ivacaftor treatment, and PK of ivacaftor and metabolites in subjects with cystic fibrosis (CF) who are <24 months of age at treatment initiation and have a CF transmembrane conductance regulator (CFTR) gene gating mutation

NCT02725567 Cystic Fibrosis Drug: ivacaftor
MeSH:Cystic Fibrosis Fibrosis

- Must have 1 of the following 9 CFTR mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D. --- G551D ---

Primary Outcomes

Measure: Part A: Safety, as determined by number of subjects with adverse events (AEs), clinically relevant abnormal laboratory values (serum chemistry and hematology), standard 12 lead electrocardiograms (ECGs), vital signs, and ophthalmologic examinations

Time: Day 1 up to Day 70

Measure: Part B: Safety, as determined by number of subjects with adverse events (AEs), clinically relevant abnormal laboratory values (serum chemistry and hematology), standard 12 lead electrocardiograms (ECGs), vital signs, and ophthalmologic examinations

Time: Day 1 up to Week 24

Measure: Part A: Peak concentrations (C3-6h) of ivacaftor, M1 ivacaftor, and M6 ivacaftor

Time: after 4 days of ivacaftor treatment

Measure: Part A: Trough concentrations (Ctrough) of ivacaftor, M1 ivacaftor, and M6 ivacaftor

Time: after 4 days of ivacaftor treatment

Secondary Outcomes

Measure: Part B: Peak concentrations (C3-6h) of ivacaftor, M1 ivacaftor, and M6 ivacaftor

Time: through Week 24

Measure: Part B: Trough concentrations (Ctrough) of ivacaftor, M1 ivacaftor, and M6 ivacaftor

Time: through Week 24

Measure: Part B: Absolute change from baseline in sweat chloride using quantitative pilocarpine iontophoresis

Time: through Week 24

29 A Phase 3b, 2-part, Randomized, Double-blind, Placebo-controlled Crossover Study With a Long-term Open-label Period to Investigate Ivacaftor in Subjects With Cystic Fibrosis Aged 3 Through 5 Years Who Have a Specified CFTR Gating Mutation

To evaluate the efficacy of ivacaftor treatment, as measured by lung clearance index (LCI), in subjects with cystic fibrosis (CF) who have a specified CF transmembrane conductance regulator (CFTR) gating mutation

NCT02742519 Cystic Fibrosis Drug: ivacaftor Drug: Placebo
MeSH:Cystic Fibrosis Fibrosis

Inclusion Criteria: - Male or female with confirmed diagnosis of CF. - Must have 1 of the following CFTR gating mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D. --- G551D ---

Exclusion Criteria: - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before Day 1 - Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject (in the opinion of the investigator) - Abnormal liver function, at Screening, defined as ≥3 × upper limit of normal (ULN), of any 3 or more of the following: serum aspartate transaminase (AST), serum alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), serum alkaline phosphatase (ALP), and total bilirubin - History of solid organ or hematological transplantation - Any clinically significant "non-CF-related" illness within 2 weeks before Day 1 - Use of any moderate or strong inducers or inhibitors of cytochrome P450 (CYP) 3A within 2 weeks before Day 1 - Participation in a clinical study involving administration of either an investigational or a marketed drug within 30 days or 5 terminal half-lives (whichever is longer or as determined by the local requirements) before Screening Inclusion Criteria: - Male or female with confirmed diagnosis of CF. - Must have 1 of the following CFTR gating mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D. --- G551D ---

Primary Outcomes

Description: LCI2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value.

Measure: Absolute Change From Baseline in Lung Clearance Index (LCI2.5) Through 8 Weeks of Treatment (Average of Week 4 and Week 8 LCI2.5)

Time: Baseline Through Week 8 for each treatment period, Up to 24 Weeks

Secondary Outcomes

Description: Serum samples were collected for evaluation of change in immunoreactive trypsinogen levels at Week 8.

Measure: Absolute Change From Baseline in Immunoreactive Trypsinogen Levels at Week 8

Time: Baseline and Week 8 of each treatment period, Up to 24 Weeks

Description: Fecal elastase-1 was used clinically to diagnose pancreatic exocrine insufficiency in participants with cystic fibrosis.

Measure: Absolute Change From Baseline in Fecal Elastase-1 Levels at Week 8

Time: Baseline and Week 8 of each treatment period, Up to 24 Weeks

Measure: Absolute Change From Baseline in Weight at Week 8

Time: Baseline and Week 8 of each treatment period, Up to 24 Weeks

Description: BMI was defined as weight in kilogram (kg) divided by height in square meter (m^2).

Measure: Absolute Change From Baseline in Body Mass Index (BMI) at Week 8

Time: Baseline and Week 8 of each treatment period, Up to 24 Weeks

Measure: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time: Baseline up to Month 15

30 A Phase 2, Randomized, Parallel-Group, Double-Blind, Placebo Controlled Study to Evaluate the Safety and Efficacy of CTP-656 With an Open-Label Active Comparator in Patients With Cystic Fibrosis With CFTR Gating Mutations.

This study will evaluate the efficacy and safety of CTP-656 in patients with cystic fibrosis (CF) who have a cystic fibrosis transmembrane conductance regulator (CFTR) gating mutation.

NCT02971839 Cystic Fibrosis Drug: CTP-656, 20 mg (QD) Drug: CTP-656, 100 mg (QD) Drug: CTP-656, 150 mg (QD) Drug: Placebo (QD) Drug: Kalydeco, 150 mg Tablet (BID; open-label)
MeSH:Cystic Fibrosis Fibrosis

Inclusion Criteria: - 18 years of age or older - Has a confirmed diagnosis of CF with at least one allele of the following CFTR gating mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, and S549R. --- G551D ---

Exclusion Criteria: - Acute upper respiratory infection or lower respiratory infection, pulmonary exacerbation, or changes in therapy within 4 weeks of study treatment - Uncontrolled type 2 diabetes, or uncontrolled CF-related diabetes - History of hepatitis C or chronic active hepatitis B infection - History of pulmonary tuberculosis, non-tuberculosis mycobacterial infections or allergic bronchopulmonary aspergillosis (ABPA) treated during screening or within 2 years prior to screening - Colonization with B. cenocepacia, B. dolosa, B. multivorans, and/or M. abcessus within 2 years prior to Screening - Abnormal liver function - History of abnormal renal function - History of prolonged QTcF > 450 msec for males or QTcF > 470 msec for females - History of solid organ or hematological transplantation - Using any inhibitor or inducer of cytochrome P450/3A during the study or within 30 days of screening - Women who are pregnant or lactating, or have plans to become pregnant during the study or within 1 month following the last dose Inclusion Criteria: - 18 years of age or older - Has a confirmed diagnosis of CF with at least one allele of the following CFTR gating mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, and S549R. --- G551D ---

Primary Outcomes

Measure: Change from baseline in sweat chloride at Day 28

Time: 28 days

Secondary Outcomes

Measure: Change from baseline in percent predicted FEV1 at Day 28

Time: 28 days

Measure: Change from baseline in CFQ-R Respiratory Domain at Day 28

Time: 28 days

31 A Phase IIa, Randomized, Double-blind, Placebo-controlled Study to Evaluate GLPG2222 in Ivacaftor-treated Subjects With Cystic Fibrosis Harbouring One F508del CFTR Mutation and a Second Gating (Class III) Mutation

This clinical study is a phase IIa, multi-center, randomized, double-blind, placebo-controlled, parallel group study to evaluate two doses of orally administered GLPG2222 in adult subjects with a confirmed diagnosis of CF harbouring one F508del CFTR mutation and a second gating (class III) mutation and on stable treatment with ivacaftor. Up to 35 evaluable subjects are planned to be included in the study. Eligible subjects must be on stable treatment with physician prescribed ivacaftor (Kalydeco®) for at least 28 days at the baseline visit. They will be randomized in a 2:2:1 ratio to receive one of two active doses of GLPG2222 (150 mg q.d. or 300 mg q.d.) or placebo q.d. administered for 29 days. Subjects will be in the study for a minimum of 6 weeks and a maximum of 10 weeks, from screening until the follow-up visit.

