HIV-1 Infection
Conditions
Brief summary
The primary objectives of this study are to evaluate the antiretroviral activity of a switch to Doravirine/Islatravir (DOR/ISL) compared with continued Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF) at Week 48; and to evaluate the safety and tolerability of a switch to DOR/ISL compared with continued BIC/FTC/TAF, through Week 48. The primary hypotheses are that (1) DOR/ISL is non-inferior to continued BIC/FTC/TAF, as assessed by the percentage of participants with HIV-1 ribonucleic acid (RNA) ≥50 copies/mL at Week 48, with a margin of 4 percentage points used to define non-inferiority; and (2) DOR/ISL is superior to BIC/FTC/TAF, as assessed by the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48.
Interventions
DRUGDOR/ISL
DOR/ISL 100 mg/0.25 mg oral tablets once daily
DRUGBIC/FTC/TAF
BIC/FTC/TAF 50 mg/200 mg/25 mg oral tablets once daily
0 mg oral tablets once daily
0 mg oral tablets once daily
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
The key inclusion and
Exclusion criteria
include but are not limited to the following: Inclusion Criteria: * Is HIV-1 positive with plasma HIV-1 RNA \<50 copies/mL * Has been receiving BIC/FTC/TAF therapy with documented viral suppression (HIV-1 RNA \<50 copies/mL) for ≥3 consecutive months prior to providing documented informed consent and has no history of prior virologic treatment failure on any past or current regimen * Female is not a participant of childbearing potential (POCBP); or if a participant of childbearing potential, not pregnant or breastfeeding, and is willing to use an acceptable contraceptive method or abstain from heterosexual intercourse for study duration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) ≥50 Copies/mL at Week 48 | Week 48 | HIV-1 RNA levels in blood samples taken at each visit were measured with a reliable lower limit of quantification of \<50 copies/mL. The percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48 is presented using the FDA Snapshot missing data approach. |
| Percentage of Participants Who Experience Adverse Events (AEs) Through Week 48 | Up to Week 48 | An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who experienced at least one AE is reported. |
| Percentage of Participants Who Discontinue Study Intervention Due to AEs Through Week 48 | Up to Week 48 | An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who discontinued study intervention due to an AE is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment-Emergent, Resistance-associated Substitutions at Week 48 | Up to Week 48 | Participants with clinically significant confirmed viremia \[2 consecutive occurences 4 weeks (+-1 week) apart of HIV-1 RNA ≥200 copies/mL at any time during the study\] or who discontinue study intervention for another reason with HIV-1 RNA ≥200 copies/mL at the time of discontinuation met the criteria for post-baseline resistance testing. Per protocol, participants with HIV-1 RNA ≥400 copies/mL or any participant for whom available genotypic or phenotypic data show evidence of resistance, irrespective of viral load were included in the resistance analysis subset. Plasma samples were collected for genotypic and phenotypic HIV-1 viral drug resistance testing and used to assess resistance-associated substitutions and virus susceptibility to study intervention. The percentage of participants in the resistance analysis subset with treatment-emergent resistance-associated substitutions to the study intervention is presented. |
| Percentage of Participants With HIV-1 RNA ≥50 Copies/mL at Week 96 | Week 96 | Percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 96 will be reported. |
| Percentage of Participants With HIV-1 RNA <200 Copies/mL at Week 96 | Week 96 | Percentage of participants with HIV-1 RNA \<200 copies/mL at Week 96 will be reported. |
| Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 96 | Week 96 | Percentage of participants with HIV-1 RNA \<50 copies/mL at Week 96 will be reported. |
| Change From Baseline in CD4+ T-cell Count at Week 96 | Baseline at Day 1 and Week 96 | Mean change from baseline at Day 1 in CD4+ T-cell count at Week 96 will be reported. |
| Number of Participants With Viral Drug Resistance Mutations at Week 96 | Week 96 | Number of participants with evidence of viral drug resistance-associated substitutions at Week 96 will be reported. |
| Percentage of Participants With HIV-1 RNA <200 Copies/mL at Week 48 | Week 48 | HIV-1 RNA levels in blood samples taken at each visit were measured with a reliable lower limit of quantification of \<50 copies/mL. The percentage of participants with HIV-1 RNA \<200 copies/mL at Week 48 is presented using the FDA Snapshot missing data approach. |
