Emtricitabine/Tenofovir Disoproxil Fumarate for HIV Prevention in Men (iPrEx)

• ClinicalTrials.gov Identifier: NCT00458393
• Recruitment Status: Completed
• First Posted: April 10, 2007
• Results First Posted: January 24, 2018
• Last Update Posted: November 2, 2021
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborator: Bill and Melinda Gates Foundation
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information

• First Submitted Date: April 6, 2007
• First Posted Date: April 10, 2007
• Results First Submitted Date: December 27, 2016
• Results First Posted Date: January 24, 2018
• Last Update Posted Date: November 2, 2021
• Study Start Date: June 2007
• Actual Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 19, 2018)

• HIV Seroconversion [ Time Frame: Monthly follow-up through a median of 1.2 years ]
  Confirmed HIV infection
• Grade 1 or Higher Creatinine Toxicity [ Time Frame: Duration of follow-up, median 1.2 years ]
  Creatinine which reach grade 1 (mild, 1.1 to 1.3 local upper limit of normal) or higher by the US Division of AIDS grading table (version 1) or a 50% increase in creatinine from the baseline value. The DAIDS table can be found at https://rsc.tech-res.com/docs/default-source/safety/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf
• Grade 3 or Higher Phosphorous Toxicity [ Time Frame: The entire follow-up period, median 1.2 years ]
  Grade 3 or higher phosphorous toxicity (hypophosphatemia) by the Division of AIDS Grading Table (severe, level at or below 1.9 mg/dL)
• Grade 2, 3, or 4 Laboratory Adverse Events [ Time Frame: Entire follow-up, median 1.2 years ]
  Number of participants with at least one Grade 2, 3, or 4 laboratory adverse events (moderate, severe of life threatening based one the US Division of AIDS Grading of adverse events, version 1.0). The table can be found at https://rsc.tech-res.com/docs/default-source/safety/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf
• Grade 2, 3, or 4 Clinical Adverse Events [ Time Frame: Entire follow-up, median 1.2 years ]
  Number of participants with at least 1 Grade 2, 3, or 4 clinical adverse events (moderate, severe of life threatening based one the US Division of AIDS Grading of adverse events, version 1.0). The table can be found at https://rsc.tech-res.com/docs/default-source/safety/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf

Original Primary Outcome Measures (submitted: April 6, 2007)

• HIV infection as measured by seroconversion
• Grade 1 or higher creatinine toxicity
• Grade 3 or higher phosphorus toxicity
• Grade 2, 3,or 4 laboratory or clinical adverse events
• HIV seroconversion

Current Secondary Outcome Measures (submitted: January 19, 2018)

