Clinical trial NCT01386294: Safety and Effectiveness of Tenofovir Gel in the Prevention of Human Immunodeficiency Virus (HIV-1) Infection in Women and the Effects of Tenofovir Gel on the Incidence of Herpes Simplex Virus (HSV-2) Infection
Official title: A Phase III, Multi-Centre, Randomized Controlled Trial to Assess the Safety and Effectiveness of the Vaginal Microbicide 1% Tenofovir Gel in the Prevention of Human Immunodeficiency Virus Type 1 Infection in Women, and to Examine Effects of the Microbicide on the Incidence of Herpes Simplex Virus Type 2 Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Prevention
Lead sponsor: CONRAD
Sponsor class: OTHER
Collaborators: name: Follow-on African Consortium for Tenofovir Studies (FACTS)
name: United States Agency for International Development (USAID)
First posted: 2011-07-01
Enrollment: 2059
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of the study is to assess the safety and effectiveness of intravaginal 1% tenofovir gel in preventing Human Immunodeficiency Virus (HIV-1) infection and Herpes Simplex Virus (HSV-2) infection in sexually active women.

Detailed description: This is a phase III, multicenter trial to assess the safety and effectiveness of 1% tenofovir gel, administered vaginally by approximately 2900 sexually active women at high risk for sexually transmitted HIV. Approximately 2600 women aged 18-30 years old will be enrolled to achieve the required number of endpoints to show an effect on HIV-1 infection, while up to 300 additional women aged 31-40 years old will be enrolled to collect more safety information in this age group.

This is an event driven study that plans to randomize seronegative women. Participants will be randomized to a 1:1 ratio to receive 1% tenofovir gel or placebo gel. Each will be asked to insert a dose of the assigned study product within 12 hours prior to a coital event and another dose as soon as possible within 12 hours after a coital event. Participants will be advised to use only two doses of gel in a 24 hour period.

All women will be evaluated for the rates of adverse events and the rate of HIV seroconversion. In addition, the study will evaluate several secondary endpoints that bear directly on potential risks and benefits of vaginal tenofovir gel use.

Eligibility criteria: Inclusion Criteria:

* Confirmed age 18-40 years (inclusive)
* Able and willing to provide written informed consent
* Able and willing to provide adequate locator information for study retention and safety purposes
* Sexually active, defined as having had vaginal intercourse at least twice in the past 30 days prior to screening
* HIV negative on two rapid tests performed by study staff within 30 days of enrolment (see algorithm in Appendix 3).
* No evidence of glycosuria
* No evidence of proteinuria greater than trace\*
* No history of pathological bone fractures
* Have a negative pregnancy test
* Women currently breastfeeding may be enrolled in the study
* Agree to use a study-approved effective non-barrier form of contraception
* Agree to adhere to study visits and procedures
* Willing to use study gel as advised
* Not using or taking any of the following groups of medications:

  * Nephrotoxic agents
  * Drugs that slow renal excretion
  * Immune system modulators
  * Other antiretrovirals

Exclusion Criteria:

* History of adverse reaction to latex.
* Plans any of the following during the study period

  * To travel away from the study site for more than 30 consecutive days.
  * To relocate away from the study site.
  * To become pregnant.
  * To enrol in any other study of an investigational product or behaviour modification related to HIV prevention.
* If in the opinion of the examining clinician, is not sexually active
* Inadequate renal function (serum creatinine greater than 1.5mg/dl and creatinine clearance less than 50ml/min, as estimated using the method of Cockcroft and Gault96 )
* Grade 3 and above ALT and AST at screening or any clinical sign of liver disease ( e.g. ascites, hepatomegaly, jaundice)
* Abnormal serum phosphate levels (Grade 3 and above)
* Has a clinically apparent finding on speculum pelvic examination (observed by study staff) involving deep epithelial disruption. Otherwise eligible participants with speculum pelvic examination findings involving deep epithelial disruption may proceed with enrolment after the findings have resolved and the inclusion/exclusion are met.
* Received previously or receiving an experimental HIV vaccine
* Currently participating in another HIV prevention intervention study or participation in any other clinical trial with a biomedical intervention in the last six months
* Has current STI symptoms and/or other reproductive tract infection requiring treatment, as assessed by study staff. Otherwise eligible participants diagnosed during screening with infection(s) requiring treatment may be enrolled provided that treatment has been completed.
* Any clinical evidence of untreated cervical abnormalities
* Has any other condition that, based on the opinion of the Investigator or designee, would preclude provision of informed consent, make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.

Primary outcomes:
measure: Effectiveness
timeFrame: 30 months
measure: Safety
timeFrame: 30 months
Secondary outcomes:
measure: Incidence of HSV-2 infection
timeFrame: 30 months
measure: Pregnancy
timeFrame: 30 months
measure: Gel and condom use
timeFrame: 30 months
measure: HIV-1 incidence after product withdrawal
timeFrame: 3 months after product withdrawal
Other outcomes:
Locations:
city: Pietermaritzburg
country: South Africa
facility: MatCH Edendale Research Center
state: Kwa-Zulu NAtal
city: Cape Town
country: South Africa
facility: Desmond Tutu HIV Centre / University of Cape Town
city: Diepkloof
country: South Africa
facility: Perinatal HIV Research Unit / University of the Witwatersrand
city: Hillbrow
country: South Africa
facility: Wits Reproductive Health and HIV Institute / University of the Witwatersrand
city: Ladysmith
country: South Africa
facility: Qhakaza Mbokodo Research Clinic
city: Pretoria
country: South Africa
facility: Medunsa Clinical Research Unit / Ga-Ra
city: Rustenburg
country: South Africa
facility: The Aurum Institute (Rustenburg)
city: Soshanguve
country: South Africa
facility: Setshaba Research Centre
city: Tembisa
country: South Africa
facility: The Aurum Institute, Tembisa Hospital
Study officials:
affiliation: University of Witwatersrand, South Africa
name: Helen Rees, Prof
role: STUDY_CHAIR
References:
citation: Delany-Moretlwe S, Lombard C, Baron D, Bekker LG, Nkala B, Ahmed K, Sebe M, Brumskine W, Nchabeleng M, Palanee-Philips T, Ntshangase J, Sibiya S, Smith E, Panchia R, Myer L, Schwartz JL, Marzinke M, Morris L, Brown ER, Doncel GF, Gray G, Rees H. Tenofovir 1% vaginal gel for prevention of HIV-1 infection in women in South Africa (FACTS-001): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2018 Nov;18(11):1241-1250. doi: 10.1016/S1473-3099(18)30428-6. Epub 2018 Oct 24.