A Safety Study of Two Dapivirine (TMC120) Vaginal Gels in the United States

Study Overview
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Brief Summary
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A double-blind, randomized, placebo-controlled Phase I/II trial to evaluate the safety of dapivirine Gel 4759, 0.05% 2.5 g and dapivirine Gel 4789, 0.05% 2.5 g formulations as compared to the vaginal HEC-based Universal placebo gel, 2.5 g in healthy HIV-negative women

Detailed Description
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This was a double-blind, randomized, placebo-controlled trial, to be conducted over 10 months at five research centers in the USA among 180 healthy, sexually active women, to assess the safety and acceptability of dapivirine Gel 4759, 0.05% 2.5 g, and dapivirine Gel 4789, 0.05% 2.5 g, both vaginal microbicides containing dapivirine, compared to the vaginal HEC-based Universal placebo gel, 2.5 g, containing no active ingredient, used once daily for a period of 12 weeks.

Official Title
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A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED PHASE I/II TRIAL TO EVALUATE THE SAFETY OF DAPIVIRINE GEL 4759, 0.05% 2.5g AND DAPIVIRINE GEL 4789, 0.05% 2.5g FORMULATIONS AS COMPARED TO THE VAGINAL HEC-BASED UNIVERSAL PLACEBO GEL, 2.5g IN HEALTHY HIV-NEGATIVE WOMEN

Conditions
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HIV-1 Infections

Intervention / Treatment
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* Drug: dapivirine 4789
* Drug: dapivirine gel 4759
* Drug: Drug placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women 18 to 40 years of age inclusive who can give written informed consent Available for all visits and consent to follow all procedures scheduled for the trial Healthy and self-reported sexually active HIV-negative as determined by an HIV test at time of enrollment Willing to be on a stable form of contraception In the absence of the use of exogenous hormone(s), have a self-reported regular menstrual cycle Upon pelvic/speculum examination and colposcopy at the enrollment visit, the cervix and vagina appear normal as determined by qualified research center staff Asymptomatic for genital infections at the time of enrollment Willing to refrain from use of vaginal products or objects for 14 days prior to enrollment and for the duration of the trial. Documentation of no abnormality on Pap smear within 90 days prior to randomization; Willing to answer acceptability and adherence questionnaires throughout the trial Willing to refrain from participation in any other research trial for the duration of this trial Willing to provide adequate locator information for trial retention purposes and be reachable per local standard procedures Willing to abstain from all the following criteria beginning 48 hours prior to each trial visit: Vaginal intercourse Oral contact with her genitalia Internal vaginal washing Penetration of the vagina by fingers, sex toys, or any other objects, including medications Willing to abstain from all of the following for 3 days after biopsy procedures: Vaginal intercourse Oral contact with her genitalia Internal vaginal washing Penetration of the vagina by fingers, sex toys, or any other objects, including medications Exclusion Criteria: Currently pregnant or having had their last pregnancy outcome within 3 months prior to screening Currently breast-feeding, or having breastfed within 3 months prior to screening Receipt of any investigational agent within 60 days prior to screening Previously participated in any HIV vaccine trial Untreated urogenital infections within 2 weeks prior to enrollment Presence of any abnormal physical finding on the vulva, vaginal walls or cervix during pelvic/speculum examination and/or colposcopy History of significant urogenital or uterine prolapse, undiagnosed vaginal bleeding, or urethral obstruction Pap smear result at screening that requires cryotherapy, biopsy or treatment (other than for infection) History of symptomatic or asymptomatic HSV-2 Any Grade 2, 3 or 4 hematology, chemistry or urinalysis laboratory abnormality at baseline Unexplained, undiagnosed abnormal bleeding per vagina during or following vaginal intercourse; or urogenital surgery within 90 days prior to enrollment Any history of anaphylaxis or severe allergy resulting in angioedema; or a history of sensitivity/allergy to latex Any serious acute, chronic or progressive disease Any condition(s) that, in the opinion of the Investigator, might interfere with adherence to trial requirements or evaluation of the trial objectives