• Hepatitis Flares Among Hepatitis B Virus (HBV) Infected Persons During and After Chemoprophylaxis [ Time Frame: Quarterly lab tests through a median follow-up of 1.2 years ]
  A hepatic flare is defined as an increase in alanine transaminase or aspartate transaminase to >5 fold upper limit of normal at any visit, or an increase to >2.5 fold upper limit of normal for 3 months, within 24 weeks of permanently stopping study drug. More details in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752387/
• Percentage Change in Bone Mineral Density [ Time Frame: baseline and week 24. ]
  % Change from baseline in bone mineral density (100 * [(value at 24 weeks- value at baseline)/ (value at baseline)]) in in hip and L1-L4 spine by dual-energy x-ray absorptiometry
• Percentage Change in Body Fat [ Time Frame: Baseline and Week 24 ]
  Percentage Change (100 * [(value at 24 weeks- value at baseline)/ (value at baseline)]) in Body Fat from Baseline by dual-energy x-ray absorptiometry
• Percentage Change in Fasting Triglycerides [ Time Frame: Baseline and Week 24 ]
  Percentage Change (Percentage Change (100 * [(value at 24 weeks- value at baseline)/ (value at baseline)]) in Triglycerides from Baseline from a fasting sample.
• Percent Change in Total Cholesterol [ Time Frame: Baseline and Week 24 ]
  Percent change (100 * [(value at 24 weeks- value at baseline)/ (value at baseline)]) in fasting total cholesterol from baseline
• Viral Load Among HIV Infected Participants [ Time Frame: At the time closest to HIV detection ]
  HIV-RNA in log10 units among HIV infected participants at the time closest to HIV detection
• Among HIV Infected Participants Drug Resistance [ Time Frame: at the time of HIV acquisition ]
  Genotypic resistance by clinical assays among the seroconverters from baseline to the end of the study treatment period
• CD4 Count Among HIV Infected Participants [ Time Frame: at the time infection was detected ]
  CD4 cell count for HIV infected participants during the trial
• Proportion of Missed Doses by Pill Count [ Time Frame: At 24 weeks ]
  Estimated proportion of missed doses by pill count (assuming pills taken in unreturned bottles)
• Percentage of Missed Doses by Estimate During CASI Interview [ Time Frame: Week 24 ]
  Percentage of missed doses by estimate during computer assisted structured interview
• Number of Condomless Sexual Partners With HIV Positive or Unknown Status [ Time Frame: At 24 weeks ]
  Participants self-report of the number of sexual partners with HIV positive or unknown status in the previous 12 weeks with whom they had condomless anal sex
• Total Number of Sexual Partners [ Time Frame: 24 weeks ]
  Self-reported total number of sexual partners in the previous 12 weeks.
• Condomless Receptive Anal Intercourse in the Previous 12 Weeks With Any Partners Regardless of Status. [ Time Frame: At 24 weeks ]
  Self-reported condomless receptive anal intercourse in the previous 12 weeks with any partners regardless of status.
• Incidence of Confirmed Syphilis During Follow-Up [ Time Frame: All Follow-Up median of 1.2 years of follow-up ]
  Number of participants who have at least 1 confirmed syphilis infection during the study
• Incidence of HSV-2 During the Follow-up Period [ Time Frame: Total study follow-up, a median of 1.2 years ]
  Incidence of HSV-2 during the follow-up period among those HIV-2 negative at baseline
• Diagnosis of Gonorrhea During the Follow-up Period [ Time Frame: All of follow-up period, median of 1.2 years ]
  Diagnosis of gonorrhea during the follow-up period by PCR

Original Secondary Outcome Measures (submitted: April 6, 2007)

• Hepatitis flares among hepatitis B virus (HBV) infected persons during and after chemoprophylaxis
• changes in bone mineral density or body fat distribution
• among HIV infected participants: viral load, drug resistance, and CD4 cell counts
• attitudinal and behavioral correlates of chemoprophylaxis failure or success
• risk behavior including condom use before, during, and after use of study medication
• the prevalence of sexually transmitted infections (STIs) before, during, and after use of study medication

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

Descriptive Information

• Brief Title: Emtricitabine/Tenofovir Disoproxil Fumarate for HIV Prevention in Men
• Official Title: Chemoprophylaxis for HIV Prevention in Men
• Brief Summary: The purpose of this study is to determine whether daily use of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) can prevent HIV infection in men who also receive HIV counseling, condoms, and treatment for other sexually transmitted infections (STIs).

Detailed Description

The Joint United Nations Programme on AIDS estimates that 14,000 persons are newly infected with HIV every day worldwide; one half of these infections occur in people between the ages of 15 and 24. New infections occur despite widespread awareness of the modes of HIV transmission and the protection afforded by condom use. Effective interventions for HIV prevention are urgently needed. This study will evaluate the safety and efficacy of chemoprophylaxis for HIV prevention in men who have sex with men (MSM) who are at high risk for HIV infection despite using condoms, receiving HIV counseling, and receiving treatment for STIs, particularly hepatitis B virus (HBV) infection. A daily combination dose of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) has been selected for evaluation because it has a well-established safety record in previous studies and was demonstrated to be effective for HIV prevention in primate models. These medications have long half-lives that allow daily dosing and do not have known interactions with hormonal contraception, methadone, or tuberculosis therapies.

Once on the study drug, participants will be followed for a variable length of time, starting within 4 weeks of their screening visit and lasting up to 144 weeks. All participants will be followed for at least 8 weeks after stopping study drug. Participants who are reactive to a Hepatitis B surface antigen (HBsAg) test will be followed for hepatic flares for 16 additional weeks for a total of 24 weeks after stopping study drug. If enrolled in the optional substudy of bone mineral density, fat distribution, and fasting lipids, the participant will be asked to return for one additional visit 24 weeks after stopping study drug. Participants who HIV seroconvert during their participation will also be followed until the end of the study.