NCT03045523 Cystic Fibrosis Drug: GLPG2222 150 mg q.d. Drug: GLPG2222 300 mg q.d. Drug: Placebo
MeSH:Cystic Fibrosis Fibrosis

2. A confirmed clinical diagnosis of CF. 3. One F508del mutation on one allele in the CFTR gene, a gating (class III) mutation (one of the following: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) on the 2nd allele in the CFTR gene (documented in the subject's medical record or CF registry). --- G551D ---

Primary Outcomes

Description: To evaluate the safety and tolerability of GLPG2222 as compared to placebo in terms of adverse events

Measure: Changes in adverse events

Time: at screening and at each study visit up to day 43 which is the final FU visit

Description: To evaluate the safety and tolerability of GLPG2222 as compared to placebo in terms of laboratory

Measure: Changes in abnormal laboratory

Time: at screening and at each study visit up to day 43 which is the final FU visit

Description: To evaluate the safety and tolerability of GLPG2222 as compared to placebo in terms of vital signs, ECG or physical examination

Measure: Changes in abnormal vital signs, ECG or physical examination

Time: at screening and at each study visit up to day 43 which is the final FU visit

Secondary Outcomes

Measure: Change from baseline of Sweat chloride concentration

Time: at screening and at each study visit up to day 43 which is the final FU visit

Measure: Change from baseline of FEV1 (L) and percent predicted FEV1 for age, gender and height as assessed by spirometry

Time: at screening and at each study visit up to day 43 which is the final FU visit

Measure: Change from baseline on the respiratory domain of Revised Cystic Fibrosis Questionnaire (CFQ-R)

Time: at screening and at each study visit up to day 43 which is the final FU visit

32 A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Efficacy of Lumacaftor/Ivacaftor Combination Therapy in Subjects With Cystic Fibrosis Who Have an A455E-CFTR Mutation

This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter, crossover study that will evaluate the efficacy of LUM/IVA in subjects with CF 12 years of age and older who have at least one A455E mutation.

NCT03061331 Cystic Fibrosis Drug: LUM/IVA Drug: Placebo
MeSH:Cystic Fibrosis Fibrosis

- A G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H mutation on at least one CFTR allele. --- G551D ---

Primary Outcomes

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

Measure: Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 8

Time: Study Baseline, Through Week 8

33 A Randomized, Double-blind, Placebo-controlled, Crossover Study to Evaluate the Efficacy of Ivacaftor in Subjects With Cystic Fibrosis Who Are 6 Years of Age and Older and Have Either a 3849 + 10KB C→T or D1152H-CFTR Mutation

This study will evaluate the efficacy of ivacaftor treatment in subjects with CF 6 years of age and older who have a 3849 + 10KB C→T or D1152H CFTR mutation.

NCT03068312 Cystic Fibrosis Drug: Ivacaftor Drug: Placebo
MeSH:Cystic Fibrosis Fibrosis

Exclusion Criteria: - A G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H mutation. --- G551D ---

Primary Outcomes

Description: LCI2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value.

Measure: Change in Lung Clearance Index 2.5 (LCI2.5)

Time: From baseline through 8 weeks

34 A Randomized, Double-blind, Phase 2, Placebo Controlled Study to Determine the Safety and Efficacy of Ivacaftor (VX-770) for the Treatment of Chronic Obstructive Pulmonary Disease (The Topic Trial)

The study is a Phase 2 Study to establish the safety and efficacy of a drug called Ivacaftor (VX-770) in patients with chronic obstructive pulmonary disease (COPD), chronic bronchitis, and acquired CFTR dysfunction as detected by sweat chloride analysis. The design is a pilot, randomized (3:1, active:placebo), double-blind, placebo-controlled study. Approximately 40 subjects with COPD will be randomized.

NCT03085485 Chronic Obstructive Pulmonary Disease Chronic Bronchitis Drug: Ivacaftor 150 MG Drug: Placebo
MeSH:Lung Diseases Lung Diseases, Obstructive Pulmonary Disease, Chronic Obstructive Bronchitis Bronchitis, Chronic
HPO:Abnormal lung morphology Bronchitis Chronic bronchitis Chronic pulmonary obstruction Pulmonary obstruction

The method provides a robust measure of MCC, and has been sensitive to the effects of inhaled pharmacologic agents in CF and COPD including improvements of an unprecedentedly large magnitude in CF patients with the G551D-CFTR mutation treated with ivacaftor measured in a multicenter study. --- G551D ---

Primary Outcomes

Description: Safety of ivacaftor will be determined by number of participants with adverse events (including serious adverse events).

Measure: Safety of ivacaftor - number of participants with adverse events

Time: From Screening to Day 98

Description: Number of participants with abnormal serum chemistry values compared to screening values will also be used to determine safety of ivacaftor.

Measure: Safety of ivacaftor - number of participants with abnormal serum chemistry

Time: From Screening to Day 98

Description: Safety of ivacaftor will also be determined by number of participants with abnormal changes in their screening hematology values.

Measure: Safety of ivacaftor - number of participants with abnormal hematology

Time: From Screening to Day 98

Description: Number of participants with abnormal changes in their screening ECGs is another factor that will be used to evaluate the safety of ivacaftor.

Measure: Safety of ivacaftor - number of participants with abnormal ECG

Time: From Screening to Day 98

Secondary Outcomes

Description: Clearance of Tc99 sulfur colloid is a measure of MCC of the lungs, and is calculated by a standard protocol developed by the Cystic Fibrosis Therapeutics Development Network. The method provides a robust measure of MCC, and has been sensitive to the effects of inhaled pharmacologic agents in CF and COPD including improvements of an unprecedentedly large magnitude in CF patients with the G551D-CFTR mutation treated with ivacaftor measured in a multicenter study. The technique allows estimates of MCC in both the small and large airway compartments.

Measure: Central CFTR activity measured by Mucociliary Clearance (MCC)

Time: From Screening to Day 98

Description: Sweat chloride abnormality is correlated with COPD severity and symptoms, and is a highly sensitive outcome measure for CFTR-directed therapeutics. We have shown sweat chloride is sensitive to the presence of cigarette smoking and COPD, and the test has been successfully used as an endpoint in multiple CF trials, including studies to detect the efficacy of ivacaftor therapy.

Measure: Peripheral CFTR activity measured by Sweat Chloride

Time: From Screening to Day 98

Description: Spirometry is a standard outcome measure in COPD and a major indicator of efficacy and safety in COPD clinical trials. Post-bronchodilator spirometry will be performed by ATS criteria. FEV1 will be measured in liters (L).

Measure: Indicators of respiratory function and COPD health : Change in FEV1

Time: From Screening to Day 98

Description: Spirometry is a standard outcome measure in COPD and a major indicator of efficacy and safety in COPD clinical trials. Post-bronchodilator spirometry will be performed by ATS criteria. FVC will be measured in liters (L).

Measure: Indicators of respiratory function and COPD health : Change in FVC.

Time: From Screening to Day 98

Description: The SOBQ is a self-reported questionnaire that assesses shortness of breath while performing a variety of activities of daily living. The Minimum Clinically Important Difference (MCID) is 5.

Measure: San Diego Shortness of Breath Questionnaire (SOBQ)

Time: From Screening to Day 98

Description: The BCSS is a three-item questionnaire rating breathlessness, cough and sputum on a 5-point Likert scale from 0 (no symptoms) to 4 (severe symptoms).

Measure: Breathlessness, Cough, and Sputum Scale (BCSS)

Time: From Screening to Day 98

Description: CAT is a self reported questionnaire that measures COPD related quality of life. The MCID is 2.

Measure: COPD Assessment Test (CAT)

Time: From Screening to Day 98

Description: The SGRQ is a disease-specific measure of health status for use in COPD with an MCID of 4.

