Study of Novel Antiretrovirals in Participants With HIV-1

Study Overview
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Brief Summary
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Master protocol: The goal of this master clinical trial study is to learn how novel antiretrovirals (medicines that stop the virus from multiplying) affect the human immunodeficiency virus-1 (HIV-1) infection in people living with HIV (PWH). Substudy-01 (GS-US-544-5905-01) will evaluate GS-5894 in PWH. Substudy-02 (GS-US-544-5905-02) will evaluate GS-1720 in PWH.

Detailed Description
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This umbrella study will begin with a substudy of GS-5894 (Substudy-01), and new substudies may be added in the future. Substudies evaluating additional study drugs will be added in a staggered manner when relevant nonclinical and/or clinical data become available. Substudy-01 enrollment closed, actual enrollment is 13. Substudy-02 planned enrollment is 30.

Official Title
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An Umbrella Phase 1b, Open-label, Multi-Cohort Study to Evaluate Safety, Pharmacokinetics, and Antiviral Activity of Novel Antiretrovirals in Participants With HIV-1

Conditions
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HIV-1-infection

Intervention / Treatment
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* Drug: GS-5894
* Drug: B/F/TAF
* Drug: Standard of Care (Substudy 01)
* Drug: GS-1720
* Drug: Standard of Care (Substudy 02)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: All Substudies: Plasma human immunodeficiency virus-1 (HIV-1) ribonucleic acid (RNA) ≥ 5000 copies/mL but ≤ 400,000 copies/mL at screening. Cluster of differentiation 4 (CD4) cell count > 200 cells/mm^3 at screening. Antiretroviral (ARV) treatment-naive or treatment-experienced but naive to the investigational ARV drug class being investigated in the given substudy and have not received any ARV within 12 weeks of screening, including medications received for pre-exposure prophylaxis (PrEP) or postexposure prophylaxis (PEP) (note that current or prior receipt of long acting (LA) parenteral ARVs such as monoclonal antibodies (mAbs) targeting HIV-1, injectable cabotegravir (CAB), or injectable rilpivirine (RPV) is exclusionary). Have adequate renal function (estimated glomerular filtration rate (eGFR) ≥ 70 mL/min/1.73 m^2) No clinically significant abnormalities in electrocardiogram (ECG) at screening. Substudy-01 and Substudy-02: Participants in substudy-01 should be willing to initiate a non-NNRTI based SOC ART on Day 11. Participants in substudy-02 should be willing to initiate any SOC ART on Day 11. Willing and able to comply with meal requirements on dosing days. Key Exclusion Criteria: All Substudies: Known historical genotypic or phenotypic resistance to 4 major ARV classes (nucleoside reverse transcriptase inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), integrase strand-transfer inhibitor (INSTI)). History of an AIDS-defining condition including present at the time of screening. Active, serious infections (other than HIV-1) requiring therapy and including active tuberculosis infection < 30 days prior to randomization. History of or current clinical decompensated liver cirrhosis (eg, ascites, encephalopathy, or variceal bleeding). Any other serious or active clinical condition or prior therapy that, in the opinion of the investigator, would make the individual unsuitable for the study or unable to comply with dosing requirements. Hepatitis C virus (HCV) antibody positive and detectable HCV RNA. Chronic hepatitis B virus (HBV) infection, as determined by either: Positive HBV surface antigen and negative HBV surface antibody, regardless of HBV core antibody status, at the screening visit, or Positive HBV core antibody and negative HBV surface antibody, regardless of HBV surface antigen status, at the screening visit. Hepatic transaminases (aspartate aminotransferase (AST) or alanine aminotransferase (ALT)) > 5 x upper limit of normal (ULN). Current alcohol or substance use judged by the investigator to potentially interfere with individual study compliance. Positive serum pregnancy test at screening or a positive pregnancy test prior to Day 1. Individuals with plan to breastfeed during the study period including