Study to Evaluate Safety, Pharmacokinetics, and Antiviral Activity of Bictegravir (GS-9883) in Human Immunodeficiency Virus (HIV)-1 Infected Participants

A Phase 1b Randomized, Double-Blinded, Sequential Cohort Placebo-Controlled Study of the Safety, Pharmacokinetics, and Antiviral Activity of GS-9883 in HIV-1 Infected Subjects

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02275065

Enrollment

Registered

2014-10-27

Start date

2014-10-24

Completion date

2015-01-29

Last updated

2020-11-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

HIV-1 Infection

Keywords

HIV-1 Infected, Adults, Treatment Naive

Brief summary

The primary objective of the study is to investigate the short-term antiviral potency of bictegravir at multiple doses in antiretroviral (ART) treatment-naive adult participants and participants who are ART-experienced but integrase strand transfer inhibitor (INSTI) naive.

Interventions

DRUGBictegravir

Bictegravir tablet(s) administered orally once daily

DRUGPlacebo

Placebo to match bictegravir administered orally once daily

Study design

Allocation

RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Inclusion criteria

Key Inclusion Criteria: * No current or prior anti-HIV treatment, including ART medications received for prevention (preexposure prophylaxis \[PrEP\]), or postexposure prophylaxis (PEP) within 12 weeks of screening * Plasma HIV-1 ribonucleic acid (RNA) ≥ 10,000 copies/mL but ≤ 400,000 copies/mL at screening * Cluster of differentiation 4+ (CD4+) cell count \> 200 cells/mm\^3 Key

Exclusion criteria

* Anticipated to start HIV-1 therapy during the study period * Active participation in another study of investigational or approved ART agents * A new acquired immunodeficiency syndrome (AIDS)-defining condition diagnosed within the 30 days prior to screening * Participants with positive hepatitis C antibody at screening * Chronic hepatitis B virus (HBV) infection * Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 42 days prior to Day 1 (baseline) Note: Other protocol defined Inclusion/

Design outcomes

Primary

Measure	Time frame	Description
Time-Weighted Average Change From Baseline up to Day 11 (DAVG11) in Plasma HIV-1 RNA	Baseline up to Day 11	DAVG11 was defined as the time-weighted average between the first postbaseline value through the last available on-treatment (ie, the last dose date + 1) value up to Day 11 minus the baseline value in plasma HIV-1 RNA (log10 copies/mL). All HIV-1 RNA data up to Day 11 were used for this analysis. DAVG11 was calculated using the trapezoidal rule and the area-under-the-curve concept.

Secondary

Measure	Time frame	Description
Percentage of Participants Who Experienced Graded Laboratory Abnormalities	First dose date up to last dose date plus 30 days (Maximum: 40 days)	A treatment-emergent graded laboratory abnormality was defined as an increase of at least 1 toxicity grade from predose assessment and occurring after the predose visit and on or before the date of the last dose of study drug plus 30 days. If the predose assessment was missing, then any abnormality of at least Grade 1 associated with the study drug was considered a treatment-emergent graded laboratory abnormality. The most severe graded abnormality from all tests was counted for each participant.
Maximum Reduction From Baseline Through Day 17 in Plasma HIV-1 RNA	Baseline to Day 17	Maximum reduction from baseline was defined as the minimum of change from baseline in plasma HIV-1 RNA (i.e. smallest change in HIV-RNA from baseline).
Viral Decay Slope in Plasma HIV-1 RNA	Baseline up to Day 11	Viral Decay Slope = (log10 \[HIV-1 RNA on Day x\] - log10 \[HIV-1 RNA on Day 1\]) / (x-1), where x is the collection day of the last available on treatment HIV-1 RNA collected up to Day 7.
Percentage of Participants With HIV-1 RNA < 50 Copies/mL	Day 17	—
Pharmacokinetic (PK) Parameter: Cmax of Bictegravir Following Single-Dose and Multiple-Dose Administration	0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose at Day 1 for single dose and Day 10 for multiple dose	Cmax is defined as the maximum concentration of drug.
PK Parameter: Tmax of Bictegravir Following Single-Dose and Multiple-Dose Administration	0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose at Day 1 for single dose and Day 10 for multiple dose	Tmax is defined as the time (observed time point) of Cmax.
PK Parameter: AUC0-24 of Bictegravir Following Single-Dose Administration	0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose at Day 1	AUC0-24 is defined as the concentration of drug over time from time zero to time 24 hours.
Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (AEs)	First dose date up to last dose date plus 30 days (Maximum: 40 days)	—
PK Parameter: AUCtau of Bictegravir Following Multiple-Dose Administration	0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose at Day 10	AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
PK Parameter: t1/2 of Bictegravir Following Multiple-Dose Administration	0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose at Day 10	t1/2 is defined as the estimate of the terminal elimination half-life of the drug.
PK Parameter: Ctau of Bictegravir Following Multiple-Dose Administration	0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose at Day 10	Ctau is defined as the observed drug concentration at the end of the dosing interval.
PK Parameter: CLss/F of Bictegravir Following Multiple-Dose Administration	0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose at Day 10	CLss/F is defined as the apparent oral clearance following multiple-dose administration of the drug.
PK Parameter: AR_AUC of Bictegravir Following Multiple-Dose Administration	0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose at Day 1 and 10	Accumulation ratio of AUC (AR\_AUC) = AUCtau on Day 10 / AUC0-24 on Day 1. Percentage of accumulation ratio has been reported.
PK Parameter: AR_Cmax of Bictegravir Following Multiple-Dose Administration	0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose at Day 1 and 10	Accumulation ratio of Cmax (AR\_Cmax) = Cmax on Day 10 / Cmax on Day 1. Percentage of accumulation ratio has been reported.
PK/Pharmacodynamic (PD) Analysis: Pearson Correlation Between AUCtau of Bictegravir and DAVG11 in Plasma HIV-1 RNA	0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose at Day 10	AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). DAVG11 was defined as the time-weighted average between the first postbaseline value through the last available on-treatment (ie, the last dose date + 1) value up to Day 11 minus the baseline value in plasma HIV-1 RNA (log10 copies/mL).
PK Parameter: AUClast of Bictegravir Following Single-Dose Administration	0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose at Day 1	AUClast is defined as the concentration of drug from time zero to the last observable concentration.

