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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
49
Administered orally
Administered orally
Antiretroviral therapy, administered orally Non-NNRTIs, examples: ABC/DTG/3TC; DTG plus (TAF or TDF) plus (FTC or 3TC)
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
Time frame: Baseline, Day 11
Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data
Time frame: Baseline, Day 8
Substudies 01, 02 and 03: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as any AEs with an onset date on or after the study drug start date. Percentages were rounded-off.
Time frame: 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
Treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from baseline at any time postbaseline. Laboratory abnormalities were graded using Division of AIDS (DAIDS) scale with grade 0 to 4 where 0 = no grade; 1 = mild, 2 = moderate, 3 = severe; 4 = potentially life-threatening. Participants with at least a 1 grade increased from baseline for an individual laboratory test where the maximum post baseline laboratory abnormality was 1) grade 1 or higher and 2) grade 3 or higher were reported. The maximum postbaseline toxicity grade across all tests for an individual participant was used in analysis. Percentages were rounded-off.
Time frame: 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
Cmax was defined as the maximum observed concentration of drug.
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Administered orally
Antiretroviral therapy, administered orally Example INSTIs: DTG/ABC/3TC or DTG/3TC
Administered orally
Antiretroviral therapy, administered orally
Long Beach Education and Research Consultants,Substudy-03
Long Beach, California, United States
Mills Clinical Research,Substudy-02
Los Angeles, California, United States
Mills Clinical Research,Substudy-03
Los Angeles, California, United States
Quest Clinical Research,Substudy-01
San Francisco, California, United States
Quest Clinical Research,Substudy-02
San Francisco, California, United States
Quest Clinical Research,Substudy-03
San Francisco, California, United States
Yale University; School of Medicine; AIDS Program (Administrative & Study Supplies),Substudy-03
New Haven, Connecticut, United States
Yale University,Substudy-02
New Haven, Connecticut, United States
Washington Health Institute,Substudy-01
Washington D.C., District of Columbia, United States
Washington Health Institute,Substudy-02
Washington D.C., District of Columbia, United States
...and 32 more locations
Time frame: 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 01: PK Parameter: AUC of Bavtavirine
AUC was defined as the area under the concentration versus time curve.
Time frame: Day 1 up to Day 11
Substudy 01: PK Parameter: Plasma Concentration of Bavtavirine
Time frame: Days 8 and 11
Substudy 02: PK Parameter: Cmax of GS-1720
Cmax was defined as the maximum observed concentration of drug.
Time frame: Days 1 and 2: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8 and (optional) 12 hours postdose
Substudy 02: PK Parameter: AUC of GS-1720
AUC was defined as the area under the concentration versus time curve.
Time frame: Day 1 up to Day 11
Substudy 02: PK Parameter: Plasma Concentration of GS-1720
Time frame: Days 8 and 11
Substudy 03: PK Parameter: Cmax of GS-6212
Cmax was defined as the maximum observed concentration of drug.
Time frame: 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
AUC0-8h was defined as the area under the concentration versus time curve spanning from 0 to 8 hours post dose.
Time frame: 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
AUCtau was defined as the area under the curve from time zero to end of dosing interval.
Time frame: Day 10 (Parameter estimated based on observed data from 0 to 8 hours postdose)
Substudy 03: PK Parameter: Plasma Concentration of GS-6212
Time frame: Days 1 and 10: 8 hours postdose
Substudy 03: PK Parameter: Ctrough of GS-6212 (Day 10)
Ctrough was defined as concentration at the end of the dosing interval.
Time frame: Day 10 (Parameter estimated based on observed data from 0 to 8 hours postdose)
Substudy 03: PK Parameter: Cavg of GS-6212 (Day 10)
Cavg was defined as average plasma concentration during dose administration.
Time frame: Day 10 (predose 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
Percentages were rounded-off.
Time frame: 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
The antiretroviral (ARV) class of given drugs would be BVY or NNRTIs (Substudy 01) or INSTIs (Substudy 02) or INSTIs (Substudy 03). Percentages were rounded-off.
Time frame: Up to Day 11
Substudy 01: Maximum Inhibitory Quotient (IQ) of Bavtavirine by Mean Plasma Concentration (Ct) up to Day 11
Inhibitory quotient was calculated as the ratio of bavtavirine in vivo exposure to in vitro plasma concentration. IQ is defined as paEC95. paEC95 = protein-adjusted effective concentration to achieve 95% effective inhibition. The IQ ≥ 2 indicated higher reduction in viral load with less rebound.
Time frame: Up to Day 11
Substudy 02: Inhibitory Quotient (IQ) of GS-1720 by Mean Plasma Concentration (Ct) at Day 11
Inhibitory quotient was calculated as the ratio of GS-1720 in vivo exposure to in vitro plasma concentration. IQ is defined as paEC95. paEC95 = protein-adjusted effective concentration to achieve 95% effective inhibition. The IQ ≥ 2 indicated higher reduction in viral load with less rebound.
Time frame: Day 11
Substudy 03: Inhibitory Quotient (IQ) of GS-6212 by Ctrough at Day 11
Ctrough is the plasma concentration of the drug just before the next dose. Inhibitory quotient was calculated as the ratio of GS-1720 in vivo exposure to in vitro Ctrough. IQ is defined as paEC95. paEC95 = protein-adjusted effective concentration to achieve 95% effective inhibition. The IQ ≥ 2 indicated higher reduction in viral load with less rebound.
Time frame: Day 11