A Phase III Study to Evaluate Long-Acting Antiretroviral Therapy in Non-Adherent HIV-Infected Individuals

Brief Summary

Detailed Description

This study compared the efficacy, safety, and durability of two different strategies to treat participants with a history of sub-optimal adherence and control of their HIV infection: long-acting (LA) antiretroviral therapy (ART) with rilpivirine (RPV) LA and cabotegravir (CAB) LA versus all-oral standard of care (SOC). As the study was originally designed, the study included four steps. Step 1, Induction Previously non-adherent individuals were enrolled and underwent a period (up to 24 weeks) of induction SOC ART regimen using conditional economic incentives (CEI). Participants who achieved virologic suppression criteria at or after Step 1, week 4, defined as: a) HIV-1 RNA ≤200 copies/mL or b) HIV-1 RNA of 201-399 copies/mL followed by HIV-1 RNA ≤200 copies/mL by Step 1, week 24, were eligible to enter Step 2. Step 2, Randomization Eligible participants were randomized at Step 2 entry in a 1:1 ratio to either of the two treatment arms: Arm A (LA ART): A combination of oral RPV + oral CAB for 4 weeks (optional) followed by the LA ART Phase, consisting of a two-drug regimen using RPV-LA + CAB-LA Q4 weeks until the end of Step 2 (Table 5.2.1-2). The option to initiate LA ART at the Step 2 Randomization visit without oral RPV + oral CAB was at the discretion of the site investigator of Record (IoR) and participant (see section 2.1, Direct-to-Inject). Arm B (SOC): Continuation of the SOC for 52 weeks. Step 3, Continuation/Crossover Arm A participants continued on RPV-LA + CAB-LA Q4 weeks for 52 weeks until the end of Step 3. Arm B participants (continuation of SOC) who achieved virologic suppression (HIV-1 RNA ≤200 copies/mL) at Step 2, week 48, or HIV-1 RNA of 201-399 copies/mL at Step 2, week 48, followed by HIV-1 RNA ≤200 copies/mL by Step 2, week 52, had the option to cross over at the end of Step 2 to oral RPV + oral CAB for 4 weeks (optional) followed by RPV-LA + CAB-LA every 4 weeks until the end of Step 3 (Table 5.2.1-3). Arm B participants who did not wish or were not eligible to cross over completed study follow-up at Step 2, week 52. If RPV-LA + CAB-LA became available before a participant finished Step 3, and the participant chose to continue RPV-LA + CAB-LA as part of their clinical care, their follow-up in the study ended at the completion of Step 3. If for some reason the participant chose not to continue LA ART at the end of Step 3 or if LA ART was not available, the participant registered to Step 4 and was followed on locally sourced oral ARV for 52 weeks. Step 4, Observation Participants who registered to Step 4 were followed for up to 52 weeks on oral ART. In addition, any participant who received at least one dose of CAB-LA or RPV-LA at any step, and prematurely discontinued the LA ART prior to the end of Step 3, completed their respective Step (either Step 2 or 3) on study/off study treatment, and registered to Step 4 and were followed to complete 52 weeks total on oral ART after their last dose of any LA injectable. If LA ART became available during follow-up in Step 4, and the participant and provider decided to restart LA ART, they were allowed to do so. In that case, the participants were not followed by the study after restarting LA ART. On February 12, 2024, based on the interim efficacy results, Data Safety and Monitoring Board (DSMB) recommended stopping randomization to Step 2 and transitioning all eligible participants in Steps 1 and 2 to LA-ART. Per recommendations from DSMB, randomization into Step 2 stopped on February 16, 2024, leaving three steps in the current study protocol 4.0: In Step 1, participants will receive a SOC oral induction regimen consisting of an ART regimen that involves at least 3 drugs for 24 weeks. Participants who achieve milestones will receive conditional economic incentives. With randomization into Step 2 ended, all eligible Step 1 participants will register to Step 3 at the completion of Step 1. Participants who are currently on Step 2: Eligible participants in Step 2 Arm A (already on RPV-LA + CAB-LA) will register to Step 3 and continue on this regimen until the end of Step 3 (52 weeks; See protocol for more information). This should happen at the next scheduled study visit after approval of Version 4.0. Eligible participants in Step 2 Arm B (SOC arm) will register to Step 3 and switch to oral RPV + oral CAB for 4 weeks (optional; see protocol for more information) followed by RPV-LA + CAB-LA Q4 weeks until the end of Step 3 (52 weeks). This should happen at the next scheduled study visit after approval of Version 4.0. Eligible participants will enter Step 4 and be followed up to 52 weeks on locally sourced oral ART. Participants will be followed for up to a total of 180 weeks. Study visits, which will occur throughout the study, may include physical examinations; blood, urine, and hair collection; liver function tests; questionnaires; and an electrocardiogram (ECG). NOTE: Data summarized in the primary analysis report were based on evaluations undertaken at visits conducted prior to the implementation of Protocol v4.0 which incorporated February 12, 2024 DSMB recommendations. Primary analyses were outlined in the A5359 primary Statistical Analysis Plan (SAP) version 6.0 (dated August 5, 2024) focusing on follow-up in Step 1 and Step 2.