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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
Interventional Model Description: All enrolled participants will apply gel on a daily basis for 12 weeks, with clinical follow-up visits at weeks 2,4,8 and 12 to monitor safety and acceptability, and a final visit 4 weeks post gel discontinuation (Visit 6, week 16) Dapivirine concentration will be measured in blood and vaginal fluid and cervical tissue.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: dapivirine gel 4789<br>will be applied by participants once daily for 12-weeks treatment period | Drug: dapivirine 4789<br>* dapivirine gel 4789, 0.05%, 2.5g applied once daily<br>* Other names: TMC120;|
| Active Comparator: dapivirine gel 4759<br>Will be applied by participants once daily for12-weeks treatment period | Drug: dapivirine gel 4759<br>* dapivirine gel 4759, 0.05%, 2.5g applied once daily<br>* Other names: TMC120;|
| Placebo Comparator: HEC-based placebo gel, 2.5g containing no Dapivirine<br>Will be applied once daily for 12-weeks treatment period | Drug: Drug placebo<br>* HEC-based universal placebo gel, 2.5g applied once daily<br>* Other names: HEC-based placebo gel, 2.5g;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Women With the Composite Endpoint of Abnormal Safety Findings. | A composite endpoint was defined as the percentage of participants with any post-baseline abnormal finding from pelvic/speculum examination, colposcopy finding, STI diagnoses, laboratory test of DAIDS grade 3 or higher and any product-related AE. DAIDS severity grades are defined as follows: Grade 1 = mild Grade 2 = moderate Grade 3 = severe Grade 4 = potentially life-threatening Grade 5 = death | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the Vaginal Flora | Cervicovaginal fluid specimens will be obtained to determine vaginal flora before first gel application and at Visits 3, 5, and 6. Appropriate statistical analyses incorporating repeated measures will be used to assess the changes in the vaginal flora in women using Dapivirine Gel 4759, 0.05% 2.5g, Dapivirine Gel 4789, 0.05% 2.5g or the vaginal HEC-based universal placebo gel, 2.5g. Nugent scores were used to assess changes in vaginal flora, and were categorized into three levels: (1) negative for BV (score: 0-3); (2) altered vaginal flora (score: 4-6); and (3) BV (score: 7-10). | 16 weeks | 
| The Distribution of Dapivirine Levels Observed in Plasma Samples at Each Specified Time Point | Dapivirine levels observed in plasma will be summarized using simple descriptive statistics. | 12 weeks | 
| The Adherence to Once Daily Application of a Vaginal Microbicide Gel Over a 12-week Period in Healthy, Sexually Active, HIV-negative Women | Adherence is defined as the percentage of participants who used the gel each day of the preceding 14 days, based on participant self reports. | 12 weeks | 
| Changes in the Vaginal pH | Cervicovaginal fluid specimens will be obtained to determine vaginal pH before first gel application and at screening, enrolment and visit 5 (week 12). Appropriate statistical analyses incorporating repeated measures will be used to assess the changes in the vaginal pH in women using Dapivirine Gel 4759, 0.05% 2.5g, Dapivirine Gel 4789, 0.05% 2.5g or the vaginal HEC-based universal placebo gel, 2.5g. | 12 weeks | 
| The Distribution of Dapivirine Levels Observed in Vaginal Fluid at Each Specified Time Point. | The distribution of dapivirine levels observed in each type of sample will be summarized using simple descriptive statistics. In addition, the proportion of women with detectable dapivirine concentrations will be calculated for each type of sample at each collection time point. Exploratory analyses of dapivirine concentration data will also be performed to take into account information reported in a diary regarding menses and tampon use throughout the trial. | 12 weeks. Measured at 2, 4, and 8 weeks post-enrolment and at one of these at week 12; 24, 48, or 72 hours after gel discontinuation. (Participants were randomized to have vaginal fluid samples collected at one of these visits (5a, 5b, or 5c). | 
| The Distribution of Dapivirine Levels Observed in Vaginal Tissue at Each Specified Time Point. | The distribution of dapivirine levels observed in vaginal tissue sample will be summarized using simple descriptive statistics. | 12 weeks. Measured at 2, 4, and 8 weeks post-enrolment and at one of these at week 12; 24, 48, or 72 hours after gel discontinuation. (Participants were randomized to have vaginal fluid samples collected at one of these visits (5a, 5b, or 5c). | 
| Acceptability of Once Daily Application of a Vaginal Microbicide Gel Over a 12-week Period in Healthy, Sexually Active, HIV-negative Women | Acceptability was assessed as the percentage of participants at week 12 who were willing to use the gel every day if proven to prevent HIV. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-1 infections