All study visits will be at 4 week intervals. At study entry, high risk, HIV uninfected MSM will be randomly assigned to receive either daily FTC/TDF or placebo, in addition to standard HIV counseling, condoms, and sexually transmitted infection (STI) management. The study will closely monitor biological and behavioral safety, including careful analysis of drug resistance, kidney and liver function, and risk behavior.

At the screening visit, participants will undergo HIV antibody and HBV testing, a medical history, a medical exam, blood and urine collection, risk behavior assessment, and STI testing. At study entry, participants will be given study medication; tested for HCV; and offered the HBV vaccine, if applicable. At all study visits, there will be HIV antibody testing, pill counts, adherence checks, study medication distribution, HIV counseling, and condom distribution. A medical history and blood will be taken on selected visits, along with STI testing and treatment if needed. Testing and treatment of STIs will be provided at no cost to the participant.

All study participants will be encouraged to join a substudy that will assess interactions between HBV infection, bone mineral density and fat distribution, and immune function. If enrolled in the substudy, the participant will be asked to return for one additional visit 24 weeks after stopping the study medication. All participants in the substudy will undergo dual energy x-ray absorptiometry (DEXA) scans, and HIV infected participants will undergo additional blood collection.

Sites will have the option of participating in the following four substudies:

The Hair Substudy: Participants who are receiving FTC/TDF will be eligible to enroll. At each 12-week follow-up study visit, hair samples will be collected and questionnaires will be completed.

The Urine Substudy: For all participants who elect to enroll in this substudy, additional testing will occur on blood and urine samples collected at each 24-week follow-up visit. An additional urine collection will occur 8 weeks after participants stop receiving FTC/TDF.

The Semen Substudy: Participants who seroconvert during the study may elect to participate in this substudy. One semen sample will be collected at participants' next study visit when plasma viral load testing is performed.

The Gonorrhea and Chlamydia Substudy: Participants in this substudy will undergo rectal and oropharyngeal swab procedures and urine collection at the 24-week study visit.

After the randomized phase ends, if the daily oral FTC/TDF arm is shown to be beneficial and safe, participants will be given the option of participating in an open label extension phase. During this extension phase, study participants will receive daily oral open-label FTC/TDF, in addition to standard counseling, condoms, and STI management.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Prevention
• Condition: HIV Infections

Intervention

• Drug: daily TDF/FTC
  daily oral medication
  Other Name: truvada
• Drug: Placebo
  daily oral medication

Study Arms

• Experimental: TDF/FTC
  Drug. Daily oral tablet of co-formulated 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate (TDF/FTC).
  Intervention: Drug: daily TDF/FTC
• Placebo Comparator: Placebo
  Drug. Daily oral placebo
  Intervention: Drug: Placebo

