FEM-PrEP (Truvada®): Study to Assess the Role of Truvada® in Preventing HIV Acquisition in Women

Study Overview
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Brief Summary
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This Phase III, double-blind, randomized, placebo-controlled trial enrolled HIV-negative women from 4 sites in 3 countries (Kenya, Tanzania, South Africa). The study's purpose was to investigate the safety and effectiveness of a once-daily Truvada® pill (compared with placebo) in preventing HIV among HIV-uninfected women at risk of becoming infected through sexual intercourse. The study population included HIV-antibody-negative women between the ages of 18-35 who were at risk of HIV acquisition through sexual intercourse. Each participant was randomized to take either a daily single oral tablet of Truvada®, which is a fixed-dose combination of emtricitabine (FTC; 200 mg) and tenofovir disoproxil fumarate (TDF; 300 mg), or an identical placebo. After enrollment, each participant was followed every four weeks. All participants were followed for an additional eight weeks after study drug was stopped. Incidence rates of HIV infection were compared between the two groups (active drug and placebo) using the intent-to-treat principle.

Detailed Description
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This Phase III, double-blind, randomized, placebo-controlled trial enrolled HIV-negative women from 4 sites in 3 countries (Kenya, Tanzania, South Africa). The study's purpose was to investigate the safety and effectiveness of a once-daily Truvada® pill (compared with placebo) in preventing HIV among HIV-uninfected women at risk of becoming infected through sexual intercourse. The study population included HIV-antibody-negative women between the ages of 18-35 who were at risk of HIV acquisition through sexual intercourse. Each participant was randomized to take either a daily single oral tablet of Truvada®, which is a fixed-dose combination of emtricitabine (FTC; 200 mg) and tenofovir disoproxil fumarate (TDF; 300 mg), or an identical placebo. All participants received risk reduction counseling and condoms. Women had to be using a study-approved effective non-barrier contraceptive method at the time of enrollment and were asked to do so for the whole period they were on study drug. They received contraceptive counseling throughout the study. Any diagnosed, treatable sexually transmitted infection was treated free of charge. After enrollment, each participant was followed every four weeks. All participants were followed for an additional eight weeks after study drug was stopped. Participants at risk for Hepatitis B Virus (HBV) flare were followed every four weeks for 12 weeks after stopping study product. Participants who acquired HIV infection during the study stopped taking the study drug at the time of HIV diagnosis, and will be followed for 52 weeks post diagnosis and were referred for care and treatment. Participants who became pregnant stopped taking the study drug but continued follow-up visits. Incidence rates of HIV infection were compared between the two groups (active drug and placebo) using the intent-to-treat principle.

Official Title
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Phase 3, Multi-center, Double-blind, Randomized, Placebo-controlled Effectiveness and Safety Study to Assess the Role of Truvada® in Preventing HIV Acquisition in Women

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Truvada
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able (see criterion 2) to provide written informed consent to be screened for and to participate in the trial Able to answer a percentage of informed consent screening (75%) and enrollment (100%) comprehension quiz questions correctly Between 18-35 years old, inclusive At higher risk of becoming HIV infected Have a final negative result according to the site-specific screening HIV testing algorithm and a final negative result at enrollment according to the study HIV testing algorithm Willing to participate in all aspects of the study and to comply with study procedures, for up to 60 weeks, including: Be randomized Use study product as directed Adhere to follow-up schedule and willing to be contacted by site staff between study visits (by phone and/or in person) Use a study-approved effective non-barrier method of contraception for the duration of the study Take study product, as evidenced by swallowing a vitamin tablet that is similar in size to the study product at enrollment Provide contact information and agrees to some form of contact method throughout the study Not intending to relocate out of the area for the duration of the study participation and does not have a job or other obligations that may require long absences from the area ( > 1 month at a time) In general good health and have no condition (social or medical) which, in the opinion of the Site Investigator, would make study participation unsafe or complicate data interpretation Not pregnant or breastfeeding, and does not anticipate a desire for pregnancy during the 52 weeks of on-product participation Medically eligible at screening including: Adequate renal function (serum creatinine ≤ upper limit of normal (ULN) of local range and creatinine clearance ≥ 60ml/min estimated by the Cockcroft-Gault Creatinine Clearance Formula Adequate hepatic function (hepatic transaminases ALT and AST < 2x ULN [according to local normal ranges]) HBsAg negative Serum phosphorus levels above the lower limit of the local normal range (according to local normal ranges - grade 3 & 4 hypophosphatemia will be excluded even if within normal local ranges) Not received or receiving an experimental HIV vaccine, participating in another HIV prevention study or participating in any other clinical trial with a biomedical intervention No clinical signs of liver disease (e.g., ascites, spider angiomata, hepatomegaly, jaundice) No definite evidence of glycosuria or proteinuria (i.e., no repeated positive [ ≥ + 1 ] urine dipstick). If a urine dipstick is positive for either glucose and/or protein at the first test, a second urine sample will be tested. No history of pathological bone fractures No history of adverse reaction to latex Not taking any of the following medications: nephrotoxic agents; aminoglycoside antibiotics (including gentamicin); intravenous (IV) amphotericin B; cidofovir; cisplatin; foscarnet; IV pentamidine; oral or IV vancomycin; oral or IV gancyclovir; other agents with significant nephrotoxic potential; drugs that slow renal excretion; probenecid; immune system modulators; systemic chemotherapeutic agents (i.e. cancer treatment medications); systemic corticosteroids; interleukin-2 (IL-2); immunomodulators; interferon (alpha, beta, or gamma); other antiretrovirals (including nucleoside analogs, non-nucleoside reverse transcriptase inhibitors, protease inhibitors or investigational antiretroviral agents)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Female

