Safety and Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 Seronegative Adults

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and pharmacokinetics (PK) of dapivirine gel (0.05%) administered rectally to HIV-1 seronegative adults.

Detailed Description
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This study will evaluate the safety and pharmacokinetics (PK) of dapivirine gel (0.05%) administered rectally to HIV-1 seronegative adults. Participants will be randomized to receive a single dose of either rectally administered dapivirine gel (0.05%) or placebo gel at study entry (Day 0). Following a minimum 2-week washout period, participants or study staff will administer daily rectal doses of the assigned gel for 7 consecutive days under direct observation in the clinic. Participants will be in the study for approximately 40 days, and they will attend 16 study visits. Study visits may include behavioral assessments, physical examinations, blood and urine collection, and pelvic and anorectal sample collection. Some visits will include intensive PK sampling. Study staff will contact participants 1 week after Visit 16 for follow-up safety monitoring.

Official Title
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A Randomized, Double Blind, Placebo-Controlled, Phase 1 Safety and Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 Seronegative Adults

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Dapivirine gel
* Drug: Placebo gel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of 18 - 45 years (inclusive) at Screening, verified per site standard operating procedure (SOP) Able and willing to provide written informed consent HIV-1/2 uninfected at Screening and Enrollment, per applicable algorithm in Appendix II of the protocol and willing to receive HIV test results Able and willing to provide adequate locator information, as defined in site SOP Available to return for all study visits and willing to comply with study participation requirements In general good health at Screening and Enrollment, as determined by the site Investigator of Record (IoR) or designee Per participant report, a history of consensual receptive anal intercourse (RAI) at least once in the past calendar year Willing to not take part in other research studies involving drugs, medical devices, genital or rectal products, or vaccines for the duration of study participation, including the time between Screening and Enrollment Willing to be sexually abstinent for 72 hours prior to each study visit, during the study product use periods and for 72 hours after biopsy collection. Note: See Criteria 12 and 13 for additional restrictions for female participants Willing to abstain from inserting any non-study products into the rectum for 72 hours prior to each study visit and during the study product use periods. Note: See Criteria 12 and 13 for additional restrictions for female participants Females must also meet the following additional inclusion criteria to be eligible for study inclusion: Women over the age of 21 (inclusive) must have documentation of a satisfactory Pap within the past 3 years prior to Enrollment consistent with Grade 0 according to the Female Genital Grading Table for Use in Microbicide Studies Addendum 1 (dated November 2007) to the DAIDS Table for Grading Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, or satisfactory evaluation with no treatment required of Grade 1 or higher Pap result Willing to be sexually abstinent for 72 hours prior to each study visit and during the study product use periods and for 7 days after biopsy collection Willing to abstain from inserting any non-study products into the vagina for 72 hours prior to each study visit, during the study product use periods and for 7 days after biopsy collection Willing to use an effective method of contraception for at least 30 days (inclusive) prior to Enrollment and intending to continue use of an effective method for the duration of study participation; effective methods include: hormonal methods (except contraceptive ring), intrauterine device (IUD), sterilization (of participant and/or partner, as defined in site SOPs), or sexually abstinent for 90 days prior to Screening Exclusion Criteria: At Screening: Hemoglobin Grade 1 or higher* Platelet count Grade 1 or higher* White blood count Grade 2 or higher* Serum creatinine greater than 1.3× the site laboratory upper limit of normal (ULN) International normalized ratio (INR) greater than 1.5× the site laboratory ULN Aspartate aminotransferase (AST) or alanine transaminase (ALT) Grade 1 or higher* Positive for hepatitis C antibody Positive for hepatitis B surface antigen History of inflammatory bowel disease by participant report *As per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected Version 2.1, July 2017 Note: Otherwise eligible participants with an exclusionary test result (other than HIV, HBV or HCV) can be re-tested during the screening process. If a participant is re-tested and a non-exclusionary result is documented within 45 days of providing informed consent for screening, the participant may be enrolled. Anticipated use of and/or unwillingness to abstain from the following medications during study participation: Heparin, including Lovenox® Warfarin Plavix® (clopidogrel bisulfate) Aspirin (greater than 81 mg) Non-steroidal anti-inflammatory drugs (NSAIDS) Any other drugs that are associated with increased likelihood of bleeding CYP3A inducer(s) and/or inhibitor(s) as specified in the MTN-026 Study-Specific Procedures (SSP) Manual Hormone-replacement therapy in tablet, injectable or gel form Known adverse reaction to any of the components of the study products Use of post-exposure prophylaxis (PEP) for potential HIV exposure within the 6 months prior to Enrollment Use of pre-exposure prophylaxis (PrEP) for HIV prevention within the 6 months prior to Enrollment, and/or anticipated use during trial participation Use of systemic immunomodulatory medications within the 6 months prior to Enrollment, and/or anticipated use during trial participation RAI without a condom and/or penile-vaginal intercourse with a