Pharmacy and Poisons Board
Protocol No: ECCT/24/03/04 Date of Protocol: 24-10-2023
Study Title:
A Phase 3, Randomized, Active-Controlled, Double-Blind Clinical Study to Evaluate the Antiretroviral Activity, Safety, and Tolerability of Doravirine/Islatravir (DOR/ISL 100 mg/0.25 mg) Once-Daily in HIV-1 Infected Treatment-Naïve Participants
Study Objectives:

Primary Objectives:

  1. To evaluate the antiretroviral activity of DOR/ISL compared to BIC/FTC/TAF, as assessed by the percentage of participants with HIV-1 RNA <50 copies/mL at Week 48.
  2. To evaluate the safety and tolerability of DOR/ISL compared with BIC/FTC/TAF as assessed by review of the accumulated safety data through Week 48.

SecondaryObjectives:

  1. To evaluate the antiretroviral activity of DOR/ISL compared with BIC/FTC/TAF, as assessed by the percentage of participants with HIV-1 RNA <50 copies/mL at Week 96.
  2. To evaluate the antiretroviral activity of DOR/ISL compared with BIC/FTC/TAF, as assessed by the percentage of participants with HIV-1 RNA <200 copies/mL at Week 48 and Week 96.
  3. To evaluate the immunologic effect of DOR/ISL compared with BIC/FTC/TAF, as assessed by the mean change from baseline in CD4+ T-cell count at Week 48 and Week 96.
  4. To evaluate the development of viral drug resistance in participants who receive DOR/ISL and in those who receive BIC/FTC/TAF.
  5. To evaluate the effect of DOR/ISL compared with BIC/FTC/TAF on weight, as assessed by the mean change from baseline to Week 48 and Week 96.
  6. To evaluate the safety and tolerability of DOR/ISL compared with BIC/FTC/TAF as assessed by review of the accumulated safety data through study duration.

Tertiary/Exploratory Objectives:

  1. To evaluate the effects on body composition, fasting lipid and metabolic profiles, renal function, and inflammation of DOR/ISL compared with BIC/FTC/TAF, as assessed by the mean change from baseline to Week 48 and Week 96 in these parameters.
  2. To evaluate the pharmacokinetics of ISL when administered as a component of DOR/ISL.
  3. To describe PROs (assessing HRQoL and HIV symptoms) for participants who receive DOR/ISL compared with BIC/FTC/TAF at Week 48 and Week 96.
  4. To explore the relationship between genetic variation and response to the treatment(s) administered, and mechanism of disease. Variation across the human genome may be analyzed for association with clinical data collected in this study.

 
Laymans Summary:

There has been evolution in the medications for treating HIV-1 infection with life expectancy among persons living with HIV (PLWH) getting closer to those of the uninfected population. Currently, the standard of care for treating of HIV-1 infection is a 3-drug combination. Although these medications are working well, the potential for long-term toxicity cannot be excluded. Therefore, there is need for simpler and safer combinations that reduce overall drug exposure. There is evidence that 2-drug combination works in a comparable way to the 3-drug combination.

We are conducting a phase 3 trial to look at the antiretroviral activity, safety and tolerability of a 2-drug combination of Doravirine/Islatravir compared to 3-drug combination of Bictegravir/emtricitabine/tenofovir alafenamide. This will be a clinical trial of approximately 500 participants newly diagnosed with HIV-1 infection and not started on any ART treatment across 24 treatment sites globally, with our site expected to enroll a minimum of 10 participants. Participants will be in two groups, i.e., a treatment group and a control group. The treatment group will receive the 2-drug combination while the control group will receive the 3-drug combination. All participants will be followed up for 96 weeks.

At the end of the trial, we expect that the 2-drug combination will be non-inferior to the 3-drug combination in the treatment of HIV-1 infection.
Abstract of Study:

Background: With availability of simplified and potent ART treatment regimens, HIV-1 infection has become a chronic, manageable condition, and PLWH receiving effective ART regimens can expect to live near-normal lifespans. Anticipating that individuals can receive decades of treatment during their lifetime, long-term tolerability and safety of antiretrovirals have become increasingly important considerations. The current standard-of-care for the treatment of HIV-1 is a combination of 2 Nucleoside Reverse Transcriptase Inhibitors with a third agent (e.g., integrase strand transfer inhibitors, Non-Nucleoside Reverse Transcriptase Inhibitor, or Protease Inhibitor). Although such regimens have become increasingly well tolerated and highly efficacious, the current paradigm of lifelong daily treatment is associated with a need for simpler and safer regimens that reduce overall drug exposure. There is evidence that 2-drug regimens can achieve efficacy that is comparable to that of 3-drug regimens, offer better tolerability, and improve quality of life, all of which can support adherence and help to sustain virologic suppression.

Objectives:  The primary objective of this study is to evaluate the antiretroviral activity, safety and tolerability of Doravirine/Islatravir (DOR/ISL) compared to Bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), as assessed by the percentage of participants with HIV-1 RNA <50 copies/mL at Week 48. These will be measured by laboratory-confirmed HIV-1 RNA, adverse events including adverse events leading to discontinuation of study intervention.

Methods: This is a Phase 3, randomized, active-controlled, multi-site, double-blind study to evaluate the antiretroviral activity, safety, and tolerability of daily DOR/ISL in treatment naïve participants with HIV-1. The active control selected for this study is the 3-drug combination of daily BIC/FTC/TAF with demonstrated antiretroviral activity against HIV-1 in treatment naïve patients. Globally, approximately 500 participants will be randomized, stratified by screening HIV-1 RNA level (≤100,000 copies/mL, >100,000 copies/mL) and screening CD4+ T-cell count (<200 cells/mm3, ≥200 cells/mm3), in a 1:1 ratio into 1 of 2 treatment groups. All participants will receive 96 weeks of assigned therapy. Three sites in Kenya (Kisumu CGHR, KEMRI-CCR PHRD, Thika and KEMRI-CCR Nairobi) will take part in Part 2 of study enrolment that is planned to start in May 2024 and cumulatively enroll 30 participants, approximately 10 per site.

Expected results: For our primary objectives, we hypothesize that DOR/ISL is non- inferior to BIC/FTC/TAF, as assessed by the percentage of participants with HIV-1 RNA <50 copies/mL at Week 48. A margin of 10 percentage points will be used to define non-inferiority.