Study to Evaluate the Safety and Efficacy of Emtricitabine and Tenofovir Alafenamide (F/TAF) Fixed-Dose Combination Once Daily for Pre-Exposure Prophylaxis in Men and Transgender Women Who Have Sex With Men and Are At Risk of HIV-1 Infection

Study Overview
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Brief Summary
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The primary objective of this study is to assess the rates of HIV-1 infection in Men (MSM) and transgender women (TGW) who have sex with men and who are administered daily emtricitabine/tenofovir alafenamide (F/TAF) or emtricitabine/tenofovir disoproxil fumarate (F/TDF) with a minimum follow-up of 48 weeks and at least 50% of participants have 96 weeks of follow-up after randomization.

Official Title
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A Phase 3, Randomized, Double-blind Study to Evaluate the Safety and Efficacy of Emtricitabine and Tenofovir Alafenamide (F/TAF) Fixed-Dose Combination Once Daily for Pre-Exposure Prophylaxis in Men and Transgender Women Who Have Sex With Men and Are At Risk of HIV-1 Infection

Conditions
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Pre-Exposure Prophylaxis of HIV-1 Infection

Intervention / Treatment
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* Drug: F/TAF
* Drug: F/TDF
* Drug: F/TAF Placebo
* Drug: F/TDF Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Must be at high risk of sexual acquisition of HIV HIV-1 negative status MSM and TGW (male at birth) who have at least one of the following: condomless anal intercourse with at least two unique male partners in the past 12 weeks (partners must be either HIV-infected or of unknown HIV status) documented history of syphilis in the past 24 weeks documented history of rectal gonorrhea or chlamydia in the past 24 weeks Adequate renal function: estimated glomerular filtration rate ≥ 60 mL/min according to the Cockcroft-Gault formula Adequate liver and hematologic function: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN) and total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin Absolute neutrophil count ≥ 1000/mm^3; platelets ≥ 75,000/mm^3; hemoglobin ≥ 10 g/dL Key Exclusion Criteria Grade 3 or Grade 4 proteinuria or glycosuria that is unexplained or not clinically manageable. NOTE: Other protocol defined Inclusion/ Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: F/TAF<br>F/TAF+ F/TDF placebo for at least 96 weeks | Drug: F/TAF<br>* 200/25 mg tablet administered orally once daily<br>* Other names: Descovy®;Drug: F/TDF Placebo<br>* Tablet administered orally once daily<br>|
| Experimental: F/TDF<br>F/TDF+ F/TAF placebo for at least 96 weeks | Drug: F/TDF<br>* 200/300 mg tablet administered orally once daily<br>* Other names: Truvada®;Drug: F/TAF Placebo<br>* Tablet administered orally once daily<br>|
| Experimental: Open-label<br>Once all participants have been on blinded treatment for at least 96 weeks, the study will be unblinded and participants will be offered the option to continue on open-label F/TAF treatment for 96 weeks. | Drug: F/TAF<br>* 200/25 mg tablet administered orally once daily<br>* Other names: Descovy®;|
| Experimental: Open-Label Extension<br>Participants who remain on study at Open-label Week 96 will have the option to continue on open-label F/TAF treatment in the Open-label extension phase for 408 weeks. | Drug: F/TAF<br>* 200/25 mg tablet administered orally once daily<br>* Other names: Descovy®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of HIV-1 Infection Per 100 Person Years (PY) | The incidence of HIV-1 infection rate per 100 PY was calculated as the number of participants who became HIV infected during the study after the first dose of study drug divided by the sum of all participants' years (where a year is 365.25 days) of follow-up while at risk of HIV infection during the study. HIV-1 infection is defined by one or more of the following criteria of contributing HIV tests performed via central lab or local lab: Serologic evidence of seroconversion (reactive screening HIV Antigen/Antibody or Antibody test, confirmed by reactive HIV-1/HIV-2 differentiation assay), excluding HIV vaccinated participants, or Virologic evidence of HIV-1 infection (positive qualitative HIV-1 RNA test or any detectable quantitative HIV-1 RNA test), or Evidence of acute HIV-1 infection (reactive p24 Antigen or positive qualitative or quantitative RNA, in the absence of reactive HIV-1 Antibody results) | When all participants completed minimum follow-up of 48 weeks and at least 50% of the participants completed 96 weeks of follow-up after randomization or permanently discontinued from the study (maximum 125 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48 in the Blinded Phase | Percent Change = Change from baseline at Week 48 visit/value at baseline * 100%. | Baseline, Week 48 | 
