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SNPMiner SNPMiner Trials (Home Page)


Report for Mutation Y143R

Developed by Shray Alag, 2020-2021.
SNP Clinical Trial Gene

There are 3 clinical trials

Clinical Trials


1 A Single-Dose Clinical Trial to Study the Safety, Tolerability, Pharmacokinetics, and Anti-Retroviral Activity of MK-4250 Monotherapy in Anti-Retroviral Therapy (ART)-Naive, HIV-1 Infected Subjects

The study will evaluate the safety, tolerability, pharmacokinetics, and anti-retroviral activity of MK-4250 monotherapy in anti-retroviral therapy (ART)-naïve, HIV-1 infected participants. The primary hypothesis of the study is that at a dose that is sufficiently safe and generally well tolerated, MK-4250 has superior antiretroviral activity compared to a historical placebo, as measured by change from baseline in plasma HIV-1 ribonucleic acid (RNA) (log10 copies/mL) at 168 hours postdose.

NCT03351699
Conditions
  1. HIV-1 Infection
Interventions
  1. Drug: MK-4250

- No evidence at screening for mutations (e.g., E92Q, N55H, Q148K, Q148R and Y143R) affecting susceptibility to Integrase Strand Transfer Inhibitors (InSTIs) - Diagnosed with HIV-1 infection ≥ 3 months prior to screening or confirmed chronic HIV infection - Screening plasma Cluster of Differentiation (CD) 4+ T cell count of >200/mm^3 - Screening plasma HIV-1 RNA ≥5,000 copies/mL within 30 days prior to the treatment phase of this study - Anti-retroviral therapy (ART)-naïve, which is defined as having never received any antiretroviral agent OR ≤30 consecutive days of an investigational antiretroviral agent which is not an InSTI and no exposure to such an investigational antiretroviral agent within 60 days prior to screening OR ≤60 consecutive days of combination ART which does not include an InSTI and no exposure to such ART within 60 days prior to screening - Never received any InSTI - Willing to receive no other ART for the duration of the treatment phase of this study - Body Mass Index (BMI) ≤35 kg/m^2 - Other than HIV infection, have baseline health judged to be stable Exclusion Criteria: - Mentally or legally institutionalized / incapacitated, or significant emotional problems at the time of pretrial (screening) visit or expected during the conduct of the trial or has a history of clinically significant psychiatric disorder within the last 5 years - History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological (outside of HIV-1 infection), renal, respiratory, genitourinary or major neurological abnormalities or diseases - History of cancer (malignancy). --- E92Q --- --- N55H --- --- Q148K --- --- Q148R --- --- Y143R ---

Primary Outcomes

Description: Plasma HIV-1 RNA was measured at Baseline and 168 hours after dosing. The log10 plasma HIV-RNA copies/mL measurements from participants in each panel were pooled and analyzed based on a longitudinal data analysis model. The change from Baseline in plasma HIV-1 RNA in participants administered MK-4250 was compared with historical placebo data.

Measure: Change From Baseline in Plasma HIV-1 RNA Copies Per mL at 168 Hours

Time: Baseline and Day 7

Description: The percentage of participants experiencing ≥1 AE was calculated. An AE was defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy could be determined.

Measure: Percentage of Participants Experiencing ≥1 Adverse Events (AE)

Time: Up to Day 14

Description: The percentage of participants who discontinued from the study due to an adverse event was calculated. An AE was defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy could be determined.

Measure: Percentage of Participants Who Discontinued Study Due to an Adverse Event (AE)

Time: Up to Day 14

Secondary Outcomes

Description: The area under the concentration-time curve up to the last measurable concentration (AUC0-last) of MK-4250 in plasma was calculated.

Measure: Area Under the Concentration-Time Curve From 0 to Last Measurable Concentration (AUC0-last) for MK-4250

Time: Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 120, 168, 192, and 240 hours after administration of MK-4250. For Panel B only, the first three participants additionally had a 72-hour postdose time, and no 240-hour postdose time.

Description: The area under the concentration-time curve extrapolated to infinity (AUC0-inf) of MK-4250 in plasma was calculated.