| Percentage of Participants With HIV-1 RNA <200 Copies/mL at Week 144 | Week 144 | Percentage of participants with HIV-1 RNA \<200 copies/mL at Week 144 will be reported. |
| Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 144 | Week 144 | Percentage of participants with HIV-1 RNA \<50 copies/mL at Week 144 will be reported. |
| Change From Baseline in CD4+ T-cell Count at Week 144 | Baseline at Day 1 and Week 144 | Mean change from baseline at Day 1 in CD4+ T-cell count at Week 144 will be reported. |
| Number of Participants With Viral Drug Resistance Mutations at Week 144 | Week 144 | Number of participants with evidence of viral drug resistance-associated substitutions at Week 144 will be reported. |
| Percentage of Participants Who Experience AEs Through Week 144 | Up to Week 144 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. |
| Percentage of Participants Who Discontinue Study Intervention Due to AEs Through Week 144 | Up to Week 144 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. |
| Percentage of Participants With HIV-1 RNA ≥50 Copies/mL at Week 144 | Week 144 | Percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 144 will be reported. |
| Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 48 | Week 48 | HIV-1 RNA levels in blood samples taken at each visit were measured with a reliable lower limit of quantification of \<50 copies/mL. The percentage of participants with HIV-1 RNA \<50 copies/mL at Week 48 is presented using the FDA Snapshot missing data approach. |
| Change From Baseline in Cluster of Differentiation 4-positive (CD4+) T-cell Count at Week 48 | Baseline at Day 1 and Week 48 | Plasma CD4+ T-Cell Count was measured in cells/mm\^3 for baseline and 48 weeks. Baseline measurements were defined as the Day 1 value of each participant. The change from baseline to Week 48 and corresponding 2-sided 95% confidence intervals were calculated based on cLDA models adjusted by treatment group, time, and the interaction of time-by-treatment group. |
Countries
Australia, Chile, Israel, Japan, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| DOR/ISL and Placebo to BIC/FTC/TAF Participants will receive DOR/ISL 100 mg/0.25 mg and Placebo to BIC/FTC/TAF once daily (QD) orally from day 1 to week 144. After week 144, eligible participants may continue on DOR/ISL and continue study treatment until week 240 or to when DOR/ISL becomes commercially accessible (whichever comes first). | 343 |
| BIC/FTC/TAF and Placebo to DOR/ISL Participants will receive BIC/FTC/TAF 50 mg/200 mg/25 mg and Placebo to DOR/ISL once daily (QD) orally from day 1 to week 144. After week 144, eligible participants may switch to DOR/ISL and continue study treatment until week 240 or to when DOR/ISL becomes commercially accessible (whichever comes first). | 171 |
| Total | 514 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 7 | 0 |
| Overall Study | Participant moved away from trial site | 0 | 1 |
| Overall Study | Randomized by Mistake Without Study Treatment | 1 | 0 |
| Overall Study | Status not Recorded | 316 | 161 |
| Overall Study | Withdrawal by Subject | 9 | 3 |
Baseline characteristics
| Characteristic | BIC/FTC/TAF and Placebo to DOR/ISL | Total | DOR/ISL and Placebo to BIC/FTC/TAF |
|---|---|---|---|
| Age, Continuous | 47.6 Years STANDARD_DEVIATION 13.1 | 47.6 Years STANDARD_DEVIATION 12.9 | 47.6 Years STANDARD_DEVIATION 12.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 44 Participants | 117 Participants | 73 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 125 Participants | 387 Participants | 262 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 10 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 30 Participants | 20 Participants |
| Race (NIH/OMB) Black or African American | 47 Participants | 159 Participants | 112 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 9 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) White | 106 Participants | 312 Participants | 206 Participants |
| Sex: Female, Male Female | 36 Participants | 110 Participants | 74 Participants |
| Sex: Female, Male Male | 135 Participants | 404 Participants | 269 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 343 | 0 / 171 |
| other Total, other adverse events | 94 / 342 | 52 / 171 |
| serious Total, serious adverse events | 15 / 342 | 11 / 171 |
Outcome results
Primary
Percentage of Participants Who Discontinue Study Intervention Due to AEs Through Week 48
An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who discontinued study intervention due to an AE is reported.
