An Umbrella Phase 1b, Open-label, Multi-Cohort Study to Evaluate Safety, Pharmacokinetics, and Antiviral Activity of Novel Antiretrovirals in Participants With HIV-1
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 49
- 试验地点
- 42
- 主要终点
- Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data
研究概览
简要总结
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 bavtavirine in PWH.
Substudy-02 (GS-US-544-5905-02) will evaluate GS-1720 in PWH.
Substudy-03 (GS-US-544-5905-03) will evaluate GS-6212 in PWH.
详细描述
This umbrella study will begin with a substudy of bavtavirine (Substudy-01), and later substudies GS-1720 (Substudy-02) and GS-6212 (Substudy-03) will be added. 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 enrollment closed, actual enrollment is 28.
- Substudy-03 enrollment closed, actual enrollment is 8.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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, Substudy-02, and Substudy-03:
- •Participants in substudy-01 should be willing to initiate a non-NNRTI based SOC ART on Day
- •Participants in substudy-02 and Substudy-03 should be willing to initiate any SOC ART on Day
- •Willing and able to comply with meal requirements on dosing days.
排除标准
- •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
- •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, Substudy-02, Substudy-03:
- •Requirement for ongoing therapy with any prohibited medications listed in protocol.
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)
Participants receive a single dose of bavtavirine 675 mg tablet with a high-fat meal on Day 1. After assessments on Day 11 or upon early termination (ET), the participants initiate a regimen of B/F/TAF, or an alternative standard of care (SOC) antiretroviral (ART) regimen (example INSTI + NRTIs: dolutegravir (DTG)/abacavir (ABC)/3TC or DTG/3TC) up to Day 39.
干预措施: Bavtavirine (Drug)
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)
Participants receive a single dose of bavtavirine 675 mg tablet with a high-fat meal on Day 1. After assessments on Day 11 or upon early termination (ET), the participants initiate a regimen of B/F/TAF, or an alternative standard of care (SOC) antiretroviral (ART) regimen (example INSTI + NRTIs: dolutegravir (DTG)/abacavir (ABC)/3TC or DTG/3TC) up to Day 39.
干预措施: B/F/TAF (Drug)
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)
Participants receive a single dose of bavtavirine 675 mg tablet with a high-fat meal on Day 1. After assessments on Day 11 or upon early termination (ET), the participants initiate a regimen of B/F/TAF, or an alternative standard of care (SOC) antiretroviral (ART) regimen (example INSTI + NRTIs: dolutegravir (DTG)/abacavir (ABC)/3TC or DTG/3TC) up to Day 39.
干预措施: Standard of Care (Substudy 01) (Drug)
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)
Participants receive a single dose of bavtavirine 1200 mg tablet with a low-fat meal on Day 1. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 39.
干预措施: Bavtavirine (Drug)
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)
Participants receive a single dose of bavtavirine 1200 mg tablet with a low-fat meal on Day 1. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 39.
干预措施: B/F/TAF (Drug)
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)
Participants receive a single dose of bavtavirine 1200 mg tablet with a low-fat meal on Day 1. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 39.
干预措施: Standard of Care (Substudy 01) (Drug)
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)
Participants receive bavtavirine 900 mg tablet with a high-fat meal on Days 1 and 2. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 39.
干预措施: Bavtavirine (Drug)
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)
Participants receive bavtavirine 900 mg tablet with a high-fat meal on Days 1 and 2. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 39.
干预措施: B/F/TAF (Drug)
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)
Participants receive bavtavirine 900 mg tablet with a high-fat meal on Days 1 and 2. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 39.
干预措施: Standard of Care (Substudy 01) (Drug)
Substudy 02: Cohort 1: GS-1720 450 mg
Participants receive a single dose of GS-1720 450 mg tablet on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 60.
干预措施: B/F/TAF (Drug)
Substudy 02: Cohort 1: GS-1720 450 mg
Participants receive a single dose of GS-1720 450 mg tablet on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 60.
干预措施: GS-1720 (Drug)
Substudy 02: Cohort 1: GS-1720 450 mg
Participants receive a single dose of GS-1720 450 mg tablet on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 60.
干预措施: Standard of Care (Substudy 02) (Drug)
Substudy 02: Cohort 2: GS-1720 150 mg
Participants receive a single dose of GS-1720 150 mg tablet on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 60.
干预措施: B/F/TAF (Drug)
Substudy 02: Cohort 2: GS-1720 150 mg
Participants receive a single dose of GS-1720 150 mg tablet on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 60.
干预措施: GS-1720 (Drug)
Substudy 02: Cohort 2: GS-1720 150 mg
Participants receive a single dose of GS-1720 150 mg tablet on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 60.
