Pre-Exposure Prophylaxis of HIV Infection
Conditions
Brief summary
The goal of this study is to evaluate the efficacy of the study drugs, lenacapavir (LEN) in preventing HIV infection, in participants ≥ 16 years of age who have condomless receptive anal sex with partners assigned male at birth and are at risk for HIV-1 infection. The primary objective of this study is to evaluate the efficacy of LEN for HIV-1 PrEP in participants ≥ 16 years of age who have condomless receptive anal sex with partners assigned male at birth at risk of HIV-1 infection.
Interventions
Tablets administered orally without regard to food
DRUGF/TDF
Tablets administered orally
DRUGSub-cutaneous (SC) Lenacapavir (LEN)
Administered via SC injections
DRUGPlacebo SC LEN
Administered via SC injections
DRUGPTM F/TDF
Tablets administered orally
DRUGPTM Oral LEN
Tablets administered orally
DRUGF/TAF (for US participants only)
F/TAF tablets administered orally once daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: Incidence Phase * CGM, TGW, TGM, and GNB who have condomless receptive anal sex with partners assigned male at birth and are at risk for HIV infection. * HIV-1 status unknown at screening and no prior HIV-1 testing within the last 3 months. * Sexually active with ≥ 1 partner assigned male at birth (condomless receptive anal sex) in the last 12 months and 1 of the following: * Condomless receptive anal sex with ≥ 2 partners in the last 12 weeks. * History of syphilis, rectal gonorrhea, or rectal chlamydia in the last 24 weeks. * Self-reported use of stimulants with sex in the last 12 weeks. Randomized Phase * Negative local rapid fourth generation HIV-1/2 Ab/Ag, central fourth generation HIV-1/2 Ab/Ag, and HIV-1 RNA quantitative nucleic acid amplification testing (NAAT). * Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min at screening according to the Cockcroft-Gault formula for creatinine clearance (CLcr). Key
Exclusion criteria
Incidence Phase * Prior use of HIV PrEP (including F/TDF or F/TAF) or HIV postexposure prophylaxis (PEP) in the past 12 weeks or any prior use of long-acting systemic PrEP (including cabotegravir or islatravir). * Prior recipient of an HIV vaccine or HIV broadly neutralizing antibody formulation. Randomized Phase * Acute viral hepatitis A, B or C or evidence of chronic hepatitis B or C infection. * Severe hepatic impairment or a history of or current clinical decompensated liver cirrhosis. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Phase: Recent Infection Testing Algorithm (RITA) Estimate of the Background Human Immunodeficiency-1 Virus Infection Incidence Rate (bHIV) Per 100 Person Years (PY) | Incidence Phase Screening Visit (Day 1) | bHIV per 100 PY in the Incidence Phase was calculated using RITA. The RITA incorporated HIV-1 testing results and recency assay testing results to estimate the bHIV. Recency assay testing was performed for participants in the All Screened Set found to have HIV-1 infection at the Incidence Phase Screening Visit as defined below. Participants were considered to have recent HIV-1 infection if the normalized optical density (ODn) was below 1.5 threshold using the Sedia limiting antigen avidity enzyme immunoassay (LAg-EIA) and the HIV-1 RNA (viral load) was \> 75 copies/mL of blood. HIV-1 infection was defined as participants having at least one of the following central lab results at the Incidence Phase screening visit: * Positive HIV-1/2 differentiation Ab, OR * Positive HIV-1 ribonucleic acid (RNA) qualitative test, OR * HIV-1 RNA quantitative test ≥200 copies/mL. |
| Randomized Blinded Phase: HIV-1 Incidence Reported Per 100 PY for LEN Compared to Background HIV (bHIV, Participants in All Screened Set) | Up to 149 weeks | HIV-1 incidence per 100 PY for LEN was calculated as the number of participants who acquired HIV-1 divided by the total of a) for participants not diagnosed with HIV-1, sum of all duration of follow-up time in years, while at risk of HIV-1 infection (where a year is 365.25 days) and b) for participants diagnosed with HIV-1, sum of all duration of follow-up time up to confirmed HIV-1 diagnoses. HIV-1 diagnosis was determined by an HIV adjudication committee who reviewed potential HIV-1 infection events in the randomized participants. The committee, in a blinded, consistent, and unbiased manner, determined whether HIV test results confirmed HIV-1 infection and determined the date of diagnosis for each case, defined as the date of the earliest study visit with evidence of HIV infection considering both prospective HIV testing and back-testing of archived samples. bHIV incidence per 100 PY in All Screened Set was estimated as described in outcome measure#1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Randomized Blinded Phase: HIV-1 Incidence Reported Per 100 PY for LEN Compared to F/TDF | Up to 149 weeks | HIV-1 incidence per 100 PY was calculated as the number of participants who acquired HIV-1 divided by the total of a) for participants not diagnosed with HIV-1, sum of all duration of follow-up time in years, while at risk of HIV-1 infection (where a year is 365.25 days) and b) for participants diagnosed with HIV-1, sum of all duration of follow-up time up to confirmed HIV-1 diagnoses. HIV-1 diagnosis was determined by an HIV adjudication committee who reviewed potential HIV-1 infection events in the randomized participants. The committee, in a blinded, consistent, and unbiased manner, determined whether HIV test results confirmed HIV-1 infection and determined the date of diagnosis for each case, defined as the date of the earliest study visit with evidence of HIV infection considering both prospective HIV testing and back-testing of archived samples. |
