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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Truvada; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 2120
• Phase: Phase 3

Contacts and Locations

Study Locations

• Kenya
  • Nyanza
    • Bondo, Nyanza, Kenya
      • Bondo Clinic, Bondo District Hospital
• South Africa
  • Bloemfontein, South Africa
    • Josha Research Center
  • Gauteng
    • Pretoria, Gauteng, South Africa
      • Setshaba Research Centre
• Tanzania
  • Arusha, Tanzania
    • Arusha Clinic, Levolosi Health Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Willing and able (see criterion 2) to provide written informed consent to be screened for and to participate in the trial
2. Able to answer a percentage of informed consent screening (75%) and enrollment (100%) comprehension quiz questions correctly
3. Between 18-35 years old, inclusive
4. At higher risk of becoming HIV infected
5. 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

6. 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
7. 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)
8. 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
9. Not pregnant or breastfeeding, and does not anticipate a desire for pregnancy during the 52 weeks of on-product participation

10. 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)
11. 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
12. No clinical signs of liver disease (e.g., ascites, spider angiomata, hepatomegaly, jaundice)
13. 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.
14. No history of pathological bone fractures
15. No history of adverse reaction to latex
16. 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: FHI 360
• Investigators: Principal Investigator: Lut Van Damme, MD, MS, PhD, FHI 360; Principal Investigator: Amy Corneli, PhD, MPH, FHI 360; Study Director: Jennifer Deese, MPH, FHI 360

Publications and helpful links

General Publications

• Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, Malahleha M, Owino F, Manongi R, Onyango J, Temu L, Monedi MC, Mak'Oketch P, Makanda M, Reblin I, Makatu SE, Saylor L, Kiernan H, Kirkendale S, Wong C, Grant R, Kashuba A, Nanda K, Mandala J, Fransen K, Deese J, Crucitti T, Mastro TD, Taylor D; FEM-PrEP Study Group. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012 Aug 2;367(5):411-22. doi: 10.1056/NEJMoa1202614. Epub 2012 Jul 11.
• Mandala J, Nanda K, Wang M, De Baetselier I, Deese J, Lombaard J, Owino F, Malahleha M, Manongi R, Taylor D, Van Damme L. Liver and renal safety of tenofovir disoproxil fumarate in combination with emtricitabine among African women in a pre-exposure prophylaxis trial. BMC Pharmacol Toxicol. 2014 Dec 24;15:77. doi: 10.1186/2050-6511-15-77.
• Grant RM, Liegler T, Defechereux P, Kashuba AD, Taylor D, Abdel-Mohsen M, Deese J, Fransen K, De Baetselier I, Crucitti T, Bentley G, Agingu W, Ahmed K, Damme LV. Drug resistance and plasma viral RNA level after ineffective use of oral pre-exposure prophylaxis in women. AIDS. 2015 Jan 28;29(3):331-7. doi: 10.1097/QAD.0000000000000556.
• Todd CS, Deese J, Wang M, Hubacher D, Steiner MJ, Otunga S, Van Damme L; FEM-PrEP Study Group. Sino-implant (II)(R) continuation and effect of concomitant tenofovir disoproxil fumarate-emtricitabine use on plasma levonorgestrel concentrations among women in Bondo, Kenya. Contraception. 2015 Mar;91(3):248-52. doi: 10.1016/j.contraception.2014.10.008. Epub 2014 Oct 22.

Helpful Links

• Genetics Home Reference for complement factor I deficiency
• MedlinePlus: AIDS
• MedlinePlus: Hepatitis
• Drug Information: n-Octadecanoic acid
• Drug Information: Calcium stearate
• Drug Information : Aluminum monostearate
• U.S. FDA Resources
• Study based publication

Study record dates

Study Major Dates

• Study Start: May 1, 2009
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): January 1, 2013

Study Registration Dates

• First Submitted: February 19, 2008
• First Submitted That Met QC Criteria: February 26, 2008
• First Posted (Estimate): February 28, 2008

Study Record Updates

• Last Update Posted (Actual): July 26, 2018
• Last Update Submitted That Met QC Criteria: June 28, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: HIV Seronegativity; HIV; Truvada; Tenofovir; HIV Prevention; women; emtricitabine; TDF; Aspartate Aminotransferase (AST); Oral PrEP; FTC; Alanine Aminotransferase (ALT); hepatitis; Pre-exposure Prophylaxis (PrEP)
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Tenofovir; Emtricitabine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
• Other Study ID Numbers: 10015 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)