Measure: Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) for MK-4250

Time: Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 120, 168, 192, and 240 hours after administration of MK-4250. For Panel B only, the first three participants additionally had a 72-hour postdose time, and no 240-hour postdose time.

Description: The area under the concentration-time curve up to 168 hours (AUC0-168) of MK-4250 in plasma was calculated.

Measure: Area Under the Concentration-Time Curve From 0 to 168 Hours (AUC0-168) for MK-4250

Time: Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 120, and 168 hours after administration of MK-4250. For Panel B only, the first three participants additionally had a 72-hour postdose time.

Description: The maximum concentration (Cmax) of MK-4250 in plasma was observed.

Measure: Maximum Concentration (Cmax) of MK-4250 Reached in Plasma

Time: Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 120, 168, 192, and 240 hours after administration of MK-4250. For Panel B only, the first three participants additionally had a 72-hour postdose time, and no 240-hour postdose time.

Description: The concentration of MK-4250 at 168 hours postdose (C168hr) was observed.

Measure: Concentration of MK-4250 at 168 Hours (C168hr)

Time: 168 hours after administration of MK-4250.

Description: The apparent terminal half-life (t1/2) of MK-4250 in plasma was calculated.

Measure: Apparent Terminal Half-life (t1/2) of MK-4250

Time: Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 120, 168, 192, and 240 hours after administration of MK-4250. For Panel B only, the first three participants additionally had a 72-hour postdose time, and no 240-hour postdose time.

Description: The apparent clearance (CL/F) of MK-4250 in plasma was calculated.

Measure: Apparent Clearance (CL/F) of MK-4250

Time: Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 120, 168, 192, and 240 hours after administration of MK-4250. For Panel B only, the first three participants additionally had a 72-hour postdose time, and no 240-hour postdose time.

Description: The apparent volume of distribution (Vz/F) of MK-4250 in plasma was calculated.

Measure: Apparent Volume of Distribution (Vz/F) of MK-4250

Time: Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 120, 168, 192, and 240 hours after administration of MK-4250. For Panel B only, the first three participants additionally had a 72-hour postdose time, and no 240-hour postdose time.

Description: The time to maximum concentration (Vz/F) of MK-4250 in plasma was calculated.

Measure: Time to Maximum Concentration (Tmax) of MK-4250 Reached in Plasma

Time: Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 120, 168, 192, and 240 hours after administration of MK-4250. For Panel B only, the first three participants additionally had a 72-hour postdose time, and no 240-hour postdose time.

2 Efficacy and Safety of a Simplification Strategy Based on Dolutegravir and Darunavir / Cobicistat vs Optimized Treatment in Suppressed HIV-1-infected Patients Carrying Archived Multidrug Resistance Mutations.

The availability of antiretroviral therapy has led to a reduction in morbidity and mortality in patients with chronic HIV infection. The treatment, however, is not free of side effects, has potential interactions with other medications, is expensive and can be complex, especially in those patients who are very experienced and with mutations that give them resistance to multiple drugs. For this reason, the development of simplification strategies that avoid unnecessary exposure to antiretroviral agents remains of great interest. This is a simplification study, in which the investigators try to evaluate that with less medication the investigator can maintain the same virological control of the disease. This would mean a lower burden of medication for patients, facilitating its administration and reducing the number of unwanted side effects. Specifically, the investigators intend to evaluate the treatment with Darunavir / cobicistat plus Dolutegravir as a simplification strategy, since both drugs are taken once a day, have a powerful antiviral activity, even against antiretroviral resistant viruses, and are among the best tolerated (with fewer side effects). The results reported in some observational studies suggest that two-drug therapy (bitherapy) as a simplification strategy could also be safe and effective, however, as far as the investigators know, there are no data and clinical trials that specifically evaluate darunavir / cobicistat plus dolutegravir as a strategy of simplification.

NCT03683524
Conditions
  1. HIV-1 Infection
Interventions
  1. Drug: Dolutegravir (DTG) plus Darunavir/cobicistat (DRV/cobi).
  2. Drug: Current ART

T66I, 74M, E92Q, T97A, F121Y, E138A/K, G140A/S, Y143R/H/C, S147G, Q148H/K/R, N155H AND R263K) in historical genotyping tests. --- T66I --- --- E92Q --- --- T97A --- --- F121Y --- --- E138A --- --- G140A --- --- Y143R ---

Primary Outcomes

Description: HIV-1 RNA < 50 copies/mL using a Time to Loss of Virological Response (TLOVR).

