Safety and Effectiveness of TFV 1% Gel, TDF Tablets, and FTC/TDF Tablets in Preventing HIV in Women

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Emtricitabine/tenofovir disoproxil fumarate
* Drug: Emtricitabine/tenofovir disoproxil fumarate placebo
* Drug: Tenofovir disoproxil fumarate
* Drug: Tenofovir disoproxil fumarate placebo
* Drug: Tenofovir 1% vaginal gel
* Drug: Tenofovir placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>TDF 300 mg tablet taken orally once daily and one FTC/TDF placebo tablet taken orally once daily for 12 to 36 months | Drug: Emtricitabine/tenofovir disoproxil fumarate placebo<br>* placebo tablet<br>* Other names: Truvada placebo;Drug: Tenofovir disoproxil fumarate<br>* 300 mg tablet<br>* Other names: TDF;|
| Experimental: 2<br>TDF placebo tablet taken orally once daily and one FTC 200 mg/TDF 300 mg tablet taken orally once daily for 12 to 36 months | Drug: Emtricitabine/tenofovir disoproxil fumarate<br>* 200 mg/300 mg tablet<br>* Other names: Truvada;Drug: Tenofovir disoproxil fumarate placebo<br>* placebo tablet<br>* Other names: TDF placebo;|
| Experimental: 3<br>TDF placebo tablet taken orally once daily and one FTC/TDF placebo tablet taken orally once daily for 12 to 36 months | Drug: Emtricitabine/tenofovir disoproxil fumarate placebo<br>* placebo tablet<br>* Other names: Truvada placebo;Drug: Tenofovir disoproxil fumarate placebo<br>* placebo tablet<br>* Other names: TDF placebo;|
| Experimental: 4<br>Application of tenofovir 1% vaginal gel once daily | Drug: Tenofovir 1% vaginal gel<br>* 1 gm/100 ml of 1% gel<br>* Other names: 9-[2-(Phosphonomethoxy)propyl]adenine;|
| Experimental: 5<br>Application of tenofovir placebo gel once daily | Drug: Tenofovir placebo<br>* placebo gel<br>* Other names: TFV placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Person-years of Follow-up of Tenofovir 1% Gel and Vaginal Placebo Gel Arms | Participants were followed for up to 30 months. Person-years measures the amount of time for each participant, in years, from the date of enrollment to the date of the first HIV-positive test result if HIV-infected during follow-up or to the date of the last HIV-negative test result on follow-up if not HIV-infected during follow-up. | For up to 30 months of follow-up | 
| Number of HIV-1 Infections of Tenofovir 1% Gel and Vaginal Placebo Gel Arms | Participants were followed for up to 30 months. Participants were tested monthly for HIV-1 and positive rapid test results were confirmed by means of an enzyme-linked immunosorbent assay (EIA) and subsequent Western blotting (WB). | For up to 30 months of follow-up | 
| Incidence Rate of HIV-1 Infections of Tenofovir 1% Gel and Vaginal Placebo Gel Arms | This is the number of HIV-1 infections divided by the amount of person-years of follow-up time to HIV-1 infection status, multiplied by 100 (per 100 person-years). | For up to 30 months of follow-up | 
| Person-years of Follow-up of Oral TDF and Oral Placebo Arms | Participants were followed for up to 30 months. Person-years measures the amount of time for each participant, in years, from the date of enrollment to the date of the first HIV-positive test result if HIV-infected during follow-up or to the date of the last HIV-negative test result on follow-up if not HIV-infected during follow-up. Note that the data for both of these arms were censored on the date when sites were asked to discontinue treatment in the oral TDF group. | For up to 30 months of follow-up | 
| Number of HIV-1 Infections of Oral TDF and Oral Placebo Arms | Participants were followed for up to 30 months. Participants were tested monthly for HIV-1 and positive rapid test results were confirmed by means of an enzyme-linked immunosorbent assay (EIA) and subsequent Western blotting (WB). | For up to 30 months of follow-up | 
| Incidence Rate of HIV-1 Infections of Oral TDF and Oral Placebo Arms | This is the number of HIV-1 infections divided by the amount of person-years of follow-up time to HIV-1 infection status, multiplied by 100 (per 100 person-years). | For up to 30 months of follow-up | 
| Person-years of Follow-up of Oral TDF-FTC and Oral Placebo Arms | Participants were followed for up to 30 months. Person-years measures the amount of time for each participant, in years, from the date of enrollment to the date of the first HIV-positive test result if HIV-infected during follow-up or to the date of the last HIV-negative test result on follow-up if not HIV-infected during follow-up. | For up to 30 months of follow-up | 
| Number of HIV-1 Infections of Oral TDF-FTC and Oral Placebo Arms | Participants were followed for up to 30 months. Participants were tested monthly for HIV-1 and positive rapid test results were confirmed by means of an enzyme-linked immunosorbent assay (EIA) and subsequent Western blotting (WB). | For up to 30 months of follow-up | 
| Incidence Rate of HIV-1 Infections of Oral TDF-FTC and Oral Placebo Arms | This is the number of HIV-1 infections divided by the amount of person-years of follow-up time to HIV-1 infection status, multiplied by 100 (per 100 person-years). | For up to 30 months of follow-up | 
| 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 | This measure describes the number of participants with elevated serum creatinine levels, the only safety outcome of concern where a significant difference was detected between an active arm and the corresponding placebo arm. | Throughout study, up to 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of HIV-1 Drug Resistance in Women Who Acquire HIV-1 Infection While Using Study Product | The primary resistance mutations for the study were pre-defined as K65R and K70E (which confer resistance to TDF), and M184I and M184V (which confer resistance to FTC), for their potential to cause a decrease in susceptibility to the study drug. K65R, K70E, and M184I were not detected in HIV-1 from any HIV-1 seroconverters while on study product. The number of HIV-1 seroconverters while on study with the M184V resistance mutation are reported for this outcome measure. | Throughout study, up to 2.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Microbicide, HIV Seronegativity