| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pre-Exposure Prophylaxis of HIV Infection |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068341 |
| E.1.2 | Term | HIV-1 infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the efficacy of LEN in preventing the risk of HIV-1 infection relative to the background HIV-1 incidence rate. Participants are cisgender men (CGM), transgender women (TGW), transgender men (TGM), and gender nonbinary people (GNB).
The primary objective for the Incidence Phase of this study is to estimate the HIV-1 background incidence rate.
The primary objective for the Randomized Blinded Phase of this study is as follows:
• To evaluate the efficacy of LEN for HIV-1 pre-exposure prophylaxis (PrEP) 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 |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives for the Randomized Blinded Phase of this study are as follows:
• To compare the efficacy of LEN with F/TDF for HIV-1 PrEP 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
• To evaluate the efficacy of LEN for HIV-1 PrEP in participants at risk of HIV-1 infection in participants adherent to LEN
• To evaluate the safety and tolerability of LEN and F/TDF for HIV-1 PrEP 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
• To evaluate the safety and tolerability of LEN for HIV-1 PrEP in adolescent participants ≥ 16 to < 18 years of age who have condomless receptive anal sex with partners assigned male at birth and are at risk for HIV-1 infection |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria for the Incidence Phase
1)The ability to comprehend and provide a signed written informed consent, which must be obtained prior to initiation of study procedures. For adolescents, the ability to comprehend and provide a signed assent form, which must be obtained prior to initiation of study procedures. A parent/guardian may provide informed consent for adolescents (in accordance with local laws and regulations).
2) CGM, TGW, TGM, and GNB who have condomless receptive anal sex with partners assigned male at birth and are at risk for HIV-1 infection.
3)Age ≥ 16 years at screening. Enrollment of adolescents (participants 16 and 17 years of age)
will commence following the first Data Monitoring Committee (DMC) review of the unblinded safety data and recommendation to continue the study. Gilead will notify sites when they may begin enrollment of adolescents.
4) HIV-1 status unknown at screening and no prior HIV-1 testing within the last 3 months
5) Sexually active with ≥ 1 partner assigned male at birth (condomless receptive anal sex) in the last 12 months and 1 of the following:
a) Condomless receptive anal sex with ≥ 2 partners in the last 12 weeks
b) History of syphilis, rectal gonorrhea, or rectal chlamydia in the last 24 weeks
c) Self-reported use of stimulants with sex in the last 12 weeks
6) Willing and able to comply with study procedures.
Inclusion Criteria for the Randomized Blinded Phase
Participants who have a negative fourth generation HIV-1/2 antibody (Ab)/antigen (Ag) test and meet the criteria from the Incidence Phase can be screened for the Randomized Blinded Phase if additional consent is obtained. Participants who meet the following criteria will be included in the Randomized Blinded Phase.
1) 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)(Appendix 5)
2) Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min at screening according to the Cockcroft-Gault formula for creatinine clearance (CLcr) {Cockcroft 1976}:
(140 − age in years) x (weight in kg)/72 x (serum creatinine in mg/dL) x [0.85 if female] = CLcr (mL/min)
3) Body weight ≥ 35 kg
4) Participants of childbearing potential who engage in frontal (vaginal) intercourse must not intend to become pregnant during the study and must agree to utilize protocol-specified method(s) of contraception as described in Appendix 6. |
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria for the Incidence Phase
1) Prior use of HIV PrEP (including F/TDF or emtricitabine/tenofovir alafenamide [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)
2) Participants who previously received an HIV vaccine or HIV broadly neutralizing antibody (bNAb) are not eligible. Individuals may be eligible if they participated in an HIV vaccine or bNAb study but have documentation that they did not receive active product (eg, placebo recipients).
Exclusion Criteria for the Randomized Blinded Phase
Participants who meet any of the following exclusion criteria are not eligible to be randomized in the Randomized Blinded Phase of this study.
1) Participation in any other clinical trial (including observational and COVID-19 vaccine trials) without prior approval from the sponsor is prohibited while participating in this trial. An exception is made for participation in the sponsor-approved ancillary qualitative participant interview study, which is allowed and does not require medical monitor approval.
2) Known hypersensitivity to the study drug, the metabolites, or formulation excipient
3) Acute viral hepatitis A, B, or C or evidence of chronic hepatitis B or C infection
a) If a participant has a negative hepatitis B surface antigen (HBsAg), negative hepatitis B surface antibody (HBsAb), and positive hepatitis B core antibody (HBcAb), hepatitis B virus (HBV) DNA testing will be completed. If the HBV DNA result is positive, the participant is a screen failure. Participants found to be susceptible to HBV infection will be offered HBV vaccination.
b) If the hepatitis C virus (HCV) Ab result is positive, then HCV RNA will be evaluated. Participants found to be positive for HCV at screening must not have active infection or must have completed treatment and achieved a sustained virologic response.
4) Severe hepatic impairment or a history of or current clinical decompensated liver cirrhosis (eg, ascites, encephalopathy, variceal bleeding)
5) Have a suspected or known active, serious infection(s) (eg, active tuberculosis, etc)
6) Need for continued use of any contraindicated concomitant medications
7) Have a history of osteoporosis or bone fragility fractures
8) Current alcohol or substance abuse judged by the investigator to be problematic such that it potentially interferes with participant study adherence
9) Grade 3 or Grade 4 proteinuria or glycosuria at screening that is unexplained or not clinically manageable
10) Participants assigned female at birth of childbearing potential who are pregnant or lactating at screening or on Day 1. Participants must have a negative pregnancy test at screening and on Day 1 (see “Definition of Childbearing Potential” in Appendix 6).
11) Any other clinical condition, laboratory abnormalities, or psychosocial condition or prior therapy that, in the opinion of the Investigator, would make the participant unsuitable for the study or unable to comply with dosing requirements
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Incidence Phase Endpoints
The primary endpoint for the Incidence Phase of this study is the diagnosis of recent HIV-1 infection.
The background HIV-1 incidence per 100 person-years (PY) will be computed based on the recency assay algorithm.
The primary endpoint for the Randomized Blinded Phase of this study is as follows:
• Diagnosis of HIV-1 infection |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints for the Randomized Blinded Phase of this study are as follows:
• Diagnosis of HIV-1 among participants while adherent to study drug (as defined by medium and high TFV-DP concentrations in DBS at the time of HIV-1 diagnosis for the F/TDF study drug group, and by LEN on time administration in the past 26 weeks for the LEN study drug
group)
• Occurrence of treatment-emergent AEs (TEAEs) and treatment-emergent clinical laboratory
abnormalities to evaluate safety and tolerability of LEN and F/TDF for HIV-1 PrEP |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Argentina |
| Peru |
| Brazil |
| Mexico |
| South Africa |
| Thailand |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| last participant’s last observation (last visit). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial months | 17 |
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