Adherence and Acceptability to and Blood Levels of Tenofovir Gel and Tablets in HIV Uninfected 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) is an oral, FDA-approved, anti-HIV drug, and tenofovir gel is an experimental microbicide. The purpose of this study is to determine the adherence and acceptability to and blood levels of three daily regimens of tenofovir in both oral and gel form.

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 an anti-HIV drug (TDF), this study will measure the adherence and acceptability to and blood levels of the two interventions in three separate regimens given to HIV-uninfected women. The expected duration of participation for each participant is 21 weeks. Study participants will be randomly assigned into one of six study groups, each with a different regimen sequence. Each sequence will consist of three study periods and three wash-out periods. Each study period lasts 6 weeks, followed by a 1 week wash-out period. The regimen assigned for a given study period will include either oral TDF, tenofovir vaginal gel, or both. All participants will be prescribed all three regimens in the order designated by their randomized assignment. Study visits will occur at Weeks 1, 3, 6, 7, 10, 13, 14, 17, 20, and 21. Medical history, a physical exam, behavioral assessment, and urine, blood, pelvic sample collection, and counseling will occur at all visits. At some study sites rectal swabs may be performed. Counseling will include information regarding contraception, protocol adherence, HIV, HIV/Sexually Transmitted Infection risk reduction, and male condom use. Pharmacokinetic (PK) studies, to be determined by the study site, will occur during all three study periods. These studies may involve additional procedures.

Official Title
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Phase 2 Adherence and Pharmacokinetics Study of Oral and Vaginal Preparations of Tenofovir

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Tenofovir disoproxil fumarate
* Drug: Tenofovir gel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General good health HIV-uninfected Normal menstrual cycle. More information can be found in the protocol. Creatinine clearance greater than 70 ml/min Sexually active. More information can be found in the protocol. Normal Pap smear result within 12 months prior to study entry Agrees to not participate in other investigational studies Willing to use effective forms of contraception. More information can be found in the protocol. Exclusion Criteria: Adverse reaction to either of the study products Adverse reaction to latex Currently sexually active with a partner with history of adverse reaction to latex More than three sexual partners in the month prior to screening Pathologic bone fracture not related to trauma Last pregnancy outcome within 90 days or less prior to enrollment Gynecologic or genital procedure within 90 days of study entry Enrollment in other investigational study within 30 days of study entry Nontherapeutic injection drug use within 12 months of screening Any social or medical condition that, in the opinion of the investigator, would interfere with the study Abnormal laboratory values Grade 2 or higher genital lesions, erythema, and/or edema or has any other abnormal physical or pelvic exam finding that, in the opinion of the investigator, would interfere with the study Kidney, reproductive, or urinary tract infection requiring treatment. More information on this criterion can be found in the protocol. Pregnant, breastfeeding, or intend to become pregnant Unwilling to comply with study participation requirements, including attendance at all scheduled study visits Per participant report, use of the following at enrollment, and/or anticipated use during the period of study participation - use of a diaphragm, vaginal ring, and/or spermicide for contraception, acyclovir or valacyclovir, post-exposure prophylaxis for HIV exposure, TDF/emtricitabine, non-study vaginal products