Countries

United States

Participant flow

Recruitment details

Participants were enrolled at study sites in United States. The first participant was screened on 24 October 2014. The last study visit occurred on 29 January 2015.

Pre-assignment details

33 participants were screened.

Participants by arm

Arm	Count
Bictegravir 5 mg Bictegravir 5 mg (1 × 5 mg tablet) administered orally once daily for 10 days	4
Bictegravir 25 mg Bictegravir 25 mg (1 × 25 mg tablet) administered orally once daily for 10 days	4
Bictegravir 50 mg Bictegravir 50 mg (2 × 25 mg tablets) administered orally once daily for 10 days	4
Bictegravir 100 mg Bictegravir 100 mg (1 × 100 mg tablet) administered orally once daily for 10 days	4
Placebo Placebo matched to bictegravir tablet administered orally once daily for 10 days	4
Total	20

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004
Overall Study	Randomized but not treated	1	0	1	1	0

Baseline characteristics

Characteristic	Total	Bictegravir 5 mg	Bictegravir 25 mg	Bictegravir 50 mg	Bictegravir 100 mg	Placebo
Age, Continuous	33 years STANDARD_DEVIATION 11.6	29 years STANDARD_DEVIATION 4	44 years STANDARD_DEVIATION 16.5	34 years STANDARD_DEVIATION 11.5	36 years STANDARD_DEVIATION 11.2	24 years STANDARD_DEVIATION 3.2
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants	2 Participants	2 Participants	1 Participants	0 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	14 Participants	2 Participants	2 Participants	3 Participants	4 Participants	3 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Human Immunodeficiency Virus, Type 1 Ribonucleic Acid (HIV-1 RNA)	4.40 log10 copies/mL STANDARD_DEVIATION 0.745	3.76 log10 copies/mL STANDARD_DEVIATION 1.02	4.64 log10 copies/mL STANDARD_DEVIATION 0.498	4.42 log10 copies/mL STANDARD_DEVIATION 0.458	4.71 log10 copies/mL STANDARD_DEVIATION 1.04	4.50 log10 copies/mL STANDARD_DEVIATION 0.407
Race/Ethnicity, Customized Race Black	6 Participants	0 Participants	1 Participants	1 Participants	1 Participants	3 Participants
Race/Ethnicity, Customized Race Other	1 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Race White	13 Participants	4 Participants	2 Participants	3 Participants	3 Participants	1 Participants
Sex: Female, Male Female	1 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants
Sex: Female, Male Male	19 Participants	4 Participants	4 Participants	3 Participants	4 Participants	4 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	0 / 4	0 / 4	0 / 4	0 / 4	0 / 4
other Total, other adverse events	3 / 4	1 / 4	2 / 4	2 / 4	1 / 4
serious Total, serious adverse events	0 / 4	0 / 4	0 / 4	0 / 4	0 / 4

Outcome results

Primary

Time-Weighted Average Change From Baseline up to Day 11 (DAVG11) in Plasma HIV-1 RNA

DAVG11 was defined as the time-weighted average between the first postbaseline value through the last available on-treatment (ie, the last dose date + 1) value up to Day 11 minus the baseline value in plasma HIV-1 RNA (log10 copies/mL). All HIV-1 RNA data up to Day 11 were used for this analysis. DAVG11 was calculated using the trapezoidal rule and the area-under-the-curve concept.

