HIV-1-infection
Conditions
Brief summary
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.
Interventions
DRUGGS-9131
Tablet(s) administered orally once daily
DRUGBIC
Tablet(s) administered orally once daily
DRUGTAF
Tablet(s) administered orally once daily
DRUGARV regimen
ARV regimen may consist of the ARV agents containing nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitor (NNRTI)
DRUGDRV
Tablet(s) administered orally once daily
DRUGRTV
Tablet(s) administered orally once daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 Randomized Cohort: Percentage of Participants With Plasma HIV-1 RNA Decreases From Baseline Exceeding 0.5 log10 at Day 15 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 2: Percentage of Participants With Plasma HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Analysis at Week 24 | 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. |
| Part 2: Change From Baseline in Plasma log10 HIV-1 RNA at Week 24 | Baseline, Week 24 | — |
| Part 1 Randomized Cohort: Change From Baseline in Plasma log10 HIV-1 RNA at Day 15 | Baseline, Day 15 | — |
| Part 2: Number of Participants With Treatment Emergent Nucleos(t)Ide Reverse Transcriptase Inhibitor (NRTI) Mutations at the Time of Virologic Failure | From first dose up to Week 24 | 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. |
| Part 2: Number of Participants With Treatment Emergent Protease Inhibitor (PI) Mutations at the Time of Virologic Failure | From first dose up to Week 24 | 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. |
| Part 2: Number of Participants With Treatment Emergent Integrase Strand Transfer Inhibitor (INSTI) Mutations at the Time of Virologic Failure | From first dose up to Week 24 | 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. |
| Part 2: Change From Baseline in CD4+ Cell Count at Week 24 | Baseline, Week 24 | — |
Countries
Uganda, Zimbabwe
Participant flow
Recruitment details
Participants were enrolled at study sites in Uganda and Zimbawe. The first participant was screened on 03 April 2018. The last study visit occurred on 09 December 2019.
Pre-assignment details
88 participants were screened. The study was conducted in 2 parts. The Part 1 consisted of 3 cohorts- 2 Sentinel Cohorts and 1 Randomized Cohort and Part 2 consisted of 2 Sentinel Cohorts only. The Randomized Cohort in Part 1 was not initiated. The study was terminated because a majority of Sentinel Cohort 2 (Part 1) participants did not meet primary endpoint of human immunodeficiency virus ribonucleic acid (HIV-1 RNA) \> 0.5 log10 decrease from baseline in through up to 14 days of therapy.
Participants by arm
| Arm | Count |
|---|---|
| Sentinel Cohort 1: GS-9131 60 mg Participants in Sentinel Cohort 1 received GS-9131 60 mg tablets orally once daily in addition to their current failing ARV regimen for a period of 10 days in Part 1. | 11 |
| Sentinel Cohort 2: GS-9131 180 mg Participants in Sentinel Cohort 2 received GS-9131 180 mg tablets orally once daily in addition to their current failing ARV regimen for a period of 14 days in Part 1. | 10 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part 2: Combination Therapy | Pregnancy | 0 | 0 | 0 | 1 |
| Part 2: Combination Therapy | Study Terminated by Sponsor | 0 | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Sentinel Cohort 1: GS-9131 60 mg | Sentinel Cohort 2: GS-9131 180 mg | Total |
|---|---|---|---|
| Age, Continuous | 38 years STANDARD_DEVIATION 10.7 | 37 years STANDARD_DEVIATION 6.6 | 38 years STANDARD_DEVIATION 8.8 |
| CD4 Cell Count | 172 cells/µL STANDARD_DEVIATION 164.1 | 289 cells/µL STANDARD_DEVIATION 140.4 | 228 cells/µL STANDARD_DEVIATION 161 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 10 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| HIV-1 RNA | 4.77 log10 copies/mL STANDARD_DEVIATION 0.703 | 4.46 log10 copies/mL STANDARD_DEVIATION 0.584 | 4.62 log10 copies/mL STANDARD_DEVIATION 0.652 |
| HIV-1 RNA Category < 50 copies/mL | 0 Participants | 0 Participants | 0 Participants |
| HIV-1 RNA Category ≥ 50 copies/mL | 11 Participants | 10 Participants | 21 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 10 Participants | 21 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Uganda | 11 participants | 5 participants | 16 participants |
| Region of Enrollment Zimbabwe | 0 participants | 5 participants | 5 participants |
| Sex: Female, Male Female | 11 Participants | 10 Participants | 21 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 10 |
| other Total, other adverse events | 5 / 11 | 10 / 10 |
| serious Total, serious adverse events | 0 / 11 | 0 / 10 |
Outcome results
Primary
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.
Time frame: Day 15
Population: Data was not analyzed as ≥ 50% participants did not achieve HIV-1 RNA \> 0.5 log10 decrease from baseline in Part 1 sentinel cohort 2.
Secondary
Part 1 Randomized Cohort: Change From Baseline in Plasma log10 HIV-1 RNA at Day 15
Time frame: Baseline, Day 15
Population: Data was not reported as the Randomized Cohort in Part 1 was not initiated as the study was terminated early because a majority of Sentinel Cohort 2 participants did not meet primary endpoint of HIV-1 RNA \> 0.5 log10 decrease from baseline in through up to 14 days of therapy.
Secondary
Part 1 Sentinel Cohort 1: Change From Baseline in Plasma log10 HIV-1 RNA at Day 11
Time frame: Baseline, Day 11
Population: The Safety Analysis Set included all participants who took at least 1 dose of study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Randomized Cohort | Part 1 Sentinel Cohort 1: Change From Baseline in Plasma log10 HIV-1 RNA at Day 11 | -0.13 log10 copies/mL | Standard Deviation 0.268 |
Secondary
Part 1 Sentinel Cohort 2: Change From Baseline in Plasma log10 HIV-1 RNA at Day 15
Time frame: Baseline, Day 15
Population: Participants in the Safety Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Randomized Cohort | Part 1 Sentinel Cohort 2: Change From Baseline in Plasma log10 HIV-1 RNA at Day 15 | -0.29 log10 copies/mL | Standard Deviation 0.207 |
Secondary
Part 2: Change From Baseline in CD4+ Cell Count at Week 24
Time frame: Baseline, Week 24
Population: Data were collected for only 1 participant, and due to participant confidentiality data is not being reported.
Secondary
Part 2: Change From Baseline in Plasma log10 HIV-1 RNA at Week 24
Time frame: Baseline, Week 24
Population: Data were collected for only 1 participant, and due to participant confidentiality data is not being reported.
Secondary
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.
Time frame: From first dose up to Week 24
Population: Due to early study termination, data were not collected as none of the participants qualified for resistance testing after Week 8.
Secondary
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.
Time frame: From first dose up to Week 24
Population: Due to early study termination, data were not collected as none of the participants qualified for resistance testing after Week 8.
Secondary
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.
Time frame: From first dose up to Week 24
Population: Due to early study termination, data were not collected as none of the participants qualified for resistance testing after Week 8.
Secondary
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.
Time frame: Week 24
Population: Data were collected for only 1 participant, and due to participant confidentiality data is not being reported.