Measure: Plasma HIV-1 RNA < 50 copies/mL at 48 weeks

Time: week 48

Secondary Outcomes

Description: Percentage of patients developing ART-associated adverse events leading to treatment discontinuation.

Measure: Percentage of patients developing ART-associated adverse events

Time: Since baseline to week 48

Description: CD4+ cell count changes

Measure: Changes in CD4+ cell count

Time: Since baseline to week 48

Description: Emergence of new mutations in HIV-1 protease and integrase assessed with a genotyping test (attempted on any post Day 1 sample with HIV-1 RNA ≥ 50 copies/mL).

Measure: Emergence of new mutations in HIV-1 protease and integrase

Time: Baseline and in case of virological failure, defined as ≥ 50 copies/mL in 2 consecutive determinations or a single HIV-1 RNA values > 1000 copies/mL. We can observe a virological failure throughout the study (from baseline to week 48)

Description: HIV-1 RNA< 50 copies/mL at 24 weeks by TLOVR

Measure: Plasma HIV-1 RNA < 50 copies/mL at 24 weeks

Time: Week 24

Description: HIV-1 RNA < 50 copies/mL at 24 and 48 weeks using the FDA snapshot analysis (sensitivity analysis).

Measure: Plasma HIV-1 RNA < 50 copies/mL at 24 and 48 weeks

Time: Week 24 and 48

Description: Description of plasmatic trough levels of DTG and DRV/cobi in the experimental group, and in those participants experiencing virological failure.

Measure: DTG and DRV/cobi plasma concentration

Time: Week 4

Description: ART prices

Measure: Cost associated with the antirretroviral treatment of the study

Time: Since baseline to week 48

Description: Prices of clinical controls during the study

Measure: Estimated costs of clinical controls

Time: Since baseline to week 48

Measure: Genotyping tests cost

Time: At virological failure, defined as ≥ 50 copies/mL in 2 consecutive determinations or a single HIV-1 RNA values > 1000 copies/mL. We can observe a virological failure throughout the study (from baseline to week 48)

3 Drug-Drug Interactions Between Rifapentine and Dolutegravir in HIV/LTBI Co-Infected Individuals

This study will evaluate the potential drug-drug interactions between dolutegravir (DTG) and steady state rifapentine (RPT) when RPT is given with isoniazid (INH) daily for 4 weeks (1HP) as part of treatment for latent TB infection (LTBI) in HIV-1 and LTBI co-infected individuals.

NCT04272242
Conditions
  1. HIV Infection
  2. LTBI
Interventions
  1. Drug: Dolutegravir (DTG)
  2. Drug: Isoniazid (INH)
  3. Drug: Rifapentine (RPT)
  4. Drug: Antiretroviral Therapy (ART)
  5. Dietary Supplement: Pyridoxine (Vitamin B6)
MeSH:Infection HIV Infections

This includes the following INSTI mutations: Q148 substitutions, T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, G193E/R, or N155H. --- T66A --- --- L74I --- --- E138A --- --- G140S --- --- Y143R ---

Primary Outcomes

Measure: DTG PK Parameter Maximum Plasma Concentration (Cmax) by visit week and arm

Time: Measured at Days 0 and 28

Measure: DTG PK Parameter Area Under the Curve (AUC0-12 for BID & AUC0-24 for QD dosing) by visit week and arm

Time: Measured at Days 0 and 28

Measure: DTG PK Parameter Minimum Plasma Concentration (Cmin) by visit week and arm

Time: Measured at Days 0 and 28

Secondary Outcomes

Description: Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017

Measure: Proportion of participants with all adverse events meeting the reporting criteria in the study protocol during administration of DTG with 1HP, by arm

Time: Measured through Week 4

Measure: Proportion of participants who discontinue study or study drugs during DTG and 1HP dosing, by arm

Time: Measured through Week 4

Measure: Proportion of participants with HIV-1 RNA levels >50 copies/mL

Time: Measured at Days 28 and 42


HPO Nodes