Primary Outcomes

Secondary Outcomes

• Number of Participants With Virologic Non-success (>= 200 Copies/ml)(From Step 2 randomization to Step 2, Week 48 (up to 50 weeks))
• Percentage of Participants With Grade 1 or Higher Injection Site Reactions (ISR) During Step 2(Measured from Step 2 randomization through Step 2, Week 52)
• Cumulative Probability of Virologic Failure in Step 2 at Any Time Post Randomization to Week 48 Visit(From Step 2 randomization to Step 2, Week 48 visit (up to 50 weeks))
• Cumulative Probability of the Treatment-related Failure in Step 2 at Any Time Post Randomization to Week 48 Visit(From after Step 2 randomization to Step 2, Week 48 (up to 50 weeks))
• Number of Participants With Virologic Non-success (>= 50 Copies/ml)(from Step 2 randomization to Step 2, Week 48 (up to 50 weeks))
• Percentage of Participants With Plasma HIV-1 RNA Level Less Than 50 Copies/mL at Scheduled Study Visits on Steps 1(Measured from Step 1 entry through Step 1, Week 20 visit)
• Percentage of Participants With Plasma HIV-1 RNA Level Less Than 200 Copies/mL at Scheduled Study Visits on Steps 1(Measured from Step 1 entry through Step 1, Week 20 visit)
• Percentage of Participants With Plasma HIV-1 RNA Level Less Than 50 Copies/mL at Scheduled Study Visits on Steps 2(Measured from Step 2 entry through Step 2, Week 48 visit)
• Percentage of Participants With Plasma HIV-1 RNA Level Less Than 200 Copies/mL at Scheduled Study Visits on Steps 2(Measured from Step 2 entry through Step 2, Week 48 visit)
• Cumulative Probability of Discontinuation of Randomized Treatment in Step 2(Measured from Step 2 randomization through Step 2, Week 48 (up to 50 weeks))
• Median Summary Score of HIV Treatment Satisfaction Questionnaire (HIVTSQ) in Step 2(HIVTSQ status was collected on both arms at Step 2 entry and Week 24, and also at Week 48 for those randomized to SOC. At Week 48, HIVTSQ change was collected for participants on the LA-ART arm.)
• Number of Participants With Missed or Delayed Injections for Participants Who Received LA ART in Step 2(Measured from Step 2 randomization through Step 2, Week 52)
• Median of Summary Scores of HIV Treatment Adherence Self-Efficacy Scale in Step 1(Step 1 entry, Weeks 12 and 20.)
• Median of Summary Scores of HIV Treatment Adherence Self-Efficacy Scale in Step 2(As Step 2 Week 0, Week 24 and Week 48)
• Number of Participants With New Drug-resistance Mutations in Participants With Virologic Failure in Step 2(Measured at Step 1 screening/entry and at the time of virologic failure in Step 2)
• Percentage of Participants Who Preferred Monthly Injections of Long-Acting HIV Treatment or Daily Oral HIV Treatment at Each Visit(Step 2 week 48, premature treatment visit, and study discontinuation visit)
• Percentage of Participants With Opinions About Conditional Economic Incentive (CEI) Withdrawal(At Step 2 entry and Step 2, Week 8)
• Median of Average Total Score of Step 1 HIV Treatment Adherence Self-Efficacy Scale Score (HIV-ASES)(Step 1 entry, Step 1 Weeks 12, and Step 1 Weeks 20)
• Percentage of Participants With Missed Treatment Doses Among Participants Who Randomized to SOC Arm in Step 2(At Step 2 entry, Step 2 week 4, Step 2 week 8, step 2 week 16, step 2 week 24, step 2 week 36, Step 2 week 48, and Step 2 week 52)