Measure: St. George Respiratory Questionnaire (SGRQ)

Time: From Screening to Day 98

35 Anti-Inflammatory Therapy to Augment CFTR Rescue in CF Patients

The goal of this study is to execute a small clinical proof of concept trial: To examine the effects of losartan on mucociliary clearance (MCC) in patients not eligible for CFTR rescue therapies

NCT03435939 Cystic Fibrosis Drug: Losartan
MeSH:Cystic Fibrosis Fibrosis

The CFTR potentiator ivacaftor (Kalydeco™), approved by the FDA mainly for class III mutations especially G551D, improves ion transport (large decrease in sweat chloride), clinical outcome (increased FEV1 and weight, decreased exacerbations), and quality of life. --- G551D ---

Primary Outcomes

Description: Losartan (100 mg for >12 weeks) will improve MCC+CC clearance in CF patients not on CFTR augmentation therapy in % of baseline

Measure: Improvement of mucociliary clearance ( MCC) and cough clearance (CC)

Time: 12 weeks treatment

Secondary Outcomes

Description: forced expiratory volume at one second (FEV1) in %predicted

Measure: Improvement on pulmonary function tests (in %predicted)

Time: 12 weeks of treatment

Description: forced expiratory volume at one second (FEV1) in liters

Measure: Improvement on pulmonary function tests (in L)

Time: 12 weeks of treatment

Description: Changes in serum inflammatory markers (hsCRP, WBC including absolute neutrophil count, %PMNs, serum amyloid A or SAA, calprotectin, GM-CSF, TGF-β active and total)

Measure: Decrease of inflammatory markers

Time: 12 weeks

Description: Nasal cytokine changes (TGF-β1 active and total, TNF-α, IL-1β, IL-6, IL-8, IL-13, COX-2)

Measure: Nasal cytokine changes

Time: 12 weeks

36 Ivacaftor for Acquired CFTR Dysfunction in Chronic Rhinosinusitis (Randomized Pilot Study Utilizing Ivacaftor for the Treatment of Refractory Gram-Negative Bacterial CRS)

The purpose of this pilot study is to explore wither ivacaftor in refractory CRS patients will demonstrate safety and tolerability; restore CFTR-mediated Cl- secretions as measured by EDSPD testing; produce detectable improvements in validated measures of CRS including the SNOT-22 questionnaire, Lund-MacKay CT scan grading, and Lund-Kennedy endoscopic scores; and provide beneficial effects on readily measured markers of sinonasal inflammation and infection (IP-10, IL-8, and Pseudomonas CFUs).

NCT03439865 Chronic Rhinosinusitis (Diagnosis) Drug: Ivacaftor Drug: standard of care treatment
MeSH:Sinusitis
HPO:Sinusitis

Other mutations, such as the class III mutation Gly551Asp (G551D), result in adequate levels of CFTR protein at the apical cell surface, but exhibit defective function. --- Gly551Asp ---

Other mutations, such as the class III mutation Gly551Asp (G551D), result in adequate levels of CFTR protein at the apical cell surface, but exhibit defective function. --- Gly551Asp --- --- G551D ---

New compounds such as ivacaftor, which modify channel gating of WT-CFTR, F508del-CFTR, G551D-CFTR and nonsense mutations after induction of translational readthrough (i.e. --- G551D ---

The drug was licensed in 2012 both in the United States and Europe for patients with CF aged six years and over (now 2 years and over) who carry at least one copy of the G551D mutation. --- G551D ---

The efficacy and safety of ivacaftor in CF patients with at least one G551D mutation has been evaluated in two large, multicenter, randomized, double-blind, placebo-controlled trials. --- G551D ---

Since ivacaftor also ameliorates clinical disease of patients with non-G551D gating mutations, the drug does not confer activity to one specific mutation and thus should be effective potentiating ion transport regardless of external influences that impact function of the CFTR. --- G551D ---

Ivacaftor is a CFTR potentiator that has been approved by the FDA for treatment of CF individuals with at least one copy of the G551D mutation. --- G551D ---

Primary Outcomes

Description: Comparison of 22-tem Sino-Nasal Outcomes Test (SNOT-22) scores collected at Screening, Day 1, Day 14, and Day 30. The SNOT-22 is a 22-item questionnaire about rhinosinusitis symptoms and the social/emotional consequences for quality of life. The Likert scale ranges from 1-5, where 1 = "No Problem" and 5 = "Problem as bad as it can be." A total score is collected, ranging from 0-110; the higher the score, the worse the outcome.

Measure: Improvement in quality of life measures

Time: Screening to Day 30

37 Lum-Iva-biota: Exploring the Respiratory Mycobiota and Microbiota Profile in French CF Patients Taking Lumacaftor-Ivacaftor

n2015, VERTEX company - producing already KALYDECO (IVACAFTOR, VX-770) potentiator molecule that is recommended for the treatment of CF patients aged ≥ 6 y, with CFTR mutation altering the channel regulation (class III mutations) as G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549Nou S549R) -was allowed by the Federal Drug Administration (FDA) and European Medicines Agency (EMEA) for producing and using ivacaftor combination (such as lumacaftor/ ivacaftor initially, and more recently tezacaftor/ivacaftor, tezacaftor/ivacaftor/VX-659, tezacaftor/ivacaftor/VX-445 and tezacaftor/ivacaftor/VX-152) in clinical trials for patient with cystic fibrosis, according to age and mutation eligibility criteria. Since 2016, the French patients homozygous for the p.Phe508del mutation and older than 12 years are able to be treated with the association LUMACAFTOR-IVACAFTOR and this French authorization is being extended for 6-11 years old children (while the European Commission has already granted an extension of the Marketing Authorization for lumacaftor/ivacaftor to include 6-11 years old children with cystic fibrosis since January 2018). Patients treated by lumacaftor/ivacaftor (or other ivacaftor new combinations) are closely monitored according to criteria established by the working group "New Therapeutic Approaches" of the French Society Cystic fibrosis. This study is a phase IV observational trial for a period of 1 year. In this context, the team aims at initiating a comprehensive monitoring of the lung and gut mycobiota and microbiota evolution under LUMACAFTOR-IVACAFTOR (or other ivacaftor combinations) treatment. This project is directly linked to the monitoring of cystic fibrosis patients who begin treatment with LUMACAFTOR-IVACAFTOR (or other ivacaftor combinations) in France. The pro- and eukaryotic microbiota analysis is based on the secondary use of sputum and stool samples associated with several clinical data of CF patients under ivacaftor combinations and follow-up during the 1st year of therapy. According to the French law, Lum-Iva-Biota project is a non-interventional study. It aims at demonstrating that changes in the hydration of secretions at the pulmonary and intestinal levels related to LUMACAFTOR-IVACAFTOR therapy (or other new generation of ivacaftor combinations) promote a change in the lung and gut mycobiota and microbiota profiles which may achieve the characteristics of the "healthy type" (in terms of composition, richness and diversity).

NCT03565692 Cystic Fibrosis Biological: the lung mycobiota and microbiota profile Biological: the gut mycobiota and microbiota profile
MeSH:Cystic Fibrosis Fibrosis

Lum-Iva-biota: Exploring the Respiratory Mycobiota and Microbiota Profile in French CF Patients Taking Lumacaftor-Ivacaftor. Lum-Iva-biota: Exploring the Respiratory Mycobiota and Microbiota Profile in French CF Patients Taking Lumacaftor-Ivacaftor n2015, VERTEX company - producing already KALYDECO (IVACAFTOR, VX-770) potentiator molecule that is recommended for the treatment of CF patients aged ≥ 6 y, with CFTR mutation altering the channel regulation (class III mutations) as G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549Nou S549R) -was allowed by the Federal Drug Administration (FDA) and European Medicines Agency (EMEA) for producing and using ivacaftor combination (such as lumacaftor/ ivacaftor initially, and more recently tezacaftor/ivacaftor, tezacaftor/ivacaftor/VX-659, tezacaftor/ivacaftor/VX-445 and tezacaftor/ivacaftor/VX-152) in clinical trials for patient with cystic fibrosis, according to age and mutation eligibility criteria. --- G551D ---

In 2015, the American company VERTEX - producing already KALYDECO (IVACAFTOR, VX-770) potentiator molecule that is recommended for the treatment of CF patients aged ≥ 6 y, with mutation altering the channel regulation (class III mutations) as G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549Nou S549R) - was allowed by the Federal Drug Administration (FDA) and European Medicines Agency (EMA) for producing and using LUMACAFTOR-IVACAFTOR in clinical trials to manage CF patients over 12 years and having two p.Phe508del mutations. --- G551D ---

Primary Outcomes

Description: Measure by conventional methods (history of microbial culture and GM assay) and particularly by metagenomic analysis of pulmonary pro- and eukaryotic microbiota.