Publications *

• Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, Goicochea P, Casapia M, Guanira-Carranza JV, Ramirez-Cardich ME, Montoya-Herrera O, Fernandez T, Veloso VG, Buchbinder SP, Chariyalertsak S, Schechter M, Bekker LG, Mayer KH, Kallas EG, Amico KR, Mulligan K, Bushman LR, Hance RJ, Ganoza C, Defechereux P, Postle B, Wang F, McConnell JJ, Zheng JH, Lee J, Rooney JF, Jaffe HS, Martinez AI, Burns DN, Glidden DV; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587-99. doi: 10.1056/NEJMoa1011205. Epub 2010 Nov 23.
• Mehrotra ML, Westreich D, McMahan VM, Glymour MM, Geng E, Grant RM, Glidden DV. Baseline Characteristics Explain Differences in Effectiveness of Randomization to Daily Oral TDF/FTC PrEP Between Transgender Women and Cisgender Men Who Have Sex With Men in the iPrEx Trial. J Acquir Immune Defic Syndr. 2019 Jul 1;81(3):e94-e98. doi: 10.1097/QAI.0000000000002037. No abstract available.
• Glidden DV, Mulligan K, McMahan V, Anderson PL, Guanira J, Chariyalertsak S, Buchbinder SP, Bekker LG, Schechter M, Grinsztejn B, Grant RM. Metabolic Effects of Preexposure Prophylaxis With Coformulated Tenofovir Disoproxil Fumarate and Emtricitabine. Clin Infect Dis. 2018 Jul 18;67(3):411-419. doi: 10.1093/cid/ciy083.
• Glidden DV, Mulligan K, McMahan V, Anderson PL, Guanira J, Chariyalertsak S, Buchbinder SP, Bekker LG, Schechter M, Grinsztejn B, Grant RM. Brief Report: Recovery of Bone Mineral Density After Discontinuation of Tenofovir-Based HIV Pre-exposure Prophylaxis. J Acquir Immune Defic Syndr. 2017 Oct 1;76(2):177-182. doi: 10.1097/QAI.0000000000001475.
• Gandhi M, Glidden DV, Mayer K, Schechter M, Buchbinder S, Grinsztejn B, Hosek S, Casapia M, Guanira J, Bekker LG, Louie A, Horng H, Benet LZ, Liu A, Grant RM. Association of age, baseline kidney function, and medication exposure with declines in creatinine clearance on pre-exposure prophylaxis: an observational cohort study. Lancet HIV. 2016 Nov;3(11):e521-e528. doi: 10.1016/S2352-3018(16)30153-9. Epub 2016 Aug 31.
• Castillo-Mancilla J, Seifert S, Campbell K, Coleman S, McAllister K, Zheng JH, Gardner EM, Liu A, Glidden DV, Grant R, Hosek S, Wilson CM, Bushman LR, MaWhinney S, Anderson PL. Emtricitabine-Triphosphate in Dried Blood Spots as a Marker of Recent Dosing. Antimicrob Agents Chemother. 2016 Oct 21;60(11):6692-6697. doi: 10.1128/AAC.01017-16. Print 2016 Nov.
• Glidden DV, Amico KR, Liu AY, Hosek SG, Anderson PL, Buchbinder SP, McMahan V, Mayer KH, David B, Schechter M, Grinsztejn B, Guanira J, Grant RM. Symptoms, Side Effects and Adherence in the iPrEx Open-Label Extension. Clin Infect Dis. 2016 May 1;62(9):1172-7. doi: 10.1093/cid/ciw022. Epub 2016 Jan 20.
• Mulligan K, Glidden DV, Anderson PL, Liu A, McMahan V, Gonzales P, Ramirez-Cardich ME, Namwongprom S, Chodacki P, de Mendonca LM, Wang F, Lama JR, Chariyalertsak S, Guanira JV, Buchbinder S, Bekker LG, Schechter M, Veloso VG, Grant RM; Preexposure Prophylaxis Initiative Study Team. Effects of Emtricitabine/Tenofovir on Bone Mineral Density in HIV-Negative Persons in a Randomized, Double-Blind, Placebo-Controlled Trial. Clin Infect Dis. 2015 Aug 15;61(4):572-80. doi: 10.1093/cid/civ324. Epub 2015 Apr 23.
• Liu A, Glidden DV, Anderson PL, Amico KR, McMahan V, Mehrotra M, Lama JR, MacRae J, Hinojosa JC, Montoya O, Veloso VG, Schechter M, Kallas EG, Chariyalerstak S, Bekker LG, Mayer K, Buchbinder S, Grant R; iPrEx Study team. Patterns and correlates of PrEP drug detection among MSM and transgender women in the Global iPrEx Study. J Acquir Immune Defic Syndr. 2014 Dec 15;67(5):528-37. doi: 10.1097/QAI.0000000000000351.
• Liegler T, Abdel-Mohsen M, Bentley LG, Atchison R, Schmidt T, Javier J, Mehrotra M, Eden C, Glidden DV, McMahan V, Anderson PL, Li P, Wong JK, Buchbinder S, Guanira JV, Grant RM; iPrEx Study Team. HIV-1 drug resistance in the iPrEx preexposure prophylaxis trial. J Infect Dis. 2014 Oct 15;210(8):1217-27. doi: 10.1093/infdis/jiu233. Epub 2014 Apr 16.
• Buchbinder SP, Glidden DV, Liu AY, McMahan V, Guanira JV, Mayer KH, Goicochea P, Grant RM. HIV pre-exposure prophylaxis in men who have sex with men and transgender women: a secondary analysis of a phase 3 randomised controlled efficacy trial. Lancet Infect Dis. 2014 Jun;14(6):468-75. doi: 10.1016/S1473-3099(14)70025-8. Epub 2014 Mar 7.
• Amico KR, Mansoor LE, Corneli A, Torjesen K, van der Straten A. Adherence support approaches in biomedical HIV prevention trials: experiences, insights and future directions from four multisite prevention trials. AIDS Behav. 2013 Jul;17(6):2143-55. doi: 10.1007/s10461-013-0429-9.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 19, 2018): 2499
• Original Enrollment (submitted: April 6, 2007): 1400
• Actual Study Completion Date: February 2014
• Actual Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male sex (at birth)
• HIV uninfected
• Age having reached the local age of consent
• High risk for HIV infection including any of the following: 1) No condom use during anal intercourse with a male HIV-positive partner or a male partner of unknown HIV status during the last 6 months; (2) anal intercourse with more than 3 male sex partners during the last 6 months; (3) exchange of money, gifts, shelter, or drugs for anal sex with a male partner during the last 6 months; (4) sex with a male partner and STI diagnosis during the last 6 months or at screening, or (5) sexual partner of an HIV-infected man with whom condoms are not consistently used in the last 6 months.
• Able to provide a street address of residence for themselves and one personal contact who would know their whereabouts during the study period
• Healthy enough to work, as indicated by score of 80 or greater on the Karnofsky scale
• Certain laboratory values
• A urine dipstick with a negative or trace result for both glucose and protein within 28 days of enrollment.
• Ability to understand and local language for which an informed consent form has been approved by a local IRB and registered with the study sponsor.

