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Report for Clinical Trial NCT02720822
Developed by Shray Alag, 2020.
SNP Clinical Trial Gene
A Pragmatic, Phase III, Multi-site, Double-blind, Placebo Controlled, Parallel Arm, Dose Increment Randomised Trial of Regular, Low Dose Extended Release Morphine for Chronic Refractory Breathlessness
Breathlessness is an overwhelming symptom affecting tens of thousands of Australians every day. For many people, it persists even when all the underlying causes have been optimally managed (chronic breathlessness). In these circumstances, it often occurs at rest or with minimal exertion. Evidence from a number of clinical studies suggests that a small, regular dose of morphine helps to reduce safely the sensation of breathlessness. However, it is not well established which patients derive more benefit and what is the net clinical effect of this treatment (weighing benefits and harms). This is a phase III, multi-site, randomised, double-blind, placebo-controlled trial with patients with chronic obstructive pulmonary disease (COPD) and severe chronic breathlessness which will explore several important questions: - Are regular, low doses of morphine at four possible doses over 3 weeks more effective than placebo at improving breathlessness? - Does increasing the dose in people who already are experiencing some benefit provide even greater reduction in worst breathlessness? - Does the medication have any effect on daily activity and quality of life? - What are the common or serious side effects of this intervention? - Does the benefit from the medication outweigh the side effects it produces? - Are there specific characteristics of people who are more likely to receive benefit from extended release morphine? Participants will receive once daily extended release morphine (plus laxative, docusate with senna), or placebo (placebo laxative) in addition to their usual medication for up to 3 weeks at increasing doses. Participants will have a medical interview and physical examination to collect some general health information, and baseline measurements including; daily activity, symptoms, and quality of life. A small amount of blood may be required to check eligibility. Further blood samples may be taken at week 1 and 3 to enable testing on how individuals respond to opioids, further consent will be obtained for these samples. Data on benefits, side effects, and medical care will be collected during comprehensive weekly visits. Participants will also fill out a simple diary twice daily for weeks one to three of the study, and for one day each week during an optional 6 month extension stage. The outcome of this study may enable better management of symptoms and activity in people COPD with medicines that are shown to be effective and safe.
NCT02720822 Chronic Obstructive Pulmonary Disease Dyspnea MeSH:Lung Diseases, Obstructive Pulmonary Disease, Chronic Obstructive Dyspnea
HPO:Chronic obstructive pulmonary disease Dyspnea Obstructive lung disease Respiratory distress
5 Interventions
Name: Placebo
Name: Morphine Sulfate
Name: Plus laxative (Docusate with senna)
Name: Plus placebo laxative
Name: FitBit charge HR (Accelerometer)
Primary Outcomes
Description: Rated on a 0-10 numerical rating scale (NRS). Measured at baseline, Stage1-3 (daily diary) and Stage 4 (weekly diary). The primary endpoint is: The difference between morphine sulphate 8mg and placebo (end of week1) The difference of morphine sulphate 16 mg and placebo (end of week 1)
Measure: Change from baseline worst breathlessness intensity over the previous 24 hours Time: Week 1Description: Difference from the baseline in the number of steps per day measured using the Fitbit(Charge HR). Measured at baseline, end of week 1, and end of week 3. The primary endpoint is: The difference between morphine sulphate 8mg and placebo (end of week 1) The difference between morphine sulphate 16mg and placebo (end of week 1) Comparison between baseline and end of week 3
Measure: Change from the baseline in the number of steps per day Time: Week 3Secondary Outcomes
Description: Measured at baseline and at the weekly visit for the randomisation phase, and then at the study exit in order to assess the theoretical risk of opioids worsening respiratory failure. Stages 1-4.
Measure: Change from baseline end-tidal carbon dioxide Time: Up to week 15Description: Measured at baseline and at the weekly visit for the randomisation phase, and then at the study exit in order to assess the theoretical risk of opioids worsening respiratory failure. Concomitant use of oxygen will be recorded. Stages 1-4.