Measure: Change of specific bacterial and/or fungal pathogens

Time: 18 months

Secondary Outcomes

Description: Difference between the amount of air exhaled may be measured during the first second

Measure: Forced expiratory volume in 1 second (FEV1)

Time: Day 1

Description: Difference between the amount of air exhaled may be measured during the first second

Measure: Forced expiratory volume (FEV1)

Time: 6 Months

Description: Difference between the amount of air exhaled may be measured during the first second

Measure: Forced expiratory volume (FEV1)

Time: 12 Months

Description: Measure by conventional methods (history of microbial culture and GM assay) and particularly by metagenomic analysis of lung pro- and eukaryotic microbiota.

Measure: Change of specific bacterial and/or fungal pathogens

Time: 12 months

Description: Measure by metagenomic analysis of gut pro- and eukaryotic microbiota.

Measure: Change of specific bacterial and/or fungal pathogens

Time: 12 months

38 Impact of the Introduction of ORKAMBI on Anxiety, Depression, Quality of Life and Adherence of Adolescents and Young Adults

The aim of this project is to evaluate the psychological reshuffle induced by ORKAMBI. The particular focus of this study is the consequence of its introduction on anxiety, depression, quality of life and adherence to all cystic fibrosis (CF) treatment. To answer this question investigators will monitor the psychological function of CF adolescents and young adults treated with ORKAMBI and compare them to CF adolescents and young adults not treated with ORKAMBI.

NCT03659214 Cystic Fibrosis Behavioral: Questionnaires
MeSH:Cystic Fibrosis Fibrosis Depression

Inclusion Criteria: - Treated group: Patients with proven CF (sweat-test > 60 mEq, 2 DF508 CF causing mutations, 12 to 20 years, and treated with ORKAMBI - Control group: Patients not carrying 2 DF508 CF causing mutations, not treated with ORKAMBI, and not carrying the G551D, G178R, S549N, S549R, G551S, G1244E,S1251N, S1255P or G1349D mutation or treated with Kalydeco Exclusion Criteria: - Transplanted patients - Patients younger than 12 years - Patients older than 20 years Inclusion Criteria: - Treated group: Patients with proven CF (sweat-test > 60 mEq, 2 DF508 CF causing mutations, 12 to 20 years, and treated with ORKAMBI - Control group: Patients not carrying 2 DF508 CF causing mutations, not treated with ORKAMBI, and not carrying the G551D, G178R, S549N, S549R, G551S, G1244E,S1251N, S1255P or G1349D mutation or treated with Kalydeco Exclusion Criteria: - Transplanted patients - Patients younger than 12 years - Patients older than 20 years Cystic Fibrosis Cystic Fibrosis Fibrosis Depression Introduction of KALYDECO then ORKAMBI, as a personalized medicine in the therapeutic strategy of Cystic Fibrosis (CF) may deeply modify the prognosis of patients with CF. --- G551D ---

Inclusion Criteria: - Treated group: Patients with proven CF (sweat-test > 60 mEq, 2 DF508 CF causing mutations, 12 to 20 years, and treated with ORKAMBI - Control group: Patients not carrying 2 DF508 CF causing mutations, not treated with ORKAMBI, and not carrying the G551D, G178R, S549N, S549R, G551S, G1244E,S1251N, S1255P or G1349D mutation or treated with Kalydeco Exclusion Criteria: - Transplanted patients - Patients younger than 12 years - Patients older than 20 years Inclusion Criteria: - Treated group: Patients with proven CF (sweat-test > 60 mEq, 2 DF508 CF causing mutations, 12 to 20 years, and treated with ORKAMBI - Control group: Patients not carrying 2 DF508 CF causing mutations, not treated with ORKAMBI, and not carrying the G551D, G178R, S549N, S549R, G551S, G1244E,S1251N, S1255P or G1349D mutation or treated with Kalydeco Exclusion Criteria: - Transplanted patients - Patients younger than 12 years - Patients older than 20 years Cystic Fibrosis Cystic Fibrosis Fibrosis Depression Introduction of KALYDECO then ORKAMBI, as a personalized medicine in the therapeutic strategy of Cystic Fibrosis (CF) may deeply modify the prognosis of patients with CF. --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G1244E --- --- S1255P --- --- G1349D --- --- G551D ---

Primary Outcomes

Description: to assess the impact on Anxiety

Measure: Score of Generalized Anxiety Disorder-7 questionnaire (GAD-7)

Time: 24 months

Secondary Outcomes

Description: To assess the impact on Depression

Measure: Score of Patient Health Questionnaire-9 (PHQ-9 )

Time: 24 months

Description: Disease-specific instrument designed to measure impact on overall health, daily life, perceived well-being and symptoms (Quality of Life)

Measure: Scores of Cystic Fibrosis Questionnaire 14+ (CFQ 14+)

Time: 24 months

Description: The 6 items are assessed using a YES/NO answer .The scale was validated in patients with chronic disease to assess medication adherence

Measure: GIRERD Scale

Time: 24 months

39 Nutritional Impact of Ivacaftor Treatment in 6 Month to 2 Year Old Children With CF Gating Mutations

The purpose of this research study is to determine the effects of clinically prescribed ivacaftor treatment on 6-24 month old children with CF and gating mutations on sleeping energy expenditure, growth status and gut health and function.

NCT03783286 Cystic Fibrosis Drug: Ivacaftor
MeSH:Cystic Fibrosis

Each value will be used to calculate the growth velocity percentile of the subjects over the course of 12 weeks on ivacaftor treatment compared to baseline.. Inclusion Criteria: - Cystic fibrosis with at least one CFTR gating mutation (E56K, G178R, S549R, S977F, F1074L, 2789+5G→A,P67L, E193K, G551D, F1052V, D1152H, 3272-26A→G, R74W, L206W, G551S, K1060T, G1244E, 3849+10kbC→T, D110E, R347H, D579G, A1067T, S1251N, D110H, R352Q, 711+3A→G, G1069R, S1255P, R117C, A455E, E831X, R1070Q, D1270N, R117H, S549N, S945L, R1070W, G1349D) approved for treatment - Age: 6-24 months of age - In their usual state of good health - A clinical decision has been made for subject to begin ivacaftor treatment - Family committed to the 4 to 6 month study protocol with visits to CHOP that will last 2 or 3 days for the baseline visit (Visit 1) prior to ivacaftor and the 12 week visit (Visit 3) after clinically prescribed ivacaftor treatment has begun, and will last 2 days for the 6 week visit (Visit 2) after ivacaftor treatment has begun. --- E56K --- --- G178R --- --- S549R --- --- S977F --- --- F1074L --- --- P67L --- --- E193K --- --- G551D ---

Exclusion Criteria: - On parenteral nutrition - Use of any medications which are as inhibitors or inducers of cytochrome P450 (CYP) 3A - Liver function tests elevated above 3x the reference range for age and sex - Other illness affecting growth or nutritional status - Other contraindications described for ivacaftor therapy Inclusion Criteria: - Cystic fibrosis with at least one CFTR gating mutation (E56K, G178R, S549R, S977F, F1074L, 2789+5G→A,P67L, E193K, G551D, F1052V, D1152H, 3272-26A→G, R74W, L206W, G551S, K1060T, G1244E, 3849+10kbC→T, D110E, R347H, D579G, A1067T, S1251N, D110H, R352Q, 711+3A→G, G1069R, S1255P, R117C, A455E, E831X, R1070Q, D1270N, R117H, S549N, S945L, R1070W, G1349D) approved for treatment - Age: 6-24 months of age - In their usual state of good health - A clinical decision has been made for subject to begin ivacaftor treatment - Family committed to the 4 to 6 month study protocol with visits to CHOP that will last 2 or 3 days for the baseline visit (Visit 1) prior to ivacaftor and the 12 week visit (Visit 3) after clinically prescribed ivacaftor treatment has begun, and will last 2 days for the 6 week visit (Visit 2) after ivacaftor treatment has begun. --- E56K --- --- G178R --- --- S549R --- --- S977F --- --- F1074L --- --- P67L --- --- E193K --- --- G551D ---

Primary Outcomes

Description: Investigators will examine the effects of 12 weeks of Ivacaftor treatment on subject's SEE. Using indirect calorimetry, SEE will be assessed using a computerized metabolic cart Vmax ENCORE at each protocol visit while the child is asleep. SEE will be assessed in the morning if possible and careful note of previous feeding of the child, including the time of day, amount of food, and feeding interval prior to test

Measure: Sleeping Energy Expenditure

Time: 12 Weeks

Description: Investigators will examine the effects of 12 weeks of Ivacaftor treatment on subject's BMI. Investigators will compare the results to BMI Z scores over 12 weeks compared to baseline.