Inclusion Criteria for Open-Label Extension:

• Participated in a randomized, placebo-controlled, PrEP trail
• Has been unblinded
• Has provided informed consent

Exclusion Criteria:

• Previously diagnosed active and serious infections, including tuberculosis infection, osteomyelitis, or infections requiring parenteral antibiotic therapy
• Active clinically significant medical problems including heart disease (e.g., symptoms of ischemia, congestive heart failure, arrhythmia), lung disease (steroid-dependent chronic obstructive pulmonary disease), diabetes requiring hypoglycemic medication, or previously diagnosed cancer expected to require further treatment
• Acute HBV infection at the screening visit or presence of treatment indications for hepatitis B based on local practice standards; or clinical signs of hepatic cirrhosis
• History of pathological bone fractures not related to trauma
• Receiving ongoing therapy with certain HIV/AIDS-related medications or other medications as determined by the investigator
• Definitely or possibly received an anti-HIV vaccine while participating in a blinded clinical trial
• Current alcohol or drug use that, in the opinion of the investigator, may interfere with the study
• Current participation in a clinical trial or cohort study other than sub-studies of this protocol
• Any condition at enrollment that, in the opinion of the investigator, would make participation in the study unsafe or would interfere with the study
• Sites may utilize additional criteria that restrict enrollment to a subset of people who meet the protocol-defined enrollment criteria.

Exclusion Criteria for Open-Label Extension:

- Site leadership believes participant will have difficulty completing requirements

Sex/Gender

• Sexes Eligible for Study: Male

• 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: Brazil, Ecuador, Peru, South Africa, Thailand, United States

Administrative Information

• NCT Number: NCT00458393
• Other Study ID Numbers: CO-US-104-0288; 10445 ( Registry Identifier: DAIDS ES ); 1U01AI064002 ( U.S. NIH Grant/Contract ); iPrEx ( Other Identifier: Study team )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Responsible Party: Not Provided
• Current Study Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Study Sponsor: Same as current
• Collaborators: Bill and Melinda Gates Foundation

Investigators

• Principal Investigator: Robert M. Grant, MD, MPH; J. David Gladstone Institutes, University of California San Francisco

• PRS Account: National Institute of Allergy and Infectious Diseases (NIAID)
• Verification Date: October 2021