Time frame: Baseline up to Day 11

Population: The Per-Protocol Analysis Set included all randomized participants who took at least 1 dose of bictegravir with baseline HIV-1 RNA ≥ 1900 copies/mL, which allowed up to 2 log decreases in HIV-1 RNA.

Arm	Measure	Group	Value (MEAN)	Dispersion
Bictegravir 5 mg	Time-Weighted Average Change From Baseline up to Day 11 (DAVG11) in Plasma HIV-1 RNA	Baseline	4.26 log10 copies/mL	Standard Deviation 0.157
Bictegravir 5 mg	Time-Weighted Average Change From Baseline up to Day 11 (DAVG11) in Plasma HIV-1 RNA	Change at Day 11	-0.92 log10 copies/mL	Standard Deviation 0.104
Bictegravir 25 mg	Time-Weighted Average Change From Baseline up to Day 11 (DAVG11) in Plasma HIV-1 RNA	Baseline	4.64 log10 copies/mL	Standard Deviation 0.498
Bictegravir 25 mg	Time-Weighted Average Change From Baseline up to Day 11 (DAVG11) in Plasma HIV-1 RNA	Change at Day 11	-1.33 log10 copies/mL	Standard Deviation 0.174
Bictegravir 50 mg	Time-Weighted Average Change From Baseline up to Day 11 (DAVG11) in Plasma HIV-1 RNA	Baseline	4.42 log10 copies/mL	Standard Deviation 0.458
Bictegravir 50 mg	Time-Weighted Average Change From Baseline up to Day 11 (DAVG11) in Plasma HIV-1 RNA	Change at Day 11	-1.37 log10 copies/mL	Standard Deviation 0.31
Bictegravir 100 mg	Time-Weighted Average Change From Baseline up to Day 11 (DAVG11) in Plasma HIV-1 RNA	Change at Day 11	-1.61 log10 copies/mL	Standard Deviation 0.256
Bictegravir 100 mg	Time-Weighted Average Change From Baseline up to Day 11 (DAVG11) in Plasma HIV-1 RNA	Baseline	4.71 log10 copies/mL	Standard Deviation 1.04
Placebo	Time-Weighted Average Change From Baseline up to Day 11 (DAVG11) in Plasma HIV-1 RNA	Baseline	4.50 log10 copies/mL	Standard Deviation 0.407
Placebo	Time-Weighted Average Change From Baseline up to Day 11 (DAVG11) in Plasma HIV-1 RNA	Change at Day 11	-0.01 log10 copies/mL	Standard Deviation 0.144

p-value: <0.001t-test, 2 sided

Secondary

Maximum Reduction From Baseline Through Day 17 in Plasma HIV-1 RNA

Maximum reduction from baseline was defined as the minimum of change from baseline in plasma HIV-1 RNA (i.e. smallest change in HIV-RNA from baseline).

Time frame: Baseline to Day 17

Population: Participants in the Per-Protocol Analysis Set were analyzed.

Arm	Measure	Value (MEAN)	Dispersion
Bictegravir 5 mg	Maximum Reduction From Baseline Through Day 17 in Plasma HIV-1 RNA	-1.52 log10 copies/mL	Standard Deviation 0.079
Bictegravir 25 mg	Maximum Reduction From Baseline Through Day 17 in Plasma HIV-1 RNA	-2.18 log10 copies/mL	Standard Deviation 0.241
Bictegravir 50 mg	Maximum Reduction From Baseline Through Day 17 in Plasma HIV-1 RNA	-2.31 log10 copies/mL	Standard Deviation 0.191
Bictegravir 100 mg	Maximum Reduction From Baseline Through Day 17 in Plasma HIV-1 RNA	-2.91 log10 copies/mL	Standard Deviation 0.526
Placebo	Maximum Reduction From Baseline Through Day 17 in Plasma HIV-1 RNA	-0.12 log10 copies/mL	Standard Deviation 0.177

p-value: <0.001t-test, 2 sided

Secondary

Percentage of Participants Who Experienced Graded Laboratory Abnormalities

A treatment-emergent graded laboratory abnormality was defined as an increase of at least 1 toxicity grade from predose assessment and occurring after the predose visit and on or before the date of the last dose of study drug plus 30 days. If the predose assessment was missing, then any abnormality of at least Grade 1 associated with the study drug was considered a treatment-emergent graded laboratory abnormality. The most severe graded abnormality from all tests was counted for each participant.

Time frame: First dose date up to last dose date plus 30 days (Maximum: 40 days)

Population: Participants in the Safety Analysis Set were analyzed.

