Study to Evaluate the Efficacy of GS-9131 Functional Monotherapy in Human Immunodeficiency Virus (HIV)-1-Infected Adults Failing a Nucleos(t)Ide Reverse Transcriptase Inhibitor-Containing Regimen With Nucleos(t)Ide Reverse Transcriptase Inhibitor Resistant Virus

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the short-term antiviral potency of GS-9131 functional monotherapy compared to placebo-to-match (PTM) GS-9131, each administered once daily with the existing failing antiretroviral (ARV) regimen as demonstrated by the proportion of participants achieving human immunodeficiency virus ribonucleic acid (HIV-1 RNA) > 0.5 log10 decreases from baseline after up to 14 days of therapy in HIV-1 positive, ARV treatment experienced adult participants with nucleos(t)ide resistant virus. This is a two-part study. Part 1 consists of three cohorts: 2 Sentinel Cohorts and 1 Randomized Cohort. Eligible participants from Part 1 will proceed to Part 2 followed by an optional open-label extension.

Official Title
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A Phase 2 Study to Evaluate the Efficacy of GS-9131 Functional Monotherapy in HIV-1-Infected Adults Failing a Nucleos(t)Ide Reverse Transcriptase Inhibitor-Containing Regimen With Nucleos(t)Ide Reverse Transcriptase Inhibitor Resistant Virus

Conditions
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HIV-1-infection

Intervention / Treatment
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* Drug: GS-9131
* Drug: BIC
* Drug: TAF
* Drug: ARV regimen
* Drug: DRV
* Drug: RTV