Measure: Anthropometric Assessment

Time: 12 Weeks

Secondary Outcomes

Description: Investigators will examine the effects of 12 weeks of Ivacaftor treatment on subject's pancreatic function. Pancreatic function will be assessed at two visits by obtaining spot stool samples with fecal elastase 1. The concentration of fecal elastase I is indicative of pancreatic function.

Measure: Fecal Elastase I/Pancreatic Function

Time: 12 Weeks

Description: Investigators will examine the effects of 12 weeks of Ivacaftor treatment on subject's gut health and function. Spot stool samples will be obtained to determine fecal calprotectin, a marker for gut inflammation.

Measure: Fecal Calprotectin/Gut Inflammation

Time: 12 Weeks

Description: Investigators will examine the effects of 12 weeks of Ivacaftor treatment on subject's dietary fat absorption. A total plasma fatty acid panel will be assessed to measure the change in status of 22 fatty acids, the concentration of plasma fatty acids is indicative of dietary fat absorption.

Measure: Plasma Total Fatty Acids:

Time: 4 to 6 months

Other Outcomes

Description: Three day weighed food record will be obtained and to determine changes in dietary caloric intake and micro and macronutrient intake over the course of 12 weeks on ivacaftor treatment. The weighed food in grams will be used to determine the calories consumed, as well as calories from fat. The caloric intake will be used to determine micro and macro nutrient intake.

Measure: Dietary Intake

Time: 12 Weeks

Description: Investigators will examine the changes in serum vitamin A, E, D and K concentrations after 12 weeks of Ivacaftor treatment. Additionally, investigators will examine the changes in total serum bile acids concentration and 14 bile acid species. Additionally, serum calprotectin will be obtained as a marker of lung and gut inflammation.

Measure: Serum fat soluble vitamins A, D, E and K, bile acids, and serum calprotectin

Time: 12 Weeks

Description: Investigators will measure body composition to determine muscle and fat store changes over the course of 12 weeks on ivacaftor treatment compared to baseline.

Measure: Muscle/Fat Stores

Time: 12 Weeks

Description: Investigators will observe the changes in growth status/growth velocity. This will be assessed amongst three different measurements- length (cm), weight (kg) and head circumference (cm). Each value will be used to calculate the growth velocity percentile of the subjects over the course of 12 weeks on ivacaftor treatment compared to baseline.

Measure: Growth Status/Growth Velocity

Time: 12 Weeks

40 Gastrointestinal Outcome Measures Before and After Orkambi Therapy in Cystic Fibrosis (CF) Patients Carrying the F508del Mutation on Both Alleles

Ivacaftor caused a significance increase in weight in patients carrying the G551D mutation and the etiology of this has largely remained unknown but may be due to improved function of the gastrointestinal tract. The combination therapy of Orkambi has been recently approved for subjects with Cystic Fibrosis homozygous for F508del mutation. This provides an opportunity to examine if there are any improvements in gastrointestinal function. The investigators aim to investigate various aspects of gastrointestinal and pancreatic function before and 6 months after the commencement of Orkambi therapy.

NCT03859531 Cystic Fibrosis
MeSH:Cystic Fibrosis Fibrosis

Gastrointestinal Study at Orkambi Therapy in CF Patients Ivacaftor caused a significance increase in weight in patients carrying the G551D mutation and the etiology of this has largely remained unknown but may be due to improved function of the gastrointestinal tract. --- G551D ---

Primary Outcomes

Description: Is a marker of intestinal inflammation measured in the stool

Measure: Concentration of fecal calprotectin

Time: Change from baseline at 6 months after commencing treatment with Orkambi

Description: Is a test of pancreatic function measured in the stool.

Measure: Concentration of fecal elastase-1

Time: Change from baseline at 6 months after commencing treatment with Orkambi

Description: The method of SBCE has been well established as a descriptive diagnostic tool for intestinal inflammation and has been used as an outcome measure in clinical trials. Erythema, petechiae, mucosal erosions and ulcerations will be assessed according to the Maiden criteria

Measure: Change in small bowel capsule endoscopy (SBCE)

Time: Change from baseline at 6 months after commencing treatment with Orkambi

Secondary Outcomes

Description: Inflammatory marker, unit mg/L.

Measure: Change in CRP

Time: Change from baseline at 6 months after commencing treatment with Orkambi

Description: Inflammatory marker, unit mm.

Measure: Change in sedimentation rate

Time: Change from baseline at 6 months after commencing treatment with Orkambi

Description: Inflammatory markers: alpha-1-antitrypsin, haptoglobin, orosomucoid, immunoglobulin A, M and G.

Measure: Concentration of serum electrophoresis.

Time: Change from baseline, 6 months after commencing treatment with Orkambi

Description: ALT, AST, ALP, gamma-GT. Unit: mikrokat/L

Measure: Change in liver function tests

Time: Change from baseline at 6 months after commencing treatment with Orkambi

Description: Bilirubin. Unit: mikromol/L

Measure: Change in bilirubin

Time: Change from baseline at 6 months after commencing treatment with Orkambi

41 A Phase 2, Randomized, Double-blind Study to Evaluate the Efficacy and Safety of VX-561 in Subjects Aged 18 Years and Older With Cystic Fibrosis

The purpose of this study is to evaluate the efficacy, safety, pharmacodynamic (PD) and pharmacokinetic (PK) effect of VX-561.

NCT03911713 Cystic Fibrosis Drug: VX-561 Drug: IVA Drug: Placebo Drug: Placebo
MeSH:Cystic Fibrosis Fibrosis

Key Inclusion Criteria: - Must have 1 of the following 9 CFTR mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D - On ivacaftor therapy - FEV1 value ≥40% and ≤100% of predicted mean for age, sex, and height Key Exclusion Criteria: - History of clinically significant cirrhosis with or without portal hypertension - History of solid organ or hematological transplantation - Lung infection with organisms associated with a more rapid decline in pulmonary status Other protocol defined Inclusion/Exclusion criteria may apply Key Inclusion Criteria: - Must have 1 of the following 9 CFTR mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D - On ivacaftor therapy - FEV1 value ≥40% and ≤100% of predicted mean for age, sex, and height Key Exclusion Criteria: - History of clinically significant cirrhosis with or without portal hypertension - History of solid organ or hematological transplantation - Lung infection with organisms associated with a more rapid decline in pulmonary status Other protocol defined Inclusion/Exclusion criteria may apply Cystic Fibrosis Cystic Fibrosis Fibrosis null --- G551D ---

Key Inclusion Criteria: - Must have 1 of the following 9 CFTR mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D - On ivacaftor therapy - FEV1 value ≥40% and ≤100% of predicted mean for age, sex, and height Key Exclusion Criteria: - History of clinically significant cirrhosis with or without portal hypertension - History of solid organ or hematological transplantation - Lung infection with organisms associated with a more rapid decline in pulmonary status Other protocol defined Inclusion/Exclusion criteria may apply Key Inclusion Criteria: - Must have 1 of the following 9 CFTR mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D - On ivacaftor therapy - FEV1 value ≥40% and ≤100% of predicted mean for age, sex, and height Key Exclusion Criteria: - History of clinically significant cirrhosis with or without portal hypertension - History of solid organ or hematological transplantation - Lung infection with organisms associated with a more rapid decline in pulmonary status Other protocol defined Inclusion/Exclusion criteria may apply Cystic Fibrosis Cystic Fibrosis Fibrosis null --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G1244E --- --- S1251N --- --- S1255P --- --- G1349D --- --- G551D ---

Primary Outcomes

Measure: Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1)

Time: From Baseline at Week 12

Secondary Outcomes

Measure: Absolute change in sweat chloride concentrations

Time: From Baseline at Week 12

Measure: Maximum observed concentration (Cmax) of VX-561, IVA, and relevant metabolites

Time: From Baseline up to Week 16

Measure: Area under the concentration versus time curve during a dosing interval (AUCtau) of VX-561, IVA, and relevant metabolites

Time: From Baseline up to Week 16

Measure: Observed pre-dose concentration (Ctrough) of VX-561, IVA, and relevant metabolites

Time: From Baseline up to Week 16

Measure: Safety and tolerability as assessed by number of subjects with adverse events (AEs) and serious adverse events (SAEs)

Time: From baseline up to Week 16

42 Response to CFTR-modulators in Intestinal Organoids of Patients With CF Having at Least One R334W Mutation

In contrary to what is seen in FRT cells, rectal organoids of patients with a R334W mutation do respond to CFTR modulators ivacaftor and lumacaftor. The present study will investigate the response to modulators in organoids of 30 patients with CF and a R334W mutation, to allow further stratificaton for a future clinical trial assessing the clinical effect of ivacaftor/tezacaftor in patients with CF and a R334W mutation.