partner who is known to be HIV-positive in the past 6 months Non-therapeutic injection drug use in the 12 months prior to Screening and Enrollment Participation in research studies involving drugs, medical devices, genital or rectal products, or vaccines within 45 days of the Enrollment Visit At Screening, participant report of treatment for an anogenital STI within the past 3 months At Screening, participant-reported symptoms and/or clinical or laboratory diagnosis of active anorectal or reproductive tract infection requiring treatment per current World Health Organization (WHO) guidelines (http://www.who.int/hiv/pub/sti/pub6/en/) or symptomatic urinary tract infection (UTI). Infections requiring treatment include symptomatic Neisseria gonorrhea (GC), Chlamydia trachomatis (CT) infection, syphilis, active herpes simplex virus (HSV) lesions, anogenital sores or ulcers, or symptomatic genital warts, cervicitis, chancroid, pelvic inflammatory disease (PID), bacterial vaginosis (BV), symptomatic vaginal candidiasis, other vaginitis, trichomoniasis. Note: Otherwise eligible participants with an exclusionary UTI, BV and/or candida finding may be re-tested during the screening process. At Enrollment, active anorectal or reproductive tract infection requiring treatment per current WHO guidelines (http://www.who.int/hiv/pub/sti/pub6/en/) or symptomatic urinary tract infection (UTI). Infections requiring treatment include symptomatic GC, CT, syphilis, active HSV lesions, anogenital sores or ulcers, symptomatic genital warts, bacterial vaginosis, symptomatic vaginal candidiasis, other vaginitis, trichomoniasis, chancroid, cervicitis and PID. Note: HSV-1 or HSV-2 seropositive diagnosis with no active lesions is permitted since treatment is not required Has any other condition that, in the opinion of the IoR/designee, would preclude informed consent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving study objectives. Females who meet any of the following additional criteria will be excluded from the study: Pregnant or breastfeeding at either Screening or Enrollment or intends to become pregnant or start breastfeeding during study participation. Note: A documented negative pregnancy test performed by study staff is required for inclusion; however, a self-reported pregnancy is adequate for exclusion from screening/enrollment into the study. Last pregnancy outcome 90 days or less prior to Screening Has had a hysterectomy At Enrollment, has a clinically apparent Grade 1 or higher pelvic exam finding (observed by study clinician or designee) per the Female Genital Grading Table for Use in Microbicide Studies [Addendum 1, Dated November 2007]. Note: Cervical friability bleeding associated with speculum insertion and/or specimen collection judged to be within the range of normal according to the clinical judgment of the IoR/designee is considered expected non-menstrual bleeding and is not exclusionary.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapivirine gel<br>Participants will receive a single dose of dapivirine gel rectally, followed by 7 daily doses of dapivirine gel to be administered under direct observation in the clinic. | Drug: Dapivirine gel<br>* Dapivirine gel (0.05%); administered rectally<br>|
| Placebo Comparator: Placebo gel<br>Participants will receive a single dose of placebo gel rectally, followed by 7 daily doses of placebo gel to be administered under direct observation in the clinic. | Drug: Placebo gel<br>* Universal HEC placebo gel; administered rectally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Grade 2 or Higher Adverse Events (AEs) | As defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 and/or Addenda 1, 2 and 3 (Female Genital [Dated November 2007], Male Genital [Dated November 2007] and Rectal [Clarification Dated May 2012] Grading Tables for Use in Microbicide Studies) | Measured after the participant has started study product until the participant's study termination at approximately Day 40 | 
| Measurement of Dapivirine Concentrations in Plasma | As assessed by pharmacokinetic sampling and analysis | Sample collected at approximately 1, 2, 24, 48 and 72 hours after first single dose, 24 hours after first dose during daily dosing, before last dose and 1,2, 24,48, and 72 hours after last dose. | 
| Measurement of Dapivirine Concentrations in Rectal Fluid | As assessed by pharmacokinetic rectal fluid sampling and analysis | Sample collected at approximately 1, 2, 24, 48 and 72 hours after first single dose, 24 hours after first dose during daily dosing, and 1,2, 24,48, and 72 hours after last dose. | 
| Measurement of Dapivirine Concentrations in Rectal Mucosal Tissue Homogenates | As assessed by pharmacokinetic rectal mucosal tissue homogenates sampling and analysis | Sample collected at approximately 1, 2, 24, 48 and 72 hours after first single dose and 1,2, 24,48, and 72 hours after last dose. | 
| Terminal Half-life of Dapivirine Concentrations in Plasma | The terminal half-life of dapivirine in plasma samples was estimated by fitting a linear regression on the log-transformed concentrations from the 24, 48 and 72 hour time-points after the single and multiple doses.Each regression model includes an adjustment for the difference in concentration after multiple dosing. For each participant, Beta was calculated as the negative of the slope of their repression and half-life was log(2)/Beta. Due to the large number of concentrations below the limit of quantification after the single dose, the estimateion of Beta and half-life relied only on concentration after the multiple dosing for most of the participants. | From samples collected 24 hours after first dose to 72 hours after last daily dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acceptability: Ease of Use | The number of participants who responded by questionnaire that the study product was easy or very easy to use. | after completing the study (study day 40) | 
| Acceptability: Comfort | The number of participants who responded on a questionnaire that the study product was comfortable or very comfortable. | after completing the study (study day 40) |