| Percent Change From Baseline in Spine BMD at Week 48 in the Blinded Phase | Percent Change = Change from baseline at Week 48 visit/value at baseline * 100%. | Baseline, Week 48 | 
| Percent Change From Baseline in Urine Beta-2-Microglobulin to Creatinine Ratio at Week 48 in the Blinded Phase | Percent Change = Change from baseline at Week 48 visit/value at baseline * 100%. For urine creatinine, value of < 1 was handled as a missing value in its summary and the calculation of related ratios. | Baseline, Week 48 | 
| Percent Change From Baseline in Urine Retinol Binding Protein (RBP) to Creatinine Ratio at Week 48 in the Blinded Phase | Percent Change = Change from baseline at Week 48 visit/value at baseline * 100%. For urine creatinine, value of < 1 was handled as a missing value in its summary and the calculation of related ratios. | Baseline, Week 48 | 
| Number of Participants by Urine Protein (UP) and Urine Protein to Creatinine Ratio (UPCR) Categories at Week 48 in the Blinded Phase | The UPCR was only calculated when corresponding UP ≥ 4.0 mg/dL. The UPCR ≤ 200 mg/g category includes both participants with UP < 4.0 mg/dL and participants with UPCR ≤ 200 mg/g. | Baseline, Week 48 | 
| Change From Baseline in Serum Creatinine at Week 48 in the Blinded Phase |  | Baseline, Week 48 | 
| Incidence of HIV-1 Infection Per 100 PY | The incidence of HIV-1 infection rate per 100 PY was calculated as the number of participants who became HIV infected during the study after the first dose of study drug divided by the sum of all participants' years (where a year is 365.25 days) of follow-up while at risk of HIV infection during the study. HIV-1 infection is defined by one or more of the following criteria of contributing HIV tests performed via central lab or local lab: Serologic evidence of seroconversion (reactive screening HIV Antigen/Antibody or Antibody test, confirmed by reactive HIV-1/HIV-2 differentiation assay), excluding HIV vaccinated participants, or Virologic evidence of HIV-1 infection (positive qualitative HIV-1 RNA test or any detectable quantitative HIV-1 RNA test), or Evidence of acute HIV-1 infection (reactive p24 Antigen or positive qualitative or quantitative RNA, in the absence of reactive HIV-1 Antibody results) | When all participants have 96 weeks of follow-up after randomization or permanently discontinued from the study (maximum 157 weeks) | 
| Percent Change From Baseline in Hip BMD at Week 96 in the Blinded Phase | Percent Change = Change from baseline at Week 96 visit/value at baseline * 100%. | Baseline, Week 96 | 
| Percent Change From Baseline in Spine BMD at Week 96 in the Blinded Phase | Percent Change = Change from baseline at Week 96 visit/value at baseline * 100%. | Baseline, Week 96 | 
| Percent Change From Baseline in Urine Beta-2-Microglobulin to Creatinine Ratio at Week 96 in the Blinded Phase | Percent Change = Change from baseline at Week 96 visit/value at baseline * 100%. For urine creatinine, value of < 1 was handled as a missing value in its summary and the calculation of related ratios. | Baseline, Week 96 | 
| Percent Change From Baseline in Urine RBP to Creatinine Ratio at Week 96 in the Blinded Phase | Percent Change = Change from baseline at Week 96 visit/value at baseline * 100%. For urine creatinine, value of < 1 was handled as a missing value in its summary and the calculation of related ratios. | Baseline, Week 96 | 
| Number of Participants by UP and UPCR Categories at Week 96 in the Blinded Phase | The UPCR was only calculated when corresponding UP ≥ 4.0 mg/dL. The UPCR ≤ 200 mg/g category includes both participants with UP < 4.0 mg/dL and participants with UPCR ≤ 200 mg/g. | Baseline, Week 96 | 
| Change From Baseline in Serum Creatinine at Week 96 in the Blinded Phase |  | Baseline, Week 96 | 
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events |  | First dose date up to the data cut for end of blinded treatment (maximum: 157 weeks) | 
| Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality |  | First dose date up to the data cut for end of blinded treatment (maximum: 157 weeks) |