NCT04254705 Cystic Fibrosis Procedure: Rectal Biopsy
MeSH:Cystic Fibrosis

Exclusion Criteria: - A potential subject who meets any of the following criteria will be excluded from participation: 1. Subject has one of the following CFTR-mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, R117H, P67L, R117C, L206W, R352Q, A455E, D579G, 711+3A>G, S945L, S977F, R1070W, D1152H, 2789+5G>A, 3272 26A>G, 3849+10kbC>T 2. A history of hemorrhoids and recent rectal bleeding 3. FEV1 above 90% predicted or below 30% predicted during stable disease 4. History of lung transplantation. --- G551D ---

Primary Outcomes

Description: Response to tezacaftor+ivacaftor in the Forskolin Induced Swelling (FIS) assay in rectal organoids

Measure: Response to CFTR-modulator in Intestinal Organoids: Increase in Forskolin induced swelling by addition of tezacaftor+ivacaftor after stimulation with Forskolin (0.8 µmol/L)

Time: At study completion (when rectal biopsy is performed or when organoids are retrieved from the biobank and FIS has been performed), an average of 2 months


HPO Nodes


HP:0004324: Increased body weight
Genes 529
SHOX HACE1 THOC2 LIMK1 FMR1 SOX3 PHF6 CLCN4 IFT172 TNFSF4 PDX1 KCNAB2 AGRP GNAS ADCY3 HLA-DRB1 AFF4 REEP6 PRPF6 KLF11 KIAA1549 ARL6 DNM2 ELN MKS1 PWAR1 IFT27 SDC3 LIPE SYNE2 RAB39B FGF8 ARHGEF6 RDH12 ZNF408 BRAF SH2B1 BPTF HLA-DQB1 ANOS1 LMNA TRIM32 ARX AKT1 KIF7 TRIP12 FIBP SLC7A7 IL1RAPL1 SHANK3 INS EGF CFI RAI1 SYNE1 GNAS ATP6AP2 MTOR XRCC4 SLC7A14 GNAS HDAC8 BBS2 HSD11B1 MC4R AGBL5 ANK3 KMT2D ACADVL BBS4 MEGF8 CYP7A1 RAD21 PIGN ARVCF BEST1 RPS6KA3 ZNF365 ADRB3 CRX MID2 ATRX NDN UCP3 IQSEC2 SKI RBP3 CNGB1 RAB23 ZNF513 SLC25A4 FLRT3 FIBP KISS1R CCDC141 IFT140 TSPAN7 CCDC141 RAI1 ARMC5 TRAF3IP1 TP53 LZTFL1 SUFU OFD1 MAGEL2 SMC1A AKT2 GNAS ARL6 GTF2IRD1 UFD1 TRIM32 CDHR1 NF2 MEGF8 SNORD115-1 WT1 HACE1 SH2B1 CNGA1 DHDDS RFC2 PSMD12 SMO KIZ HNF1A NTRK2 BBS10 DCC PRPF8 FOXP1 EP300 SOX10 POU3F4 DIS3L2 BAP1 TMEM43 NEK2 DEAF1 GNAS-AS1 BBS9 SIN3A SNRPN MAK FGFR1 PHF6 CLIP2 BBS2 COMT BBS2 HESX1 MTOR HESX1 GNAS PRKACA JMJD1C TCF20 MCM3AP NEUROD1 LZTFL1 ARL6 CFH ABCA4 C8ORF37 GHR TMEM67 USP8 AP4B1 UCP2 HIRA LEP IQSEC2 CERKL NRL PAX6 TBX1 SRY H6PD CREBBP PRKAR1A PROM1 ZNF41 PCSK1 RYR1 PCSK1 EHMT1 IMPDH1 CNNM2 RNPC3 C8ORF37 ZNF711 LEPR TTC8 ALMS1 PRCD PROKR2 ELN PNPLA6 MTMR14 PAX4 MKKS GATA4 SYP EDNRB VPS13B FGF17 PRPF4 HNF1A CA4 GDI1 TUB POMC AIP TTC8 ENPP1 KIDINS220 SLC9A7 CEP164 NSD1 NR2E3 TBX1 HNF4A PWRN1 MC3R KIDINS220 USP7 KMT2A BDNF MTTP PCARE ARL6 POMC SUFU PIGT P2RY11 IQSEC2 BBS10 RAB23 KCNJ18 PDE4D BBS9 HDAC4 TUB XYLT1 SEC24C PDSS1 HGSNAT EIF2S3 IGF1R MAGEL2 IPW FTO GCK SPRY4 KCNJ11 PRMT7 ARHGEF18 DYRK1B XYLT1 RP1 GNAS CLRN1 AHR MED12 HDAC8 CTSH BRAF TTC8 ABCC9 PNKP IFT172 FGFR1 SIM1 MKKS FTSJ1 MAPK8IP3 ALB IFT74 ALMS1 GUCA1B UPF3B ATRX PDE6G CTNNB1 CCDC28B HERC1 SETD2 SLC10A7 APOE NIPBL BBS7 RAI1 GLI3 HCFC1 PRDM16 TOPORS WDR11 BBS5 IDH3B PIK3CA SCAPER MYF6 ARL2BP SPG11 IGSF1 CXORF56 ADRB2 HS6ST1 RREB1 LAS1L PDE6B AP4M1 BLK UBE2A IL17RD ADNP TBX3 NPAP1 P4HTM TMCO1 EIF2S3 PRPF3 CARTPT SMC3 POMC SPATA7 SH3KBP1 MECP2 CYP19A1 BBS12 MKS1 NKAP HDAC8 RERE PRKAR1A TAF1 UBE3A MLXIPL KCNJ11 KCNJ11 INPP5E HCRT IGF1 ABCC8 RPGR HNF4A APC2 CNKSR2 PIGA BLK BIN1 PRMT7 MC4R PPARG RPS6KA3 HUWE1 BAZ1B PDGFB PROKR2 NIN AHI1 RBMX SOX2 SAG MECP2 TRAF7 WDPCP HERC2 ABCC8 GP1BB TRAPPC9 BBS12 CEP290 TRIP4 ADNP MKRN3-AS1 PTCHD1 ACSL4 CUL4B BAP1 NR0B2 PROK2 TERT PCNT PCNT EYS WT1 FGFR3 IFT27 RGR GTF2I ZNF711 SDCCAG8 EMD LAS1L CACNA1S GNAS DHX38 IDH3A USP27X DYNC2I2 PIGT MEN1 ATP7B THOC2 PDE4D TACR3 LEPR RHO POGZ MRAP2 EXOC6B BBS5 ZBTB20 PIGL FOXP1 AP4S1 RP9 PTCH1 BBS7 SH2B1 KLHL7 EHMT1 DNMT3A ARMC5 RLBP1 ALG13 AGTR2 HNF4A MYT1L VPS13B CDH23 PAX6 PAK3 SMARCB1 THRA LEP BBS4 ARL13B DUSP6 MKRN3 TRAPPC9 AFF4 SDCCAG8 TBX1 GHRL BBS1 STX16 BBIP1 USH2A MOG LMNA PROK2 OFD1 SIM1 FLII RP2 SETD5 MOG FRMPD4 DPYD IFT172 APPL1 ARNT2 SNORD116-1 NSMF BBS1 DLG3 AP4E1 FAM161A RPE65 PDE4D PRPH2 ROM1 TBL2 OTX2 FHL1 RNF135 ERMARD C8ORF37 NPHP1 CEP19 DMD SEMA4A HELLPAR ARL3 PHIP CEL MAN1B1 LRAT CANT1 GABRD TULP1 SNRNP200 IFT88 MTFMT AKT2 FSCN2 CEP290 MERTK SEMA3A BBIP1 PDE11A CHD7 IMPG2 POMGNT1 SMARCE1 CD46 ABCC8 SMAD4 IFT172 MAN1B1 CUL4B USP9X PRPF31 PTEN KDM6A IGFALS WNT4 SETD2 GNAS TBX3 PDE6A FEZF1 USP8 CRB1 ZNF81 GABRA3