Time frame: Up to Week 48
Population: The analysis population includes all randomized participants who received ≥1 dose of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DOR/ISL and Placebo to BIC/FTC/TAF | Percentage of Participants Who Discontinue Study Intervention Due to AEs Through Week 48 | 2.9 Percentage of Participants |
| BIC/FTC/TAF and Placebo to DOR/ISL | Percentage of Participants Who Discontinue Study Intervention Due to AEs Through Week 48 | 1.8 Percentage of Participants |
Primary
Percentage of Participants Who Experience Adverse Events (AEs) Through Week 48
An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who experienced at least one AE is reported.
Time frame: Up to Week 48
Population: The analysis population includes all randomized participants who received ≥1 dose of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DOR/ISL and Placebo to BIC/FTC/TAF | Percentage of Participants Who Experience Adverse Events (AEs) Through Week 48 | 74.6 Percentage of Participants |
| BIC/FTC/TAF and Placebo to DOR/ISL | Percentage of Participants Who Experience Adverse Events (AEs) Through Week 48 | 71.3 Percentage of Participants |
Primary
Percentage of Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) ≥50 Copies/mL at Week 48
HIV-1 RNA levels in blood samples taken at each visit were measured with a reliable lower limit of quantification of \<50 copies/mL. The percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48 is presented using the FDA Snapshot missing data approach.
Time frame: Week 48
Population: The analysis population includes all randomized participants who received ≥1 dose of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DOR/ISL and Placebo to BIC/FTC/TAF | Percentage of Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) ≥50 Copies/mL at Week 48 | 1.5 Percentage of Participants |
| BIC/FTC/TAF and Placebo to DOR/ISL | Percentage of Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) ≥50 Copies/mL at Week 48 | 0.6 Percentage of Participants |
p-value: 0.00395% CI: [-1.86, 2.9]Miettinen and Nurminen method
p-value: 0.19295% CI: [-1.86, 2.9]Miettinen and Nurminen method
Secondary
Change From Baseline in CD4+ T-cell Count at Week 144
Mean change from baseline at Day 1 in CD4+ T-cell count at Week 144 will be reported.
Time frame: Baseline at Day 1 and Week 144
Secondary
Change From Baseline in CD4+ T-cell Count at Week 96
Mean change from baseline at Day 1 in CD4+ T-cell count at Week 96 will be reported.
Time frame: Baseline at Day 1 and Week 96
Secondary
Change From Baseline in Cluster of Differentiation 4-positive (CD4+) T-cell Count at Week 48
Plasma CD4+ T-Cell Count was measured in cells/mm\^3 for baseline and 48 weeks. Baseline measurements were defined as the Day 1 value of each participant. The change from baseline to Week 48 and corresponding 2-sided 95% confidence intervals were calculated based on cLDA models adjusted by treatment group, time, and the interaction of time-by-treatment group.
Time frame: Baseline at Day 1 and Week 48
Population: The analysis population includes all randomized participants who received ≥1 dose of study intervention and who had baseline data for CD4+ T-cell count.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| DOR/ISL and Placebo to BIC/FTC/TAF | Change From Baseline in Cluster of Differentiation 4-positive (CD4+) T-cell Count at Week 48 | 30.40 Cells/mm^3 |
| BIC/FTC/TAF and Placebo to DOR/ISL | Change From Baseline in Cluster of Differentiation 4-positive (CD4+) T-cell Count at Week 48 | 28.19 Cells/mm^3 |
Secondary
Number of Participants With Viral Drug Resistance Mutations at Week 144
Number of participants with evidence of viral drug resistance-associated substitutions at Week 144 will be reported.
Time frame: Week 144
Secondary
Number of Participants With Viral Drug Resistance Mutations at Week 96
Number of participants with evidence of viral drug resistance-associated substitutions at Week 96 will be reported.
