Clinical trial NCT00705679: Safety and Effectiveness of TFV 1% Gel, TDF Tablets, and FTC/TDF Tablets in Preventing HIV in Women
Official title: Phase 2B Safety and Effectiveness Study of Tenofovir 1% Gel, Tenofovir Disproxil Fumarate Tablet and Emtricitabine/Tenofovir Disoproxil Fumarate Tablet for the Prevention of HIV Infection in Women
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: Microbicide
HIV Seronegativity
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Microbicide Trials Network
First posted: 2008-06-26
Enrollment: 5029
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: A new approach to HIV prevention currently being studied includes the use of microbicides, substances that kill microbes. Tenofovir disoproxil fumarate (TDF) and emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) are oral, FDA-approved, anti-HIV drugs, and tenofovir gel is an experimental microbicide. The purpose of this study is to determine the safety and effectiveness of daily tenofovir 1% gel compared to a vaginal placebo gel, and the safety and effectiveness of oral TDF and oral FTC/TDF compared to an oral placebo in preventing HIV infection among women at risk for sexually transmitted infections.

Detailed description: It is necessary to monitor both the adherence and blood levels of microbicides in order to gauge its efficacy in a study population. Utilizing an experimental microbicide (tenofovir gel) and anti-HIV drugs (TDF, FTC/TDF), this study will measure the effectiveness and safety to and blood levels of the three interventions in three regimens given to HIV uninfected women.

The expected duration of participation for each participant ranges from a minimum of 12 months to a maximum of 38 months. Study participants will be randomly assigned into one of five study groups, each with a different regimen. Group 1 participants will take one TDF tablet daily and one FTC/TDF placebo tablet daily. Group 2 participants will take one TDF placebo tablet daily and one FTC/TDF tablet daily. Group 3 participants will take one TDF placebo tablet daily and one FTC/TDF placebo tablet daily. Group 4 participants will apply tenofovir 1% gel vaginally once daily. Group 5 participants will apply tenofovir 1% placebo gel vaginally once daily.

Study visits will occur every 28 days after enrollment. Medical history, a physical exam, behavioral and adherence assessment, urine and blood collection, and counseling will occur at all visits. Blood will also be collected and archived for future research at select visits. Pharmacokinetic studies will occur at some visits. A pap smear will occur at select visits. Some participants may have hair samples collected on an optional basis at study visits every 2 months.

Eligibility criteria: Inclusion Criteria:

* Willing to provide adequate locator information
* Sexually active, defined as having vaginal intercourse at least once in the 3 months prior to screening
* Agree to not participate in other research studies involving drugs, medical devices, or vaginal products for duration of study.
* Agree to use effective method of contraception. More information on this criterion can be found in the protocol.

Exclusion Criteria:

* HIV infected
* Known adverse reaction to any of the study products
* Known adverse reaction to latex
* Pathologic bone fracture not related to trauma
* Non-therapeutic injection drug use in the 12 months prior to screening
* Post-exposure prophylaxis for HIV exposure within 6 months prior to enrollment
* Last pregnancy outcome 42 days or less prior to enrollment
* Gynecologic or genital procedure 42 days or less prior to enrollment
* Participation in any other research study involving drugs, medical devices, or vaginal products 30 days or less prior to enrollment
* Currently using spermicide, interferon or interleukin therapy, or certain medications. More information on this criterion can be found in the protocol.
* Any significant uncontrolled active or chronic disease. More information on this criterion can be found in the protocol.
* Certain abnormal laboratory values. More information on this criterion can be found in the protocol.
* Intends to become pregnant in the 24 months after enrollment
* Plans to relocate or travel away from the study site for more than 8 consecutive weeks in the 24 months after enrollment
* Urinary tract infection
* Pelvic inflammatory disease, an STI, or reproductive tract infection requiring treatment
* Grade 2 or higher pelvic exam finding
* Any condition that, in the opinion of the investigator, would interfere with the study
* Pregnant or breastfeeding