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Truvada Arm<br>Daily single oral tablet of Truvada (TDF/FTC), a fixed-dose combination of emtricitabine (FTC; 200 mg) and tenofovir disoproxil fumarate (TDF; 300 mg). | Drug: Truvada<br>* Daily single oral tablet of Truvada - a fixed-dose combination of emtricitabine (FTC; 200 mg) and tenofovir disoproxil fumarate (TDF; 300 mg).<br>* Other names: TDF/FTC - emtricitabine and tenofovir disoproxil fumarate;|
| Placebo Comparator: Placebo Arm<br>Daily single oral tablet of Placebo. Tablets are identical to Truvada tablets in taste and appearance; however, they contain no active ingredients. | Other: Placebo<br>* Daily single oral tablet of Placebo. Tablets are identical to Truvada tablets in taste and appearance; however, they contain no active ingredients.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HIV Infection | HIV Seroconversion, with time to infection refined based on PCR results obtained from stored specimens. | Cumulative HIV infection between enrollment and 52 weeks | 
| Confirmed Grade 2 or Higher Serum Creatinine Toxicity | Repeat specimens were collected to confirm chemistry toxicities. Grade 2 or higher serum creatinine toxicity was defined as ≥1.4 times the upper limit of normal | cumulative toxicity through 52 weeks of product use and 4 weeks post product | 
| Frequency of Adverse Events (AEs) During and Within 4 Weeks After Study Product Administration | The total number of adverse events in the placebo and Truvada arms during and within 4 weeks after study product administration. | 10-26 months per site | 
| Confirmed Grade 3 or Higher Reduction in Phosphorus | Repeat specimens were collected to confirm chemistry toxicities. Grade 3 phosphorus reduction was defined as ≤2.4mg/dL | Through 52 weeks on product and 4 weeks post-product | 
| Confirmed Grade 3 or Higher ALT Elevation | Grade 3 or higher ALT elevation was defined as ≥ 2.6 times the upper limit of normal | Through 52 weeks on product and 4 weeks post-product | 
| Confirmed Grade 3 or Higher AST Elevation | Grade 3 or higher AST elevation was defined as ≥ 2.6 times the upper limit of normal | Through 52 weeks on product and 4 weeks post-product | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma HIV RNA Level (HIV-1 Viral Load) | Viral load at the time of HIV detection, HIV conversion and through 16 weeks | up to 16 weeks | 
| CD4+ T-cell Count | CD4+ T-cell Count at the Time of HIV Seroconversion through 16 weeks | Up to 16 weeks | 
| FTC and/or Tenofovir Resistance | Genotypic resistance to FTC and/or tenofovir at the time of HIV diagnosis and 4 weeks later. If resistance was present, testing was repeated at weeks 12, 24, 36 and 52 as necessary (resistance testing will stop if no resistance is detected). participants were classified as having resistance if they had one or more visits in which resistance was detected, even if the resistance became undetectable over time. | up to 52 weeks | 
| Pregnancy Complications | Reported complications during pregnancy, including spontaneous abortion, vaginal or uterine bleeding, emergency c-section and other complications | up to 60 weeks | 
| Pill Counts and Participant Report of Adherence to Once-daily Pill Taking | Pill counts and participant report of adherence to once-daily pill taking reported as mean days study product could have been used according to pill counts | Up to 52 weeks | 
| Participant Report of Change in Number of Sexual Partners | Difference in mean number of reported sexual partners between final study visit and enrollment visit | Up to 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), HIV, HIV Prevention, Oral PrEP, Truvada, women, Tenofovir, TDF, FTC, emtricitabine, hepatitis, Pre-exposure Prophylaxis (PrEP), HIV Seronegativity