Time frame: Week 96
Secondary
Percentage of Participants Who Discontinue Study Intervention Due to AEs Through Week 144
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
Time frame: Up to Week 144
Secondary
Percentage of Participants Who Experience AEs Through Week 144
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
Time frame: Up to Week 144
Secondary
Percentage of Participants With HIV-1 RNA <200 Copies/mL at Week 144
Percentage of participants with HIV-1 RNA \<200 copies/mL at Week 144 will be reported.
Time frame: Week 144
Secondary
Percentage of Participants With HIV-1 RNA <200 Copies/mL at Week 48
HIV-1 RNA levels in blood samples taken at each visit were measured with a reliable lower limit of quantification of \<50 copies/mL. The percentage of participants with HIV-1 RNA \<200 copies/mL at Week 48 is presented using the FDA Snapshot missing data approach.
Time frame: Week 48
Population: The analysis population includes all randomized participants who received ≥1 dose of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DOR/ISL and Placebo to BIC/FTC/TAF | Percentage of Participants With HIV-1 RNA <200 Copies/mL at Week 48 | 91.8 Percentage of Participants |
| BIC/FTC/TAF and Placebo to DOR/ISL | Percentage of Participants With HIV-1 RNA <200 Copies/mL at Week 48 | 94.2 Percentage of Participants |
Secondary
Percentage of Participants With HIV-1 RNA <200 Copies/mL at Week 96
Percentage of participants with HIV-1 RNA \<200 copies/mL at Week 96 will be reported.
Time frame: Week 96
Secondary
Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 144
Percentage of participants with HIV-1 RNA \<50 copies/mL at Week 144 will be reported.
Time frame: Week 144
Secondary
Percentage of Participants With HIV-1 RNA ≥50 Copies/mL at Week 144
Percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 144 will be reported.
Time frame: Week 144
Secondary
Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 48
HIV-1 RNA levels in blood samples taken at each visit were measured with a reliable lower limit of quantification of \<50 copies/mL. The percentage of participants with HIV-1 RNA \<50 copies/mL at Week 48 is presented using the FDA Snapshot missing data approach.
Time frame: Week 48
Population: The analysis population includes all randomized participants who received ≥1 dose of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DOR/ISL and Placebo to BIC/FTC/TAF | Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 48 | 91.5 Percentage of Participants |
| BIC/FTC/TAF and Placebo to DOR/ISL | Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 48 | 94.2 Percentage of Participants |
Secondary
Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 96
Percentage of participants with HIV-1 RNA \<50 copies/mL at Week 96 will be reported.
Time frame: Week 96
Secondary
Percentage of Participants With HIV-1 RNA ≥50 Copies/mL at Week 96
Percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 96 will be reported.
Time frame: Week 96
Secondary
Percentage of Participants With Treatment-Emergent, Resistance-associated Substitutions at Week 48
Participants with clinically significant confirmed viremia \[2 consecutive occurences 4 weeks (+-1 week) apart of HIV-1 RNA ≥200 copies/mL at any time during the study\] or who discontinue study intervention for another reason with HIV-1 RNA ≥200 copies/mL at the time of discontinuation met the criteria for post-baseline resistance testing. Per protocol, participants with HIV-1 RNA ≥400 copies/mL or any participant for whom available genotypic or phenotypic data show evidence of resistance, irrespective of viral load were included in the resistance analysis subset. Plasma samples were collected for genotypic and phenotypic HIV-1 viral drug resistance testing and used to assess resistance-associated substitutions and virus susceptibility to study intervention. The percentage of participants in the resistance analysis subset with treatment-emergent resistance-associated substitutions to the study intervention is presented.
Time frame: Up to Week 48
Population: Per protocol, participants with HIV-1 RNA ≥400 copies/mL or any participant for whom available genotypic or phenotypic data show evidence of resistance, irrespective of viral load were included in the resistance analysis subset. Participants without available assay results were not included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DOR/ISL and Placebo to BIC/FTC/TAF | Percentage of Participants With Treatment-Emergent, Resistance-associated Substitutions at Week 48 | 0 Percentage of Participants |