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 (DISCOVER)

• ClinicalTrials.gov Identifier: NCT02842086
• Recruitment Status: Active, not recruiting
• First Posted: July 22, 2016
• Results First Posted: March 17, 2020
• Last Update Posted: December 21, 2023
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Tracking Information

• First Submitted Date: July 20, 2016
• First Posted Date: July 22, 2016
• Results First Submitted Date: January 29, 2020
• Results First Posted Date: March 17, 2020
• Last Update Posted Date: December 21, 2023
• Actual Study Start Date: September 2, 2016
• Actual Primary Completion Date: January 31, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 28, 2020)

Incidence of HIV-1 Infection Per 100 Person Years (PY) [ Time Frame: 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) ]

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)

• Original Primary Outcome Measures (submitted: July 20, 2016): Incidence of Seroconversions per 100 Person Years (PY) as Defined by the HIV-1 RNA by Polymerase Chain Reaction (PCR) [ Time Frame: When the last participant has a minimum of 48 weeks of follow-up and at least 50% of the participants have at least 96 weeks of follow-up after randomization ]

Current Secondary Outcome Measures (submitted: May 28, 2020)

• Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48 in the Blinded Phase [ Time Frame: Baseline, Week 48 ]
  Percent Change = Change from baseline at Week 48 visit/value at baseline * 100%.
• Percent Change From Baseline in Spine BMD at Week 48 in the Blinded Phase [ Time Frame: Baseline, Week 48 ]
  Percent Change = Change from baseline at Week 48 visit/value at baseline * 100%.
• Percent Change From Baseline in Urine Beta-2-Microglobulin to Creatinine Ratio at Week 48 in the Blinded Phase [ Time Frame: Baseline, Week 48 ]
  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.
• Percent Change From Baseline in Urine Retinol Binding Protein (RBP) to Creatinine Ratio at Week 48 in the Blinded Phase [ Time Frame: Baseline, Week 48 ]
  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.
• Number of Participants by Urine Protein (UP) and Urine Protein to Creatinine Ratio (UPCR) Categories at Week 48 in the Blinded Phase [ Time Frame: Baseline, Week 48 ]
  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.
• Change From Baseline in Serum Creatinine at Week 48 in the Blinded Phase [ Time Frame: Baseline, Week 48 ]
• Incidence of HIV-1 Infection Per 100 PY [ Time Frame: When all participants have 96 weeks of follow-up after randomization or permanently discontinued from the study (maximum 157 weeks) ]
  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)
• Percent Change From Baseline in Hip BMD at Week 96 in the Blinded Phase [ Time Frame: Baseline, Week 96 ]
  Percent Change = Change from baseline at Week 96 visit/value at baseline * 100%.
• Percent Change From Baseline in Spine BMD at Week 96 in the Blinded Phase [ Time Frame: Baseline, Week 96 ]
  Percent Change = Change from baseline at Week 96 visit/value at baseline * 100%.
• Percent Change From Baseline in Urine Beta-2-Microglobulin to Creatinine Ratio at Week 96 in the Blinded Phase [ Time Frame: Baseline, Week 96 ]
  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.
• Percent Change From Baseline in Urine RBP to Creatinine Ratio at Week 96 in the Blinded Phase [ Time Frame: Baseline, Week 96 ]
  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.
• Number of Participants by UP and UPCR Categories at Week 96 in the Blinded Phase [ Time Frame: Baseline, Week 96 ]
  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.
• Change From Baseline in Serum Creatinine at Week 96 in the Blinded Phase [ Time Frame: Baseline, Week 96 ]
• Percentage of Participants Experiencing Treatment-Emergent Adverse Events [ Time Frame: 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 [ Time Frame: First dose date up to the data cut for end of blinded treatment (maximum: 157 weeks) ]

Original Secondary Outcome Measures (submitted: July 20, 2016)

• Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48 in the Blinded Phase in a Subset of Participants [ Time Frame: Baseline; Week 48 ]
• Percent Change From Baseline in Spine BMD at Week 48 in the Blinded Phase in a Subset of Participants [ Time Frame: Baseline; Week 48 ]
• Percent Change From Baseline in Renal Biomarkers of Urine Retinol-Binding Protein (RBP) to Creatinine Ratio at Week 48 in the Blinded Phase [ Time Frame: Baseline; Week 48 ]
• Percent Change From Baseline in Renal Biomarkers of Beta-2-Microglobulin to Creatinine Ratio at Week 48 in the Blinded Phase [ Time Frame: Baseline; Week 48 ]
• Percent Change From Baseline in Renal Biomarkers of Urine Protein-to-Creatinine Ratio (UPCR) at Week 48 in the Blinded Phase [ Time Frame: Baseline; Week 48 ]
• Change From Baseline in Serum Creatinine at Week 48 in the Blinded Phase [ Time Frame: Baseline; Week 48 ]
• Incidence of Seroconversions per 100 PY as Defined by the HIV RNA-1 by PCR at the end of the Blinded Phase [ Time Frame: At least 96 weeks ]
• Percent Change from Baseline in Hip BMD at Week 96 in the Blinded Phase in a Subset of Participants [ Time Frame: Baseline; Week 96 ]
• Percent Change from Baseline in Spine BMD at Week 96 in the Blinded Phase in a Subset of Participants [ Time Frame: Baseline; Week 96 ]
• Percent Change From Baseline in Renal Biomarkers of Urine RBP to Creatinine Ratio at Week 96 in the Blinded Phase [ Time Frame: Baseline; Week 96 ]
• Percent Change From Baseline in Renal Biomarkers of Urine Beta-2-Microglobulin to Creatinine Ratio at Week 96 in the Blinded Phase [ Time Frame: Week 96 ]
• Percent Change From Baseline in Renal Biomarkers of Urine Protein-to-Creatinine Ratio (UPCR) at Week 96 in the Blinded Phase [ Time Frame: Week 96 ]
• Change From Baseline in Serum Creatinine at Week 96 in the Blinded Phase [ Time Frame: Week 96 ]
• Incidence of Treatment-Emergent Adverse Events [ Time Frame: At least 144 weeks plus 30 days ]
• Incidence of Treatment-Emergent Laboratory Toxicities [ Time Frame: At least 144 weeks plus 30 days ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Pre-Exposure Prophylaxis of HIV-1 Infection

Intervention

• Drug: F/TAF
  200/25 mg tablet administered orally once daily
  Other Name: Descovy®
• Drug: F/TDF
  200/300 mg tablet administered orally once daily
  Other Name: Truvada®
• Drug: F/TAF Placebo
  Tablet administered orally once daily
• Drug: F/TDF Placebo
  Tablet administered orally once daily

Study Arms

• Experimental: F/TAF
  F/TAF+ F/TDF placebo for at least 96 weeks
  Interventions:

  • Drug: F/TAF
  • Drug: F/TDF Placebo
• Experimental: F/TDF
  F/TDF+ F/TAF placebo for at least 96 weeks
  Interventions:

  • Drug: F/TDF
  • Drug: F/TAF Placebo
• Experimental: Open-label
  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.
  Intervention: Drug: F/TAF
• Experimental: Open-Label Extension
  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.
  Intervention: Drug: F/TAF

Publications *

• Hare B. The Phase 3 DISCOVER Study: Daily F/TAF or F/TDF for HIV Preexposure Prophylaxis [Presentation]. Conference on Retroviruses and Opportunistic Infections (CROI); 2019 04-07 March; Seattle, WA.
• Mayer KH, Molina JM, Thompson MA, Anderson PL, Mounzer KC, De Wet JJ, DeJesus E, Jessen H, Grant RM, Ruane PJ, Wong P, Ebrahimi R, Zhong L, Mathias A, Callebaut C, Collins SE, Das M, McCallister S, Brainard DM, Brinson C, Clarke A, Coll P, Post FA, Hare CB. Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet. 2020 Jul 25;396(10246):239-254. doi: 10.1016/S0140-6736(20)31065-5.
• Ogbuagu O, Ruane PJ, Podzamczer D, Salazar LC, Henry K, Asmuth DM, Wohl D, Gilson R, Shao Y, Ebrahimi R, Cox S, Kintu A, Carter C, Das M, Baeten JM, Brainard DM, Whitlock G, Brunetta JM, Kronborg G, Spinner CD; DISCOVER study team. Long-term safety and efficacy of emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV-1 pre-exposure prophylaxis: week 96 results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet HIV. 2021 Jul;8(7):e397-e407. doi: 10.1016/S2352-3018(21)00071-0. Erratum In: Lancet HIV. 2021 Dec;8(12):e734.
• Glidden DV, Das M, Dunn DT, Ebrahimi R, Zhao Y, Stirrup OT, Baeten JM, Anderson PL. Using the adherence-efficacy relationship of emtricitabine and tenofovir disoproxil fumarate to calculate background hiv incidence: a secondary analysis of a randomized, controlled trial. J Int AIDS Soc. 2021 May;24(5):e25744. doi: 10.1002/jia2.25744.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 3, 2020): 5399
• Original Estimated Enrollment (submitted: July 20, 2016): 5000
• Estimated Study Completion Date: September 2027
• Actual Primary Completion Date: January 31, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Men and Transgender Women

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Canada, Denmark, France, Germany, Ireland, Italy, Netherlands, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT02842086
• Other Study ID Numbers: GS-US-412-2055; 2022-501763-40 ( Other Identifier: European Medicines Agency ); 2016-001399-31 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Gilead Sciences
• Original Responsible Party: Same as current
• Current Study Sponsor: Gilead Sciences
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Gilead Study Director; Gilead Sciences

• PRS Account: Gilead Sciences
• Verification Date: December 2023