| Randomized Blinded Phase: HIV-1 Incidence Among Participants Adherent to LEN | Up to 149 weeks | A participant was defined as adherent to LEN if they have received all per-protocol administrations of LEN within 28 weeks since the previous administration. The incidence of HIV-1 infection per 100 PY calculation is defined in outcome measure #2. |
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | Up to 4 years | TEAEs were defined as 1 or both of the following: Any adverse events (AEs) leading to premature discontinuation of study drug, or Any AEs with an onset date on or after the study drug start date and no later than the last exposure date after permanent discontinuation of the study drug. An AE was any untoward medical occurrence in a clinical study participant administered a study drug that did not necessarily have a causal relationship with the treatment. |
| Percentage of Participants Experiencing Clinically Significant Laboratory Abnormalities | Up to 4 years | Treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from baseline at any post-baseline visit, up to and including the last exposure date for participants who permanently discontinued study drug, or the last available date in the database snapshot for participants who were still on treatment at the time of an analysis. |
Countries
Argentina, Brazil, Mexico, Peru, Puerto Rico, South Africa, Thailand, United States
Participant flow
Recruitment details
4807 participants were screened. Out of 4807, 4634 participants had at least 1 non-missing HIV-1 diagnosis based on HIV test results from a central laboratory. Therefore, 4634 participants were considered for screening in the Incidence Phase and were included in the All Screened Set. Out of 4634, 3292 were enrolled and randomized in Randomized Blinded Phase. Incidence Phase refers to the Screening Phase.
Pre-assignment details
Participants were enrolled in Argentina, Brazil, Mexico, Peru, South Africa, Thailand, Puerto Rico and United States. Data submitted represent primary analysis from data collected by Primary Completion Date (PCD) (Per pre-specified analysis, PCD is when at least 50% of the planned randomized participants were followed up for at least 52 weeks in the study or prematurely discontinued from the study). Complete data will be submitted within 1 year of actual study completion date.
Participants by arm
| Arm | Count |
|---|---|
| Randomized Blinded Phase: LEN + Placebo-to-match (PTM) F/TDF Participants received lenacapavir (LEN) 927 mg subcutaneous (SC) injection, every 26 weeks, starting on Day 1 for up to approximately 52 weeks. Participants also received loading dose of LEN 600 mg tablet orally, once daily on Day 1 and Day 2. Participants received placebo to match (PTM) emtricitabine/tenofovir disoproxil fumarate (F/TDF) tablet orally, once daily, up to approximately 52 weeks. | 2,183 |
| Randomized Blinded Phase: Placebo LEN + F/TDF Participants received F/TDF tablet on Day 1 orally, once daily for up to approximately 52 weeks. Participants also received PTM LEN SC injection every 26 weeks starting on Day 1 up to approximately 52 weeks and PTM LEN tablet, orally, once daily on Day 1 and Day 2. | 1,088 |
| Total | 3,271 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 |
| Overall Study | Death | 4 | 2 |
| Overall Study | Hiv-1 Infection | 6 | 7 |
| Overall Study | Investigator's discretion | 8 | 5 |
| Overall Study | Lost to Follow-up | 73 | 47 |
| Overall Study | Non-compliance with Study Drug | 8 | 5 |
| Overall Study | Protocol Violation | 1 | 3 |
| Overall Study | Randomized but Never Treated | 12 | 9 |
| Overall Study | Still on Study | 1,826 | 926 |
| Overall Study | Withdrew Assent | 1 | 0 |
| Overall Study | Withdrew Consent | 128 | 59 |
Baseline characteristics
| Characteristic | Randomized Blinded Phase: LEN + Placebo-to-match (PTM) F/TDF | Randomized Blinded Phase: Placebo LEN + F/TDF | Total |
|---|---|---|---|
| Age, Continuous | 30 years STANDARD_DEVIATION 8.7 | 31 years STANDARD_DEVIATION 9.5 | 30 years STANDARD_DEVIATION 9 |
| Age, Customized 16 to <18 years | 3 Participants | 1 Participants | 4 Participants |
| Age, Customized 18 to ≤ 25 years | 749 Participants | 343 Participants | 1092 Participants |
| Age, Customized > 25 to < 35 years | 912 Participants | 423 Participants | 1335 Participants |