Primary outcomes:
measure: Person-years of Follow-up of Tenofovir 1% Gel and Vaginal Placebo Gel Arms
timeFrame: For up to 30 months of follow-up
measure: Number of HIV-1 Infections of Tenofovir 1% Gel and Vaginal Placebo Gel Arms
timeFrame: For up to 30 months of follow-up
measure: Incidence Rate of HIV-1 Infections of Tenofovir 1% Gel and Vaginal Placebo Gel Arms
timeFrame: For up to 30 months of follow-up
measure: Person-years of Follow-up of Oral TDF and Oral Placebo Arms
timeFrame: For up to 30 months of follow-up
measure: Number of HIV-1 Infections of Oral TDF and Oral Placebo Arms
timeFrame: For up to 30 months of follow-up
measure: Incidence Rate of HIV-1 Infections of Oral TDF and Oral Placebo Arms
timeFrame: For up to 30 months of follow-up
measure: Person-years of Follow-up of Oral TDF-FTC and Oral Placebo Arms
timeFrame: For up to 30 months of follow-up
measure: Number of HIV-1 Infections of Oral TDF-FTC and Oral Placebo Arms
timeFrame: For up to 30 months of follow-up
measure: Incidence Rate of HIV-1 Infections of Oral TDF-FTC and Oral Placebo Arms
timeFrame: For up to 30 months of follow-up
measure: Extended Safety of Daily Tenofovir 1% Gel, Oral TDF, and Oral FTC/TDF in Women at Risk for Sexually Transmitted HIV Infection Based on Occurrence of Grade 2, 3, and 4 Adverse Events
timeFrame: Throughout study, up to 2.5 years
Secondary outcomes:
measure: Frequency of HIV-1 Drug Resistance in Women Who Acquire HIV-1 Infection While Using Study Product
timeFrame: Throughout study, up to 2.5 years
Other outcomes:
Locations:
city: Johannesburg
country: South Africa
facility: Wits Reproductive Health and HIV Institute CRS (WRHI CRS)
state: Gauteng
city: Johannesburg
country: South Africa
facility: Soweto MTN CRS
state: Gauteng
city: Asherville
country: South Africa
facility: Overport CRS
state: KwaZulu-Natal
city: Chatsworth
country: South Africa
facility: Chatsworth CRS
state: KwaZulu-Natal
city: Durban
country: South Africa
facility: eThekwini CRS
state: KwaZulu-Natal
city: Tongaat
country: South Africa
facility: Tongaat CRS
state: KwaZulu-Natal
city: Umkomaas
country: South Africa
facility: Umkomaas CRS
state: KwaZulu-Natal
city: Verulam
country: South Africa
facility: Verulam CRS
state: KwaZulu-Natal
city: Westville
country: South Africa
facility: Botha's Hill CRS
state: KwaZulu-Natal
city: Westville
country: South Africa
facility: Isipingo CRS
state: KwaZulu-Natal
city: Klerksdorp
country: South Africa
facility: CAPRISA Aurum CRS
city: Kampala
country: Uganda
facility: MU-JHU Research Collaboration CRS
city: Chitungwiza
country: Zimbabwe
facility: Seke South CRS
city: Chitungwiza
country: Zimbabwe
facility: Zengeza CRS
city: Harare
country: Zimbabwe
facility: Spilhaus CRS
Study officials:
affiliation: UZ-UCSF Collaborative Research Programme
name: Zvavahera M. Chirenje, MD, FRCOG
role: STUDY_CHAIR
affiliation: University of Washington, Division of Allergy and Infectious Disease
name: Jeanne Marrazzo, MD, MPH
role: STUDY_CHAIR
References:
citation: Mayer KH, Maslankowski LA, Gai F, El-Sadr WM, Justman J, Kwiecien A, Masse B, Eshleman SH, Hendrix C, Morrow K, Rooney JF, Soto-Torres L; HPTN 050 Protocol Team. Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women. AIDS. 2006 Feb 28;20(4):543-51. doi: 10.1097/01.aids.0000210608.70762.c3.
citation: Rosen RK, Morrow KM, Carballo-Dieguez A, Mantell JE, Hoffman S, Gai F, Maslankowski L, El-Sadr WM, Mayer KH. Acceptability of tenofovir gel as a vaginal microbicide among women in a phase I trial: a mixed-methods study. J Womens Health (Larchmt). 2008 Apr;17(3):383-92. doi: 10.1089/jwh.2006.0325.
citation: Chirenje ZM, Gundacker HM, Richardson B, Rabe L, Gaffoor Z, Nair GL, Mirembe BG, Piper JM, Hillier S, Marrazzo J. Risk Factors for Incidence of Sexually Transmitted Infections Among Women in a Human Immunodeficiency Virus Chemoprevention Trial: VOICE (MTN-003). Sex Transm Dis. 2017 Mar;44(3):135-140. doi: 10.1097/OLQ.0000000000000568.
citation: Moodley J, Naidoo S, Moodley J, Ramjee G. Sharing of Investigational Drug Among Participants in the Voice Trial. AIDS Behav. 2016 Nov;20(11):2709-2714. doi: 10.1007/s10461-016-1414-x.
citation: van der Straten A, Brown ER, Marrazzo JM, Chirenje MZ, Liu K, Gomez K, Marzinke MA, Piper JM, Hendrix CW; MTN-003 VOICE Protocol Team for Microbicide Trials Network. Divergent adherence estimates with pharmacokinetic and behavioural measures in the MTN-003 (VOICE) study. J Int AIDS Soc. 2016 Feb 4;19(1):20642. doi: 10.7448/IAS.19.1.20642. eCollection 2016.
citation: Noguchi LM, Richardson BA, Baeten JM, Hillier SL, Balkus JE, Chirenje ZM, Bunge K, Ramjee G, Nair G, Palanee-Phillips T, Selepe P, van der Straten A, Parikh UM, Gomez K, Piper JM, Watts DH, Marrazzo JM; VOICE Study Team. Risk of HIV-1 acquisition among women who use diff erent types of injectable progestin contraception in South Africa: a prospective cohort study. Lancet HIV. 2015 Jul;2(7):e279-87. doi: 10.1016/S2352-3018(15)00058-2.
citation: Dai JY, Hendrix CW, Richardson BA, Kelly C, Marzinke M, Chirenje ZM, Marrazzo JM, Brown ER. Pharmacological Measures of Treatment Adherence and Risk of HIV Infection in the VOICE Study. J Infect Dis. 2016 Feb 1;213(3):335-42. doi: 10.1093/infdis/jiv333. Epub 2015 Jun 29.
citation: Marrazzo JM, Ramjee G, Richardson BA, Gomez K, Mgodi N, Nair G, Palanee T, Nakabiito C, van der Straten A, Noguchi L, Hendrix CW, Dai JY, Ganesh S, Mkhize B, Taljaard M, Parikh UM, Piper J, Masse B, Grossman C, Rooney J, Schwartz JL, Watts H, Marzinke MA, Hillier SL, McGowan IM, Chirenje ZM; VOICE Study Team. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015 Feb 5;372(6):509-18. doi: 10.1056/NEJMoa1402269.