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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Oral tenofovir disoproxil fumarate (TDF) for Weeks 1 through 6, vaginal tenofovir gel application for Weeks 8 through 13, and oral TDF and vaginal tenofovir gel application for Weeks 15 through 20 | Drug: Tenofovir disoproxil fumarate<br>* 300 mg tablet daily<br>* Other names: TDF;Drug: Tenofovir gel<br>* 1 gm/100 ml of 1% gel vaginally daily<br>* Other names: 9-[2-(Phosphonomethoxy)propyl]adenine;|
| Experimental: 2<br>Vaginal tenofovir gel application for Weeks 1 through 6, oral TDF for Weeks 8 through 13, and oral TDF and vaginal tenofovir gel application for Weeks 15 through 20 | Drug: Tenofovir disoproxil fumarate<br>* 300 mg tablet daily<br>* Other names: TDF;Drug: Tenofovir gel<br>* 1 gm/100 ml of 1% gel vaginally daily<br>* Other names: 9-[2-(Phosphonomethoxy)propyl]adenine;|
| Experimental: 3<br>Oral TDF and vaginal tenofovir gel application for Weeks 1 through 6, oral TDF for Weeks 8 through 13, and vaginal tenofovir gel application for Weeks 15 through 20 | Drug: Tenofovir disoproxil fumarate<br>* 300 mg tablet daily<br>* Other names: TDF;Drug: Tenofovir gel<br>* 1 gm/100 ml of 1% gel vaginally daily<br>* Other names: 9-[2-(Phosphonomethoxy)propyl]adenine;|
| Experimental: 4<br>Oral TDF and vaginal tenofovir gel application for Weeks 1 through 6, vaginal tenofovir gel application for Weeks 8 through 13, and oral TDF for Weeks 15 through 20 | Drug: Tenofovir disoproxil fumarate<br>* 300 mg tablet daily<br>* Other names: TDF;Drug: Tenofovir gel<br>* 1 gm/100 ml of 1% gel vaginally daily<br>* Other names: 9-[2-(Phosphonomethoxy)propyl]adenine;|
| Experimental: 5<br>Oral TDF for Weeks 1 through 6, oral TDF and vaginal tenofovir gel application for Weeks 8 through 13, and vaginal tenofovir gel application for Weeks 15 through 20 | Drug: Tenofovir disoproxil fumarate<br>* 300 mg tablet daily<br>* Other names: TDF;Drug: Tenofovir gel<br>* 1 gm/100 ml of 1% gel vaginally daily<br>* Other names: 9-[2-(Phosphonomethoxy)propyl]adenine;|
| Experimental: 6<br>Vaginal tenofovir gel application for Weeks 1 through 6, oral TDF and vaginal tenofovir gel application for Weeks 8 through 13, and oral TDF for Weeks 15 through 20 | Drug: Tenofovir disoproxil fumarate<br>* 300 mg tablet daily<br>* Other names: TDF;Drug: Tenofovir gel<br>* 1 gm/100 ml of 1% gel vaginally daily<br>* Other names: 9-[2-(Phosphonomethoxy)propyl]adenine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Self-reported Adherence to Each Regimen | Participant self-reported product use. For each woman, adherence to each regimen was computed by dividing the number of daily doses she reported having taken by the number of doses expect if she were fully adherent. | Measured through Week 21 | 
| Proportion of Participants Who Indicate They Would be Unlikely Use Study Product in the Future |  | Measured through Week 21 | 
| Systemic and Local PK Among Three Regimens of Tenofovir (Oral, Vaignal, and Dual Use) | PK measures, including maximum concentrations (Cmax) in serum, tissue, and cervicovaginal lavage. | Measured through Week 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Product Use | This number represents how often participant used study product during the preceding 3 weeks and is measured twice during each 6 week product period. | Measured through Week 21 | 
| Number of Days Product Missed | This represents the longest number of days in a row during the past 3 weeks that a participant missed using the study product. | Measured through Week 21 | 
| Proportion of Women Who Report Taking at Least 90% of Expected Daily Doses |  | Measured through Week 21 | 
| Frequency of Sexual Activity | This represents the rate during the past 3 weeks at which participants engaged in vaginal sex. | Measured through Week 21 | 
| Frequency of Male Condom Use |  | Measured through Week 21 | 
| Tablet Usage Before Sex | These summaries represent counts and percentages of participants using tablet before last instance of vaginal sex. | Measured through Week 21 | 
| Length of Time Vaginal Sexual Intercourse Took Place After Using Tablet. | Median and inter-quartile range of the time between product usage and instance of vaginal intercourse (given tablet was used before the encounter). | Measured through Week 21 | 
| Tablet Usage After Sex | These summaries represent counts and percentages of participants using tablet after last instance of vaginal sex. | Measured through Week 21 | 
| Length of Time Vaginal Sexual Intercourse Took Place Before Using Tablet. | Median and inter-quartile range of the time between product usage and instance of vaginal intercourse (given tablet was used after the encounter). | Measured through Week 21 | 
| Gel Usage Before Sex | These summaries represent counts and percentages of participants using gel before last instance of vaginal sex. | Measured through Week 21 | 
| Length of Time Vaginal Sexual Intercourse Took Place After Using Gel. | Median and inter-quartile range of the time between product usage and instance of vaginal intercourse (given gel was used before the encounter). | Measured through Week 21 | 
| Gel Usage After Sex | These summaries represent counts and percentages of participants using gel after last instance of vaginal sex. | Measured through Week 21 | 
| Length of Time Vaginal Sexual Intercourse Took Place Before Using Gel. | Median and inter-quartile range of the time between product usage and instance of vaginal intercourse (given gel was used after the encounter). | Measured through Week 21 | 
| Reported Sharing of Product | Number and percentage of participants who had a product sharing event during the 6-week product use period, where a sharing event includes 1) being asked for the study product, or 2) selling, trading, or giving away study product, or 3) having someone take the study product from the participant. | Measured through Week 21 | 
| Grade 3 or Higher Toxicity for Systemic and Local Effects as Defined by the Protocol |  | Measured through Week 21 | 

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