the protocol-defined follow-up period. Requirement for ongoing therapy with or prior use of any prohibited medications listed in the protocol. Any prescription medications or over the counter medications, including herbal products, within 28 days prior to start of study drug dosing must be reviewed and approved by the sponsor, with the exception of vitamins and/or acetaminophen and/or ibuprofen. Any current or prior receipt of LA parenteral ARVs such as mAbs targeting HIV-1, injectable CAB, or injectable RPV, for treatment or prophylaxis (PrEP, PEP). Substudy-01 and Substudy-02: Requirement for ongoing therapy with any prohibited medications listed in protocol. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Substudy-01: GS-5894<br>Participants will receive GS-5894. After assessments on Day 11 or upon early termination (ET), participants will initiate a regimen of Biktarvy® (bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF, BVY)), or other non-nonnucleoside reverse transcriptase inhibitor (NNRTI) based standard of care (SOC) antiretroviral therapy (ART) regimen up to Day 39. Non-NNRTI SOC ART regimen may include: abacavir (ABC)/dolutegravir (DTG)/lamivudine (3TC), (ABC/DTG/3TC) DTG plus (tenofovir alafenamide fumarate (TAF) or tenofovir disoproxil fumarate (TDF) plus (emtricitabine (FTC) or 3TC) Approximately 5 cohorts may enroll. Participants will be enrolled in Cohort 1 initially and then dosing in subsequent cohorts will proceed after safety review team (SRT) review of emerging data. | Drug: GS-5894<br>* Administered orally<br>Drug: B/F/TAF<br>* Administered orally<br>* Other names: Biktarvy®;Drug: Standard of Care (Substudy 01)<br>* Antiretroviral therapy, administered orally Non-NNRTIs, examples: ABC/DTG/3TC; DTG plus (TAF or TDF) plus (FTC or 3TC)<br>|
| Experimental: Substudy-02: GS-1720<br>Participants will receive GS-1720. After assessments on Day 11 or upon ET, participants will initiate a regimen of Biktarvy® (bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF, BVY)), or an alternative SOC ART regimen up to Day 60. SOC ART regimen, example INSTIs: DTG/ABC/3TC or DTG/3TC Approximately 5 cohorts may enroll. Participants will be enrolled in Cohort 1 initially and then dosing in subsequent cohorts will proceed after safety review team (SRT) review of emerging data. | Drug: B/F/TAF<br>* Administered orally<br>* Other names: Biktarvy®;Drug: GS-1720<br>* Administered orally<br>Drug: Standard of Care (Substudy 02)<br>* Antiretroviral therapy, administered orally Example INSTIs: DTG/ABC/3TC or DTG/3TC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Substudies: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 copies/mL) at Day 11 |  | Baseline; Day 11 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Substudies: Change From Baseline in Plasma HIV-1 RNA (log10 copies/mL) at Day 8 |  | Baseline; Day 8 | 
| All Substudies: Percentage of Participants Experiencing Adverse Events (AEs) |  | Substudy-01: First dose date up to Day 39; Substudy-02: First dose date up to Day 60 | 
| All Substudies: Percentage of Participants Experiencing Graded Laboratory Abnormalities |  | Substudy-01: First dose date up to Day 39; Substudy-02: First dose date and upto Day 60 | 
| Substudy-01 and Substudy-02: Pharmacokinetic (PK) Parameter: Cmax of GS-5894 and GS-1720 | Cmax is defined as the maximum observed concentration of drug. | Day 1 Predose up to Day 11 | 
| Substudy-01 and Substudy-02: PK Parameter of: AUC of GS-5894 and GS-1720 | AUC is defined as the area under the concentration versus time curve. | Substudy-01: Day 1 Predose up to Day 39; Substudy-02: Day 1 Predose up to Day 60 | 
| Substudy-01 and Substudy-02: PK Parameter: Ct of GS-5894 and GS-1720 | Ct is defined as the concentration at specified time t. | Day 1 Predose up to Day 11 | 
| All Substudies: Correlation Between Ct and/or AUC versus the Reduction of Plasma HIV-1 RNA (Log10 Copies/mL) from Day 1 Through Day 11 |  | Day 1 up to Day 11 | 
| All Substudies: Percentage of Participants at Any Measurement Achieving HIV-1 RNA < 50 Copies/mL by Day 11 at Each Dose Level |  | Up to Day 11 | 
| Percentage of Participants with Emergence of Viral Resistance to the ARV Class of the Given Drug | The ARV class of given drugs would be BVY or NNRTIs (Substudy 01) or INSTIs (Substudy 02). | Up to Day 11 |