Arm	Measure	Value (NUMBER)
Bictegravir 5 mg	Percentage of Participants Who Experienced Graded Laboratory Abnormalities	75.0 percentage of participants
Bictegravir 25 mg	Percentage of Participants Who Experienced Graded Laboratory Abnormalities	25.0 percentage of participants
Bictegravir 50 mg	Percentage of Participants Who Experienced Graded Laboratory Abnormalities	0 percentage of participants
Bictegravir 100 mg	Percentage of Participants Who Experienced Graded Laboratory Abnormalities	25.0 percentage of participants
Placebo	Percentage of Participants Who Experienced Graded Laboratory Abnormalities	50.0 percentage of participants

Secondary

Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (AEs)

Time frame: First dose date up to last dose date plus 30 days (Maximum: 40 days)

Population: The Safety Analysis Set included participants who were randomized and received at least 1 dose of bictegravir or matched placebo.

Arm	Measure	Value (NUMBER)
Bictegravir 5 mg	Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (AEs)	75.0 percentage of participants
Bictegravir 25 mg	Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (AEs)	25.0 percentage of participants
Bictegravir 50 mg	Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (AEs)	50.0 percentage of participants
Bictegravir 100 mg	Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (AEs)	50.0 percentage of participants
Placebo	Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (AEs)	25.0 percentage of participants

Secondary

Percentage of Participants With HIV-1 RNA < 50 Copies/mL

Time frame: Day 17

Population: Participants in the Per-Protocol Analysis Set were analyzed.

Arm	Measure	Value (NUMBER)
Bictegravir 5 mg	Percentage of Participants With HIV-1 RNA < 50 Copies/mL	0 percentage of participants
Bictegravir 25 mg	Percentage of Participants With HIV-1 RNA < 50 Copies/mL	0 percentage of participants
Bictegravir 50 mg	Percentage of Participants With HIV-1 RNA < 50 Copies/mL	25.0 percentage of participants
Bictegravir 100 mg	Percentage of Participants With HIV-1 RNA < 50 Copies/mL	50.0 percentage of participants
Placebo	Percentage of Participants With HIV-1 RNA < 50 Copies/mL	0 percentage of participants

Secondary

Pharmacokinetic (PK) Parameter: Cmax of Bictegravir Following Single-Dose and Multiple-Dose Administration

Cmax is defined as the maximum concentration of drug.

Time frame: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose at Day 1 for single dose and Day 10 for multiple dose

Population: The PK Analysis Set included all participants who were randomized and received at least 1 dose of bictegravir and had at least 1 nonmissing concentration of bictegravir.

Arm	Measure	Group	Value (MEAN)	Dispersion
Bictegravir 5 mg	Pharmacokinetic (PK) Parameter: Cmax of Bictegravir Following Single-Dose and Multiple-Dose Administration	Single-Dose	493.3 ng/mL	Standard Deviation 72.12
Bictegravir 5 mg	Pharmacokinetic (PK) Parameter: Cmax of Bictegravir Following Single-Dose and Multiple-Dose Administration	Multiple-Dose	741.5 ng/mL	Standard Deviation 134.65
Bictegravir 25 mg	Pharmacokinetic (PK) Parameter: Cmax of Bictegravir Following Single-Dose and Multiple-Dose Administration	Multiple-Dose	3475.0 ng/mL	Standard Deviation 712.67
Bictegravir 25 mg	Pharmacokinetic (PK) Parameter: Cmax of Bictegravir Following Single-Dose and Multiple-Dose Administration	Single-Dose	2565.0 ng/mL	Standard Deviation 331.31
Bictegravir 50 mg	Pharmacokinetic (PK) Parameter: Cmax of Bictegravir Following Single-Dose and Multiple-Dose Administration	Single-Dose	4957.5 ng/mL	Standard Deviation 667.6
Bictegravir 50 mg	Pharmacokinetic (PK) Parameter: Cmax of Bictegravir Following Single-Dose and Multiple-Dose Administration	Multiple-Dose	6080.0 ng/mL	Standard Deviation 1323.2
Bictegravir 100 mg	Pharmacokinetic (PK) Parameter: Cmax of Bictegravir Following Single-Dose and Multiple-Dose Administration	Single-Dose	7367.5 ng/mL	Standard Deviation 2293.9
Bictegravir 100 mg	Pharmacokinetic (PK) Parameter: Cmax of Bictegravir Following Single-Dose and Multiple-Dose Administration	Multiple-Dose	12235.0 ng/mL	Standard Deviation 3040.98

Secondary

PK Parameter: AR_AUC of Bictegravir Following Multiple-Dose Administration

Accumulation ratio of AUC (AR\_AUC) = AUCtau on Day 10 / AUC0-24 on Day 1. Percentage of accumulation ratio has been reported.

Time frame: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose at Day 1 and 10