干预措施: Standard of Care (Substudy 02) (Drug)
Substudy 02: Cohort 3: GS-1720 30 mg
Participants receive a single dose of GS-1720 30 mg tablet on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 60.
干预措施: B/F/TAF (Drug)
Substudy 02: Cohort 3: GS-1720 30 mg
Participants receive a single dose of GS-1720 30 mg tablet on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 60.
干预措施: GS-1720 (Drug)
Substudy 02: Cohort 3: GS-1720 30 mg
Participants receive a single dose of GS-1720 30 mg tablet on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 60.
干预措施: Standard of Care (Substudy 02) (Drug)
Substudy 02: Cohort 4: GS-1720 900 mg
Participants receive a single dose of GS-1720 900 mg tablet on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 60.
干预措施: B/F/TAF (Drug)
Substudy 02: Cohort 4: GS-1720 900 mg
Participants receive a single dose of GS-1720 900 mg tablet on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 60.
干预措施: GS-1720 (Drug)
Substudy 02: Cohort 4: GS-1720 900 mg
Participants receive a single dose of GS-1720 900 mg tablet on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 60.
干预措施: Standard of Care (Substudy 02) (Drug)
Substudy 03: Cohort 1: GS- 6212 100 mg
Participants receive GS-6212 100 mg tablet twice daily on Days 1 through 10. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 25.
干预措施: B/F/TAF (Drug)
Substudy 03: Cohort 1: GS- 6212 100 mg
Participants receive GS-6212 100 mg tablet twice daily on Days 1 through 10. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 25.
干预措施: GS-6212 (Drug)
Substudy 03: Cohort 1: GS- 6212 100 mg
Participants receive GS-6212 100 mg tablet twice daily on Days 1 through 10. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 25.
干预措施: Standard of Care (Substudy 03) (Drug)
结局指标
主要结局
Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data
时间窗: Baseline, Day 11
次要结局
- Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data(Baseline, Day 8)
- Substudy 01: PK Parameter: AUC of Bavtavirine(Day 1 up to Day 11)
- Substudy 01: PK Parameter: Plasma Concentration of Bavtavirine(Days 8 and 11)
- Substudy 02: PK Parameter: AUC of GS-1720(Day 1 up to Day 11)
- Substudy 02: PK Parameter: Plasma Concentration of GS-1720(Days 8 and 11)
- Substudies 01, 02 and 03: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)(First dose up to last dose (Substudy 01: Up to Day 39; Substudy 02: Up to Day 60; Substudy 03: Up to Day 25))
- Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities(First dose up to last dose (Substudy 01: Up to Day 39; Substudy 02: Up to Day 60; Substudy 03: Up to Day 25))
- Substudy 01: Pharmacokinetic (PK) Parameter: Cmax of Bavtavirine(Cohorts 1, 2 and 3 (Day 1: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose); Cohort 3: Day 2: Predose, 0.5, 1, 2, 3, 4, 5, 6, and 8 hours postdose)
- Substudy 03: PK Parameter: Ctrough of GS-6212 (Day 10)(Day 10 (Parameter estimated based on observed data from 0 to 8 hours postdose))
- Substudies 01, 02 and 03: Percentage of Participants at Any Measurement Achieving HIV-1 RNA < 50 Copies/mL by Day 11 at Each Dose Level(Up to Day 11)
- Substudies 01, 02 and 03: Percentage of Participants With Emergence of Viral Resistance to the ARV Class of the Given Drug(Up to Day 11)
- Substudy 02: Inhibitory Quotient (IQ) of GS-1720 by Mean Plasma Concentration (Ct) at Day 11(Day 11)
- Substudy 03: Inhibitory Quotient (IQ) of GS-6212 by Ctrough at Day 11(Day 11)
- Substudy 02: PK Parameter: Cmax of GS-1720(Days 1 and 2: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8 and (optional) 12 hours postdose)
- Substudy 03: PK Parameter: Cmax of GS-6212(Days 1 and 10 (Predose, 0.25, 0.5, 1, 2, 3, 4, 6, 8 and (optional) 12 hours postdose))
- Substudy 03: PK Parameter: AUC0-8h of GS-6212(Days 1 and 10 (Predose, 0.25, 0.5, 1, 2, 3, 4, 6, 8 and (optional) 12 hours postdose))
- Substudy 03: PK Parameter: AUCtau of GS-6212(Day 10 (Parameter estimated based on observed data from 0 to 8 hours postdose))
- Substudy 03: PK Parameter: Plasma Concentration of GS-6212(Days 1 and 10: 8 hours postdose)
- Substudy 03: PK Parameter: Cavg of GS-6212 (Day 10)(Day 10 (predose to 8 hours postdose))
- Substudy 01: Maximum Inhibitory Quotient (IQ) of Bavtavirine by Mean Plasma Concentration (Ct) up to Day 11(Up to Day 11)