Measure: Change from baseline pulse oximetry Time: Up to week 15Description: Rated on a 0-10 numerical rating scale (NRS). Measured at baseline, weeks 1-3 (daily diary) and stage 4 (weekly diary).
Measure: Change from baseline intensity of breathlessness "average" Time: Up to week 15Description: Rated on a 0-10 numerical rating scale (NRS). Measured at baseline, weeks 1-3 (daily diary) and stage 4 (weekly diary).
Measure: Change from baseline distress from breathlessness over the previous 24 hours Time: Up to week 15Description: Chronic Respiratory Questionnaire - Dyspnoea and Mastery Subscales. Baseline and end of Weeks 1-3.
Measure: Change from baseline perceived-impact of breathlessness Time: Up to week 3Description: Rated on the Modified Medical Research Council Breathlessness Scale (mMRC). Measured at baseline and at the conclusion of the study.
Measure: Change from baseline functional impact of breathlessness Time: Up to week 15Description: Measured using the Fitbit(Charge HR). Assessed at baseline (2 days), weeks 1 and 3.
Measure: Change from baseline sleep minutes Time: Week 3Description: Measured using the Fitbit(Charge HR). Given in number of movements per night (e.g. rolling over). Assessed at baseline (2 days), weeks 1 and 3.
Measure: Change from baseline sleep activity Time: Week 3Description: Measured using the Fitbit(Charge HR). Difference from baseline in the number of active minutes per day. Assessed at baseline (2 days), weeks 1 and 3.
Measure: Change from baseline in activity levels Time: Week 3Description: Measured using the Fitbit(Charge HR). Difference from baseline number of calories spent per day. Assessed at baseline (2 days), weeks 1 and 3.
Measure: Change from baseline total energy expenditure Time: Week 3Description: Measured using Australian-modified Karnofsky Performance Status (AKPS). Baseline, Stage1, Stage2, Stage3 and Stage 4.
Measure: Change from baseline performance status Time: Up to week 15Description: Measured using Barthel Index. Baseline and Stage 4.
Measure: Change from baseline activities of daily living Time: Up to week 15Description: Rated on a 4 point Likert scale. Measured at baseline, weeks 1-3 (daily diary) and stage 4 (weekly diary).
Measure: Change from baseline in sleep quality Time: Up to week 15Description: Thirty (30) participants at the Sydney and Adelaide sites will be invited to undertake a simple, non-invasive home sleep study using the ResMed ApneaLink Plus device. Baseline and Stage3.
Measure: Change from baseline in objective sleep testing Time: Week 3Description: Up to ten (10) participants will also undergo two (baseline and Stage 1) in-laboratory overnight sleep studies in Sydney and Adelaide.
Measure: Change from baseline Polysomnography Time: Week 3Description: Twenty (20) participants in Adelaide and Sydney. Baseline and on day 2 and 7 of the first week in an office-based simulator - AusEd.
Measure: Change from baseline Driving ability Time: Week 3 + 2 daysDescription: The baseline blood samples will be analysed to detect the presence of UGT2B7*2 and *28 polymorphisms.
Measure: Pharmacogenetic opioid profile - Number of participants with UGT2B7*2 and *28 polymorphisms Time: Baseline (1 day)Description: The baseline blood samples will be analysed to detect the presence of P-glycoprotein polymorphism (ABCB1 5SNPs in a haplotype block)
Measure: Pharmacogenetic opioid profile - Number of participants with P-glycoprotein polymorphism (ABCB1 5SNPs in a haplotype block) Time: Baseline (1 day)Description: The baseline blood samples will be analysed to detect the presence of 5-hydroxytryptamine type 3B (HTR3B) gene rs7103572 polymorphism
Measure: Pharmacogenetic opioid profile - Number of participants with 5-hydroxytryptamine type 3B (HTR3B) gene rs7103572 polymorphism Time: Baseline (1 day)Description: The baseline blood samples will be analysed to detect the presence of Mu receptor (A118G) polymorphism
Measure: Pharmacogenetic opioid profile - Mu receptor (A118G) polymorphism Time: Baseline (1 day)Description: In a subset of 55 participants, morphine peak plasma concentrations will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).
Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine Peak Plasma Concentration [Cmax] Time: Week 1Description: In a subset of 55 participants, morphine AUC will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).
Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine Area Under the Curve (AUC) Time: Week 1Description: In a subset of 55 participants, M6G Peak Plasma Concentration will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).
Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-6-glucuronide (M6G) Peak Plasma Concentration [Cmax] Time: Week 1Description: In a subset of 55 participants, M6G AUC will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).
Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-6-glucuronide (M6G) Area Under the Curve (AUC) Time: Week 1Description: In a subset of 55 participants, M3G Peak Plasma Concentration will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).
Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-3-glucuronide (M3G) Peak Plasma Concentration [Cmax] Time: Week 1Description: In a subset of 55 participants, M3G AUC will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).
Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-3-glucuronide (M3G) Area Under the Curve (AUC) Time: Week 1Description: Baseline and study completion. To explore whether longer term morphine treatment is associated with decreased levels of testosterone.
Measure: Change from baseline serum testosterone level Time: Week 15Description: Rated on a Lickert Scale. Baseline, weeks 1-3 (daily diary), Stage 4 (weekly diary): Includes constipation, anxiety, appetite, nausea, vomiting, drowsiness, difficulty thinking clearly, problems passing urine, itch, other symptoms.
Measure: Adverse Effects Time: Up to 15 weeksDescription: Measured using the Edmonton Symptoms Assessment Scale (ESAS)
Measure: Change from baseline in concurrent symptoms Time: Up to 15 weeksDescription: Rated using the Hospital Anxiety and Depression Scale (HADS). At baseline, completion of randomization stage and study exit.
Measure: Change from the baseline anxiety and depression Time: Up to Week 15Description: Participant-rated 7 point scale of the perception of their change, specifically their improvement since the commencement of the study. Measured at the end of Stages 1-3 and conclusion.
Measure: Change in baseline global impression of change Time: Up to 15 weeksDescription: Measured with EQ-5D-5L questionnaire. Baseline, Stages 1-3, Stage 4, conclusion.
Measure: Change from baseline health-related quality of life Time: Up to 15 weeksDescription: Measured with the COPD Assessment Test (CAT) Baseline, Stages 1-3, Stage 4 and conclusion.
Measure: Change from baseline health-status in COPD Time: Week 3Description: Asked at the end of week 1 and at the conclusion/drop-out of the study. A 3-point Likert scale will be used.
Measure: Blinded-patient preference to continue the treatment [3-point Likert Scale] Time: Up to week 15Description: Scored using the Zarit Burden Interview (ZBI) 12 item short-form questionnaire. Baseline, end of weeks 1-3, stage 4.
Measure: Change from baseline caregiver Impact Time: Up to week 15Description: From randomisation to 28 days post treatment or death (whichever is the shorter period). Estimated based on all health-care contacts including length of hospitalizations, emergency department visits, DRG codes, community health visits, GP and community nurse visits, outpatient visits and date of death. These participant level data allow within trial modeling using bootstrapping methods of replicates for costs and consequences of alternative strategies, allowing for covariance between costs and effects. Incremental net monetary benefit and cost-effectiveness acceptability curves will be estimated at potential threshold values for an additional responder.
Measure: Economic Evaluation - Cost per responder Time: Up to week 4Description: Evaluation using the Subjective Opioid Withdrawal Scale (SOWS) for 3 consecutive days. After the completion of the study (Weeks 1-15).
Measure: Opioid Withdrawal Time: Up to week 15 + 3 daysPurpose: Treatment
Allocation: Randomized
Parallel Assignment
There is one SNP
SNPs
1 rs7103572
Pharmacogenetic opioid profile - Number of participants with 5-hydroxytryptamine type 3B (HTR3B) gene rs7103572 polymorphism.
The baseline blood samples will be analysed to detect the presence of 5-hydroxytryptamine type 3B (HTR3B) gene rs7103572 polymorphism.