Protein Mutations 1
G551D
HP:0002088: Abnormal lung morphology
Genes 1242
CCDC39 KMT2D FGFR3 GLI3 PRSS1 RAG1 DSG1 ELP1 TSC2 IL17F NEK9 BLNK BACH2 ARHGAP31 SGSH ARID1B PTEN STK11 STAT3 SPINK1 CD19 DNAH1 AICDA RRAS2 MEFV CASP10 CTLA4 PDGFRA GATA6 SFTPC FOXN1 GPR35 MED25 DYNC2LI1 RAG2 CBL STAT3 TTC37 ATM LTBP3 STN1 RSPH3 GLA WDR35 REN LAT KRAS CCR1 TYK2 BGN NR5A1 CCR6 TTC7A GPC3 LGI4 IL6 GAS8 DGCR8 COLQ TCF4 COL11A2 RUNX1 BCOR ORC6 DCLRE1C SERPINA1 SLC7A7 HRAS TBX1 GBA RNF113A ICOS SETBP1 CFI IRF2BP2 MYBPC3 CEP57 CHST14 CHRND CEP120 ESS2 BMP15 HPS4 BCOR IFT43 GBA BCL2 MRAS DICER1 MECP2 WRN GLB1 CSF2RB SELENON CHRNG BCOR INPPL1 CD3G ACADVL PAX3 SFTPC NSMCE3 AGA CCDC65 POU6F2 HGSNAT C4A SFTPB NFIX BUB3 MARS1 GREB1L SLC26A2 EXOSC9 FCGR2A DYNC2I1 ABCA12 TRIP11 DGCR6 MST1 DSE NCF4 FGFR1 ARSB LYST RAG1 TPP2 RAG2 PHGDH EDNRB SCNN1A EVC2 ITCH DICER1 WDR19 WNT4 SFTPA2 WT1 IGHM DNAAF4 CRTAP OCRL TP53 CFB TNNI3 TINF2 DCLRE1C MAGEL2 ATP11A LTBP4 TAF1 SCNN1B GTF2IRD1 IFT80 UFD1 MUC5B NUP107 BRAF FAS SNORD115-1 IL2RG MYH3 GPKOW RFXANK ICOS CEP57 LPIN2 TAP1 CD3D IRF5 FOXJ1 AGRN KITLG PIK3R1 CHRNG WIPF1 GPC4 CTLA4 CYP2A6 RPGR CORO1A ZMPSTE24 EP300 JAGN1 LFNG TGFB1 CD3E DNAL1 EXTL3 NCF1 SNRPN CLIP2 COMT SFTPC STAT4 HLA-DRB1 WAS DOK7 RMRP RSPH9 HLA-DRB1 IL23R DIS3L2 ERCC3 RAB27A POLR3H ERAP1 FOXP1 ITGA3 CFH PCGF2 ATP6V0A2 DNMT3B NOTCH1 BICC1 HIRA DKC1 LEP BCR TGFBR2 AKT1 ATP5F1A RNF125 FBN1 TGM1 CCDC40 NEK10 TGFBR1 RAC1 CREBBP TMEM94 ELN DNAI2 PLG UGP2 COL6A1 SLC25A1 DYNC2I2 IGLL1 IRAK1 CHRM3 SOS1 MYH7 COG6 CD8A STX1A GSN DNAJB13 PRKN EDARADD TERT NSD2 HLA-B CYTB WNT3 LEPR MKS1 IL2RB ZMPSTE24 PARN GRIP1 TRPV3 MEFV GATA4 CHAMP1 C11ORF95 DNAJB13 FOXP3 RAF1 DYNC2H1 BTK RFXANK MYH3 SMARCE1 DGCR2 ALPL SLC18A3 NR2F2 NEK1 STRA6 NKX2-1 TERC CAV1 NAA10 TGFBR2 PWRN1 RYR1 AGA CR2 TERC PIGN CCNO PKD1L1 RPL10 COL5A2 BLM H19 ABL1 CFTR RIT1 NCF1 CR2 IL2RA PSMC3IP ARID2 SLC7A7 SLC35C1 TIMM8A CDC45 NFKB2 CCDC114 TPM3 SCNN1B ADA LRRC56 HLA-DRB1 PEPD KATNIP LYST GRHL3 TAPT1 NBN GDF1 PRKCD CTC1 RCBTB1 PMM2 RET COL2A1 SMAD3 POLR3A LIPN BMPR2 SCNN1B SDR9C7 ASAH1 DNAAF6 CRELD1 OSTM1 RNU4ATAC COL13A1 DHCR7 GPC6 MGP MCIDAS IL17RC PSAP NAB2 KEAP1 TSC1 CITED2 SLC1A4 NGLY1 PPP1CB MANBA FGF20 A2ML1 MITF MAP3K8 ALB SMARCD1 HES7 POLA1 ERBB2 ALMS1 GUSB SMN1 SLCO2A1 CD79B CFAP221 VHL FGFR3 CYP4F22 IGLL1 STK36 TP53 HSPG2 PLOD1 DSP GMNN NHP2 COL11A2 OFD1 TNFRSF11A ARHGAP31 MALT1 CSF2RA COG4 RREB1 SCNN1A CD40LG NME8 SELENON NPHP3 LMNA CFTR CFAP298 SMPD1 FAT4 BTNL2 ALG12 IL21 BCL10 PRKDC TNFRSF13C HLA-DRB1 FOXE1 NXN BLM ERCC6 RSPH9 TBX5 LIG4 TBCE GALNS ACTA2 SLC12A6 SOX10 ZBTB16 FBLN5 SMAD4 NAGLU HELLS CTSC PRKG1 RASGRP1 CRELD1 ADGRG6 DYNC2I1 TINF2 SMARCB1 SP110 RSPH1 CCDC39 ARMC4 SMPD1 LAMTOR2 ABCA3 NHLRC2 FAS IKBKB MBTPS2 PTPRC NFKB2 MMP21 TCIRG1 MS4A1 MTHFD1 RYR1 ADA DNAI1 DVL3 PLCG2 PTPN22 BCL11B BAZ1B RTEL1 CALCRL CCBE1 SFTPB PTH1R DNAH11 CTLA4 DCLRE1C ASXL1 SAMD9L WT1 PIK3CA TREX1 GBA CFTR TRIM28 GP1BB TGFB1 CLPB ICOS FLNA GFI1 ARID1B IRAK4 DNAAF2 SFTPA2 JAG1 EGFR IGH KIAA0586 RIT1 PCNT DNAH5 NFKB1 GBA STAT1 TET2 RAG2 HLA-DRB1 CCDC151 MFAP5 EPG5 SLC25A22 DYNC2I2 HYLS1 XIAP MUSK SLC35A1 GNPTAB MS4A1 LOX LEPR CRKL RAG1 ZMYND10 COL6A2 PIGL ATM MIF IFT81 STAT4 LMOD3 GAS2L2 CDCA7 MEFV PRPS1 TGFB3 ERF KLHL40 SLC34A2 EPHB4 RFX5 KAT6B HYDIN RELB RLIM ADAMTS3 MEFV PUF60 KRAS SCN9A BTNL2 FOXC2 SH2D1A LEP PGM3 NOS1 ERCC2 TBX1 TBC1D24 CHD7 DLL3 POLE ALG9 LRRC6 TNFRSF13B CD28 CFTR CTRC OFD1 RANBP2 CHRNA1 IL7R MYL2 LZTR1 TRAIP CCDC22 IGH CCDC40 IL2RG SNORD116-1 MYOD1 ALOX12B NFKB1 KIF11 TINF2 GLI3 TRPS1 SGCG CCN2 PARN EOGT CHAT TSC1 SERPINH1 CDT1 CTCF UBB FOXF1 PRKAR1A PIK3CD BAP1 FBN1 DHCR24 TTC25 CARD11 SERPINF2 HELLPAR