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Plasma HIV-1 RNA ≥ 500 copies/mL at screening Visit Currently taking a failing ARV regimen that contains 2 NRTIs and a NNRTI No prior or current ARV regimens containing integrase inhibitor (INSTI) or protease inhibitor (PI) Screening genotype must show at least the protocol defined resistance mutation profile Key Exclusion Criteria: Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to Day 1 Participation in any other clinical trial, including observational studies, without prior approval from the sponsor is prohibited while participating in this trial Use of an investigational drug other than the study drug Individuals with chronic hepatitis B virus (HBV) infection are not permitted to participate Active tuberculosis infection NOTE: Other protocol defined Inclusion/ Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Sentinel Cohort 1: GS-9131 60 mg<br>Treatment experienced participants will receive GS-9131 60 mg in addition to their current failing ARV regimen for a period of 10 days. | Drug: GS-9131<br>* Tablet(s) administered orally once daily<br>Drug: ARV regimen<br>* ARV regimen may consist of the ARV agents containing nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitor (NNRTI)<br>|
| Experimental: Part 1 Sentinel Cohort 2: GS-9131 180 mg<br>Treatment experienced participants will receive GS-9131 180 mg in addition to their current failing ARV regimen for a period of 14 days. | Drug: GS-9131<br>* Tablet(s) administered orally once daily<br>Drug: ARV regimen<br>* ARV regimen may consist of the ARV agents containing nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitor (NNRTI)<br>|
| Experimental: Part 1: Randomized Cohort<br>Participants will be randomized in 1:1:1:1 so as to receive GS-9131 in 3 active dose levels up to a maximum of 180 mg or Placebo to match GS-9131 in addition to their current failing ARV regimen for a period of 14 days in Part 1. | Drug: GS-9131<br>* Tablet(s) administered orally once daily<br>Drug: ARV regimen<br>* ARV regimen may consist of the ARV agents containing nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitor (NNRTI)<br>|
| Experimental: Part 2 Sentinel Cohort 1: GS-9131 + BIC + DRV + RTV<br>Participants who complete dosing in Sentinel Cohort 1 of Part 1 and show a reduction in plasma HIV RNA > 0.5 log10 from their pre-GS-9131 baseline value at Day 11 and discontinue their current failing regimen will receive an optimized regimen consisting of GS-9131 60 mg + bictegravir (BIC) 30 mg + darunavir (DRV) 800 mg + ritonavir (RTV) 100 mg for a period of 24 weeks. After Week 24, participants will be given the option to participate in an open label extension and receive GS-9131 60 mg + BIC 75 mg + tenofovir alafenamide (TAF) 25 mg, for an additional 24 weeks or until Gilead Sciences elects to discontinue the study drug in that country, whichever occurs first. | Drug: GS-9131<br>* Tablet(s) administered orally once daily<br>Drug: BIC<br>* Tablet(s) administered orally once daily<br>Drug: DRV<br>* Tablet(s) administered orally once daily<br>* Other names: Prezista®;Drug: RTV<br>* Tablet(s) administered orally once daily<br>* Other names: Norvir®;|
| Experimental: Part 2 Sentinel Cohort 2: GS-9131 + BIC + TAF<br>Participants who complete dosing in Sentinel Cohort 2 of Part 1 and show a reduction in plasma HIV RNA > 0.5 log10 from their pre-GS-9131 baseline value at Day 15 and discontinue their current failing regimen will receive an optimized regimen consisting of GS-9131 180 mg + BIC 75 mg + TAF 25 mg, for a period of 24 weeks. After Week 24, participants will be given the option to participate in an open label extension and receive GS-9131 180 mg + BIC 75 mg + TAF 25 mg, for an additional 24 weeks or until Gilead Sciences elects to discontinue the study drug in that country, whichever occurs first. | Drug: GS-9131<br>* Tablet(s) administered orally once daily<br>Drug: BIC<br>* Tablet(s) administered orally once daily<br>Drug: TAF<br>* Tablet(s) administered orally once daily<br>* Other names: Vemlidy®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 Randomized Cohort: Percentage of Participants With Plasma HIV-1 RNA Decreases From Baseline Exceeding 0.5 log10 at Day 15 | The criteria for analyzing percentage of participants with plasma HIV-1 RNA > 0.5 log10 decrease from baseline in randomized cohort was at least 50% of the participants should achieve HIV-1 RNA > 0.5 log10 decrease from baseline in the Part 1 sentinel cohort 2. | Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 Sentinel Cohort 1: Change From Baseline in Plasma log10 HIV-1 RNA at Day 11 |  | Baseline, Day 11 | 
| Part 1 Sentinel Cohort 2: Change From Baseline in Plasma log10 HIV-1 RNA at Day 15 |  | Baseline, Day 15 | 
| Part 1 Randomized Cohort: Change From Baseline in Plasma log10 HIV-1 RNA at Day 15 |  | Baseline, Day 15 | 
| Part 2: Percentage of Participants With Plasma HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Analysis at Week 24 | The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 24 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. | Week 24 | 
| Part 2: Change From Baseline in Plasma log10 HIV-1 RNA at Week 24 |  | Baseline, Week 24 | 
| Part 2: Change From Baseline in CD4+ Cell Count at Week 24 |  | Baseline, Week 24 | 
| Part 2: Number of Participants With Treatment Emergent Nucleos(t)Ide Reverse Transcriptase Inhibitor (NRTI) Mutations at the Time of Virologic Failure | Treatment emergent virological failure was defined as an event with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of the study drug. Virologic failure was defined as virologic rebound or as suboptimal virologic response in relation to pre-GS-9131 baseline plasma HIV-1 RNA levels. Virological rebound was defined as if participant at any visit after achieving HIV-1 RNA < 50 copies/mL, a rebound in HIV-1 RNA ≥ 50 copies/mL, or a >1 log10 increase in HIV-1 RNA from the nadir which was subsequently confirmed at the following scheduled or unscheduled visit. Suboptimal virologic response was defined as plasma HIV-1 RNA ≥ 200 copies/mL and reduction in HIV-1 RNA ≤ 1 log10 from pre-GS-9131 baseline at the Week 8 visit with confirmation at the next scheduled or unscheduled visit. | From first dose up to Week 24 | 
| Part 2: Number of Participants With Treatment Emergent Protease Inhibitor (PI) Mutations at the Time of Virologic Failure | Treatment emergent virological failure was defined as an event with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of the study drug. Virologic failure was defined as virologic rebound or as suboptimal virologic response in relation to pre-GS-9131 baseline plasma HIV-1 RNA levels. Virological rebound was defined as if participant at any visit after achieving HIV-1 RNA < 50 copies/mL, a rebound in HIV-1 RNA ≥ 50 copies/mL, or a >1 log10 increase in HIV-1 RNA from the nadir which was subsequently confirmed at the following scheduled or unscheduled visit. Suboptimal virologic response was defined as plasma HIV-1 RNA ≥ 200 copies/mL and reduction in HIV-1 RNA ≤ 1 log10 from pre-GS-9131 baseline at the Week 8 visit with confirmation at the next scheduled or unscheduled visit. | From first dose up to Week 24 | 
| Part 2: Number of Participants With Treatment Emergent Integrase Strand Transfer Inhibitor (INSTI) Mutations at the Time of Virologic Failure | Treatment emergent virological failure was defined as an event with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of the study drug. Virologic failure was defined as virologic rebound or as suboptimal virologic response in relation to pre-GS-9131 baseline plasma HIV-1 RNA levels. Virological rebound was defined as if participant at any visit after achieving HIV-1 RNA < 50 copies/mL, a rebound in HIV-1 RNA ≥ 50 copies/mL, or a >1 log10 increase in HIV-1 RNA from the nadir which was subsequently confirmed at the following scheduled or unscheduled visit. Suboptimal virologic response was defined as plasma HIV-1 RNA ≥ 200 copies/mL and reduction in HIV-1 RNA ≤ 1 log10 from pre-GS-9131 baseline at the Week 8 visit with confirmation at the next scheduled or unscheduled visit. | From first dose up to Week 24 |