Clinical trial NCT00625404: FEM-PrEP (Truvada®): Study to Assess the Role of Truvada® in Preventing HIV Acquisition in Women
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: Aspartate Aminotransferase (AST)
Alanine Aminotransferase (ALT)
HIV
HIV Prevention
Oral PrEP
Truvada
women
Tenofovir
TDF
FTC
emtricitabine
hepatitis
Pre-exposure Prophylaxis (PrEP)
HIV Seronegativity
Lead sponsor: FHI 360
Sponsor class: OTHER
First posted: 2008-02-28
Enrollment: 2120
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: HIV Infection
timeFrame: Cumulative HIV infection between enrollment and 52 weeks
measure: Confirmed Grade 2 or Higher Serum Creatinine Toxicity
timeFrame: cumulative toxicity through 52 weeks of product use and 4 weeks post product
measure: Frequency of Adverse Events (AEs) During and Within 4 Weeks After Study Product Administration
timeFrame: 10-26 months per site
measure: Confirmed Grade 3 or Higher Reduction in Phosphorus
timeFrame: Through 52 weeks on product and 4 weeks post-product
measure: Confirmed Grade 3 or Higher ALT Elevation
timeFrame: Through 52 weeks on product and 4 weeks post-product
measure: Confirmed Grade 3 or Higher AST Elevation
timeFrame: Through 52 weeks on product and 4 weeks post-product
Secondary outcomes:
measure: Plasma HIV RNA Level (HIV-1 Viral Load)
timeFrame: up to 16 weeks
measure: CD4+ T-cell Count
timeFrame: Up to 16 weeks
measure: FTC and/or Tenofovir Resistance
timeFrame: up to 52 weeks
measure: Pregnancy Complications
timeFrame: up to 60 weeks
measure: Pill Counts and Participant Report of Adherence to Once-daily Pill Taking
timeFrame: Up to 52 weeks
measure: Participant Report of Change in Number of Sexual Partners
timeFrame: Up to 52 weeks
Other outcomes:
Locations:
city: Bondo
country: Kenya
facility: Bondo Clinic, Bondo District Hospital
state: Nyanza
city: Pretoria
country: South Africa
facility: Setshaba Research Centre
state: Gauteng
city: Bloemfontein
country: South Africa
facility: Josha Research Center
city: Arusha
country: Tanzania
facility: Arusha Clinic, Levolosi Health Center
Study officials:
affiliation: FHI 360
name: Lut Van Damme, MD, MS, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: FHI 360
name: Amy Corneli, PhD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: FHI 360
name: Jennifer Deese, MPH
role: STUDY_DIRECTOR
References:
citation: Lut Van Damme, M.D., Amy Corneli, Ph.D. and Douglas Taylor, Ph.D. New England Journal of Medicine 367: 411-422, 2012
citation: 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.
citation: 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.
citation: 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.
citation: 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.