CXCR4 DYNC2I2 MASP2 IL6ST TBC1D24 GATA6 TBCD SMN1 RSPH3 COG4 MARS1 CSPP1 ITGA8 KIF20A PERP MUSK HLA-DRB1 HYDIN TGFBR1 CASP8 SCNN1G CD46 TNFSF12 RRAS RHOH SPINK5 MAT2A CCR6 ABCA3 LACC1 PRKCD FCGR2A CCN2 FAT4 KDM6A IDUA DNAH11 RSPH1 DOCK8 DYNC2LI1 NKX2-1 CCNO SPAG1 LIMK1 MPLKIP MINPP1 BIRC3 FBN1 FGF20 TERT IKBKB CD79A AFF4 FSHR STAT5B TNFRSF13C MYO5A NOTCH3 ELN LAMTOR2 IL12A-AS1 NADK2 RELA DPM2 PWAR1 MESP2 ELANE CD81 PNP PRSS2 ZAP70 WRAP53 DNAAF1 CHRNG MYRF TSC1 CLCA4 HABP2 DNAH9 FAM13A BTK TERT LRBA RSPH4A NSDHL SOX11 RYR1 TNNT2 KLRC4 SMARCD2 PIEZO2 SLC5A7 EVC KIF1A ACVRL1 ROR2 NCF4 IFT172 TNFRSF13B HLA-B CCDC65 FADD NOD2 CTLA4 FADD CACNA1C ITGA8 CYBC1 MGP VPS33A MYD88 COL13A1 DOCK6 MYSM1 DNAAF4 FLI1 FLNB MAN2B1 FRAS1 HLA-DQA1 SCNN1A IL21R IRF5 FASLG FANCB FAM20C COL6A3 KIAA0319L MCTP2 AP3D1 AGGF1 PIGN EMG1 ARVCF NUMA1 DLL4 RAG2 KIAA0586 NFKB2 TFRC NDN MAPK1 LAMA2 AGTR1 DONSON FANCB TGFB1 INPPL1 TNFSF11 XIAP RBPJ SLC18A3 UNG FLCN MKKS TRIM28 DNAAF6 SCN10A B3GLCT IL2RG CCDC103 CLCN7 PTPN22 GNPTAB SPP1 CXCR4 PLEC HLA-DPB1 RFXAP SCN11A NPM1 APOE LMNA PEX1 CARD11 USB1 CSPP1 ELN SOS2 CCDC103 MYH11 HLA-DQB1 TBC1D23 TTC21B DLL3 EFEMP2 MYO9A PORCN FLCN SCNN1G RBM10 CD79A IL12A RIPK4 RFC2 SLC22A18 FCGR2B RSPH4A IL2RG ACTA1 REST SRP54 RAF1 SNAP25 TSC1 CAV1 IRF8 CCNQ NCF2 GAS8 SMAD3 ZNHIT3 DHCR24 FOXP1 ZBTB24 TNFRSF13B PTPN11 NABP1 TERC B2M ELN SCNN1G LRRC56 FUCA1 SKIV2L JMJD1C PEX13 VANGL1 GATA4 CFI PDGFRB STAT6 TNFRSF13C FLNA TRIP13 ZBTB24 CEP55 NELFA NECTIN1 EPM2A TBL1XR1 CCND1 JAK3 NAA10 MYPN ZFPM2 DDR2 LMNA NME8 ECM1 ITCH CD3E NFKBIA DICER1 BUB1B SERPINF2 PRTN3 DNAI1 ZEB2 CYBB IDUA EPG5 TCIRG1 HOXD13 SNAI2 SLC35A1 CR2 SOX4 GAA TARS1 ELP1 ALMS1 ETFDH BMP2 ELN PLVAP SULT2B1 RAG2 TERT SLC25A24 SMPD1 TSC2 WDR19 GLE1 GATA6 RNU4ATAC PLP1 ARID1A ATP6V1E1 CFAP410 TCTN3 BRAF FCN3 STRA6 IL17RA PIEZO1 BNC1 PARN SCNN1G TBX1 CCBE1 EFEMP2 SLC52A3 BUB1 DCLRE1C CIITA MYLK LRRC6 CFAP298 ASCC1 DNAAF5 WNT4 LCK UMPS RNF168 USP9X CD3D INTU RUNX2 NGLY1 SPECC1L SEC24C GLDN FAS FLT4 IPW CCDC151 MRPS22 SYT2 SPAG1 LAMB2 GDF1 TERT DNAAF3 FLNC DNAAF1 SON PRKAG2 DPP9 STAT1 TECPR2 GPC3 RAG1 TNFRSF1B NUP88 AARS2 CEP120 RSPO2 RIPPLY2 LIFR MYSM1 GBA CYBA CBL TERT NPHP3 TRIP4 PHGDH VAMP1 NOTCH2 FASLG SMARCC2 G6PC3 KAT6B PIK3R1 CD81 CHST14 NOP10 IFT80 SHROOM4 SCNN1A CD19 SLC26A2 TGFB2 WDR35 SLC11A1 TTC25 RIPK1 UNC119 IGHM SAMD9 GTF2H5 GLI3 PML SLC29A3 RPGR SCNN1B ACE NKX2-5 DNAAF5 SCARB2 HFE FBLN5 RAG1 NEB DYNC2I1 GNS NFE2L2 RTEL1 CD19 DCTN4 FRAS1 ADNP IFT140 TGFB2 NPAP1 TRIP13 MESP2 CFTR ADAMTS2 DOCK8 RAG1 BRCA2 P4HTM MAN2B1 SLC26A2 CFAP300 RAB3GAP2 PAX6 JAK3 GTF2E2 NRAS SH3KBP1 RSPO2 ZNF341 BCL6 RFXAP SPEF2 MSN MCM4 CCND1 FARSB FUZ NIPBL BMPR2 STAT3 ACTA1 ZMYND10 IL7R SLC2A10 COQ7 NIPAL4 MLXIPL COL3A1 FREM2 ALDH18A1 LETM1 NKX2-5 TNFRSF1A MBTPS2 IKZF1 PIGN UBAC2 DNAI2 FBLN5 ACP5 ZAP70 RARA TPM2 NEK10 SFTPA1 ARMC4 NRAS AGT RPS15A CARMIL2 UBE2A EGFR SLC2A10 NAA10 CASP8 DNMT3B TAPBP RTEL1 EWSR1 PTEN ABCA12 SNX10 CSF2RA MESP2 SMARCA4 CBL AK2 KCNJ6 FIP1L1 HACD1 ETFA PNP ITGA7 ALOXE3 HLA-DPA1 HERC2 NEK8 SLC46A1 SMO LRRC8A IER3IP1 RARB TSC2 TLR4 TRAF3IP2 HPS6 ADA TRIP4 FAM111B FMO3 DPF2 RAPSN LBR MKRN3-AS1 VPS33A NOTCH2 DYNC2H1 IRF1 WNT3 DRC1 COPA PKHD1 ETFB CRLF1 ENG ELANE PANK2 GAS2L2 GTF2I CD247 PRKAR1A KLHL41 BMPER WAS PIGT RASA2 DNASE1L3 DHCR7 THOC2 TK2 IL10 IFNGR1 RASGRP1 CIITA NPM1 SLC26A2 RNF168 INHBA SPIDR EHMT1 CDC42 RB1 NHLRC1 TBX6 STAT3 MUC5B VPS13A NOTCH3 TMEM260 ASAH1 DNAH5 RPL10 FCGR3A WT1 FLCN INVS GLI1 COL5A1 TTC12 ITPR1 PTPN22 FLCN RARB CYBA GRIP1 IL17RA MKRN3 AFF4 SDCCAG8 IFIH1 CD79B GATA2 KAT6B TERC EIF2AK4 TAP2 HPS1 WASHC5 TRPV4 SERPINA1 SRSF2 PTPN11 CSF2RB STING1 NCF2 FSHR COL1A1 TBL2 ACTA1 CACNA1B PEPD SOX18 DNAAF3 DNAAF2 DNASE1 PPP2R1B WT1 DRC1 TCF3 CC2D2A CYBB PIK3R1 IL1RN NOP10 CCNQ TNFSF12 USP9X NHP2 LMNA NBN PYROXD1 IL7R CCDC114 HPGD BTK ELN PSAT1 BLNK CD55 GLE1 IDUA GATA6 USB1 SIK1 FLNA FLNB CLEC7A SMAD4 MAP3K20 KPTN RFX5 FOXE3 DKC1 COL2A1 POLA1 TRIP11 PGM3 GUSB AP3B1 COL3A1 SOX18 KRAS