| Age, Customized 35 to < 50 years | 454 Participants | 267 Participants | 721 Participants |
| Age, Customized ≥ 50 years | 65 Participants | 54 Participants | 119 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1378 Participants | 675 Participants | 2053 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 804 Participants | 413 Participants | 1217 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 20 Participants | 13 Participants | 33 Participants |
| Race/Ethnicity, Customized Asian | 269 Participants | 144 Participants | 413 Participants |
| Race/Ethnicity, Customized Black or African American | 584 Participants | 301 Participants | 885 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Not Collected | 8 Participants | 2 Participants | 10 Participants |
| Race/Ethnicity, Customized Other or More Than One Race | 577 Participants | 284 Participants | 861 Participants |
| Race/Ethnicity, Customized White | 722 Participants | 344 Participants | 1066 Participants |
| Region of Enrollment Argentina | 161 Participants | 64 Participants | 225 Participants |
| Region of Enrollment Brazil | 769 Participants | 396 Participants | 1165 Participants |
| Region of Enrollment Mexico | 8 Participants | 4 Participants | 12 Participants |
| Region of Enrollment Peru | 309 Participants | 138 Participants | 447 Participants |
| Region of Enrollment Puerto Rico | 9 Participants | 2 Participants | 11 Participants |
| Region of Enrollment South Africa | 246 Participants | 112 Participants | 358 Participants |
| Region of Enrollment Thailand | 250 Participants | 139 Participants | 389 Participants |
| Region of Enrollment United States | 431 Participants | 233 Participants | 664 Participants |
| Sex: Female, Male Female | 43 Participants | 24 Participants | 67 Participants |
| Sex: Female, Male Male | 2140 Participants | 1064 Participants | 3204 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 2,195 | 2 / 1,097 |
| other Total, other adverse events | 1,912 / 2,183 | 882 / 1,088 |
| serious Total, serious adverse events | 71 / 2,183 | 43 / 1,088 |
Outcome results
Primary
Incidence Phase: Recent Infection Testing Algorithm (RITA) Estimate of the Background Human Immunodeficiency-1 Virus Infection Incidence Rate (bHIV) Per 100 Person Years (PY)
bHIV per 100 PY in the Incidence Phase was calculated using RITA. The RITA incorporated HIV-1 testing results and recency assay testing results to estimate the bHIV. Recency assay testing was performed for participants in the All Screened Set found to have HIV-1 infection at the Incidence Phase Screening Visit as defined below. Participants were considered to have recent HIV-1 infection if the normalized optical density (ODn) was below 1.5 threshold using the Sedia limiting antigen avidity enzyme immunoassay (LAg-EIA) and the HIV-1 RNA (viral load) was \> 75 copies/mL of blood. HIV-1 infection was defined as participants having at least one of the following central lab results at the Incidence Phase screening visit: * Positive HIV-1/2 differentiation Ab, OR * Positive HIV-1 ribonucleic acid (RNA) qualitative test, OR * HIV-1 RNA quantitative test ≥200 copies/mL.
Time frame: Incidence Phase Screening Visit (Day 1)
Population: Participants in the All Screened Set were analyzed. The All Screened Set included all participants who were screened for HIV-1 in the Incidence Phase and had a non-missing HIV-1 diagnosis based on HIV test results at Incidence Phase screening. As the outcome measure was assessed prior to Randomized Blinded Phase, the data is reported in one arm consisting of all participants screened in Incidence Phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Incidence Phase: All Screened Participants With Non-missing HIV-1 Diagnosis | Incidence Phase: Recent Infection Testing Algorithm (RITA) Estimate of the Background Human Immunodeficiency-1 Virus Infection Incidence Rate (bHIV) Per 100 Person Years (PY) | 2.374 HIV-1 events per 100 person-years |
Primary
Randomized Blinded Phase: HIV-1 Incidence Reported Per 100 PY for LEN Compared to Background HIV (bHIV, Participants in All Screened Set)
HIV-1 incidence per 100 PY for LEN was calculated as the number of participants who acquired HIV-1 divided by the total of a) for participants not diagnosed with HIV-1, sum of all duration of follow-up time in years, while at risk of HIV-1 infection (where a year is 365.25 days) and b) for participants diagnosed with HIV-1, sum of all duration of follow-up time up to confirmed HIV-1 diagnoses. HIV-1 diagnosis was determined by an HIV adjudication committee who reviewed potential HIV-1 infection events in the randomized participants. The committee, in a blinded, consistent, and unbiased manner, determined whether HIV test results confirmed HIV-1 infection and determined the date of diagnosis for each case, defined as the date of the earliest study visit with evidence of HIV infection considering both prospective HIV testing and back-testing of archived samples. bHIV incidence per 100 PY in All Screened Set was estimated as described in outcome measure#1.
Time frame: Up to 149 weeks
Population: Participants in the LEN group in the Full Analysis Set (FAS) were analyzed. The FAS included all randomized participants who received at least 1 dose of any study drug and had not been diagnosed with HIV-1 on or prior to the first dose date. Per prespecified analysis, HIV-1 incidence for this outcome measure was reported only for participants who received LEN. The HIV-1 incidence was compared with participants in the All Screened Set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Incidence Phase: All Screened Participants With Non-missing HIV-1 Diagnosis | Randomized Blinded Phase: HIV-1 Incidence Reported Per 100 PY for LEN Compared to Background HIV (bHIV, Participants in All Screened Set) | 0.103 HIV-1 events per 100 person-years |
| Incidence Phase: All Screened Participants With Non-missing HIV-1 Diagnosis | Randomized Blinded Phase: HIV-1 Incidence Reported Per 100 PY for LEN Compared to Background HIV (bHIV, Participants in All Screened Set) | 2.374 HIV-1 events per 100 person-years |
Comparison: Null Hypothesis 01: LEN/bHIV\>= 1; Null hypothesis was to be rejected if HIV-1 incidence in LEN was significantly lower than bHIV.p-value: <0.000195% CI: [0.01, 0.182]Wald test
Comparison: Null Hypothesis 02: LEN/bHIV\>= 0.8; Null hypothesis was to be rejected if HIV-1 incidence in LEN was significantly and at least 20% lower than bHIV.p-value: <0.000195% CI: [0.01, 0.182]Wald test
Secondary
Percentage of Participants Experiencing Clinically Significant Laboratory Abnormalities
Treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from baseline at any post-baseline visit, up to and including the last exposure date for participants who permanently discontinued study drug, or the last available date in the database snapshot for participants who were still on treatment at the time of an analysis.
Time frame: Up to 4 years
Secondary
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)
TEAEs were defined as 1 or both of the following: Any adverse events (AEs) leading to premature discontinuation of study drug, or Any AEs with an onset date on or after the study drug start date and no later than the last exposure date after permanent discontinuation of the study drug. An AE was any untoward medical occurrence in a clinical study participant administered a study drug that did not necessarily have a causal relationship with the treatment.
Time frame: Up to 4 years
Secondary
Randomized Blinded Phase: HIV-1 Incidence Among Participants Adherent to LEN
A participant was defined as adherent to LEN if they have received all per-protocol administrations of LEN within 28 weeks since the previous administration. The incidence of HIV-1 infection per 100 PY calculation is defined in outcome measure #2.
Time frame: Up to 149 weeks
Population: Participants in the Full Analysis Set who were adherent to LEN were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Incidence Phase: All Screened Participants With Non-missing HIV-1 Diagnosis | Randomized Blinded Phase: HIV-1 Incidence Among Participants Adherent to LEN | 0.125 HIV-1 events per 100 person-years |
Secondary
Randomized Blinded Phase: HIV-1 Incidence Reported Per 100 PY for LEN Compared to F/TDF
HIV-1 incidence per 100 PY was calculated as the number of participants who acquired HIV-1 divided by the total of a) for participants not diagnosed with HIV-1, sum of all duration of follow-up time in years, while at risk of HIV-1 infection (where a year is 365.25 days) and b) for participants diagnosed with HIV-1, sum of all duration of follow-up time up to confirmed HIV-1 diagnoses. HIV-1 diagnosis was determined by an HIV adjudication committee who reviewed potential HIV-1 infection events in the randomized participants. The committee, in a blinded, consistent, and unbiased manner, determined whether HIV test results confirmed HIV-1 infection and determined the date of diagnosis for each case, defined as the date of the earliest study visit with evidence of HIV infection considering both prospective HIV testing and back-testing of archived samples.
Time frame: Up to 149 weeks
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Incidence Phase: All Screened Participants With Non-missing HIV-1 Diagnosis | Randomized Blinded Phase: HIV-1 Incidence Reported Per 100 PY for LEN Compared to F/TDF | 0.103 HIV-1 events per 100 person-years |
| Incidence Phase: All Screened Participants With Non-missing HIV-1 Diagnosis | Randomized Blinded Phase: HIV-1 Incidence Reported Per 100 PY for LEN Compared to F/TDF | 0.931 HIV-1 events per 100 person-years |
p-value: <0.000195% CI: [-1.669, -0.255]Hybrid approach
Comparison: Null Hypothesis 04: LEN vs F/TDF\>= 1; Null hypothesis was to be rejected if HIV-1 incidence in LEN was significantly lower than F/TDF.p-value: 0.0024595% CI: [0.024, 0.513]Poisson model