Safety and Pharmacokinetics of Two Vaginal Film Formulations Containing the Integrase Inhibitor MK-2048

Study Overview
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Brief Summary
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This is a proof of concept study to determine whether an extended release vaginal film can deliver drug for seven days. Two film formulations containing MK-2048 which differ by dissolution and spreadability attributes will be compared for safety and pharmacokinetic outcomes.

Detailed Description
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This is a phase I randomized trial assessing the safety, acceptability, and pharmacokinetics of two formulations of MK-2048 vaginal film. While the primary objective is to evaluate the safety of the product, the overarching objective of this study is to provide proof of concept that an antiretroviral drug can be delivered in an extended release film formulation to provide drug delivery for 7 days or more after a single application. Forty eight women will be randomized with equal frequency to receive a single dose of a vaginal film containing MK-2048 (either the high Eudragit® or low Eudragit® formulation). The film will be inserted by a clinician on the day of enrollment. Vaginal swabs and plasma will be collected at days 0, 3, 5, 7, 10, 14 and 28 for all participants. On the day of enrollment, some participants may elect to participate in immediate post insertion sample collection (vaginal swab and plasma) at one or two time points within 6 hours of insertion. Genital biopsy samples and a rectal swab will be obtained on day 7, and cervicovaginal lavage will be collected at screening and days 14 and 28. The primary endpoint is the frequency of Grade 2 or higher adverse events. The secondary endpoints are: MK-2048 concentrations in plasma, cervical tissue homogenate, cervicovaginal lavage fluid, rectal and vaginal swab eluents; self-reported assessment of qualities of the experience with the films drawn from existing survey on microbicidal films, and general acceptability ratings drawn from market research methodology.

Official Title
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A Randomized, Double Blinded Study of the Safety and Pharmacokinetics of Two Vaginal Film Formulations Containing the Integrase Inhibitor MK-2048

Conditions
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Pharmacokinetics, Safety

Intervention / Treatment
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* Combination Product: MK-2048 High Eudragit Vaginal Film
* Combination Product: MK-2048 Low Eudragit Vaginal Film


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to provide written informed consent. Willing to use an effective method of birth control throughout the duration of the study. Examples of effective methods include: hormonal methods (other than NuvaRing®), intrauterine device, bilateral tubal ligation, same sex partner, partner with a vasectomy, abstinence (defined as no vaginal sex for one month prior to screening). Able and willing to provide adequate locator information HIV-uninfected based on testing performed by study staff at screening In general good health as determined by the site clinician Agree to be sexually abstinent, including use of sex toys, from visit 2 (Enrollment) until visit 7 (7 days after the biopsy visit) and 48 hours prior to all study visits. Agree to refrain from use of vaginal device or products (for example, lubricants, creams, suppositories) throughout participation in the study. Tampons may be used except between visit 5 (biopsy visit) and visit 7 (day 14). Willingness to undergo all study-related assessments and follow all study-related procedures At screening and enrollment, agrees not to participate in other research studies involving drugs, medical devices, or vaginal products while enrolled in this trial Participants over the age of 21 (inclusive) must have documentation of a satisfactory Pap within three 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 Division of Acquired Immune Deficiency Syndrome 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 results. If no documentation of a Pap smear can be provided, a Pap smear will be collected at the screening visit. Exclusion Criteria: Menopause (as defined as amenorrhea for one year or more without an alternative etiology) Hysterectomy Participant report of any of the following: Known adverse reaction to any of the study products (ever) Non- therapeutic injection drug use in the 12 months prior to Screening Surgical procedure involving the pelvis in the 60 days prior to enrollment (includes dilation and curettage or evacuation, and cryosurgery; does not include cervical biopsy for evaluation of an abnormal pap smear) Participation in a drug, spermicide and/or microbicide study in the 30 days prior to enrollment Currently pregnant or pregnancy within 42 days prior to enrollment Currently lactating Use of a diaphragm, NuvaRing®, or spermicide for contraception Urogenital infection or suspected infection within 7 days of enrollment including: symptomatic candidiasis, trichomonas vaginalis, and symptomatic bacterial vaginosis; or cervical infection, including N. gonorrhoeae, C. trachomatis, or mucopurulent cervicitis; syphilis; herpes simplex virus lesions, or other sores (Note: seropositive herpes simplex virus without active lesions will not be excluded); acute pelvic inflammatory disease; urinary tract infection; recent exposure to a partner with N. gonorrhoeae, C. trachomatis, Trichomonas, syphilis, or non-gonorrheal urethritis Antibiotic or antifungal therapy (vaginal or systemic) within 7 days of enrollment As determined by the primary investigator, has any significant uncontrolled active or chronic cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, endocrine *including poorly controlled diabetes), respiratory, immunologic disorder or infectious disease Menses-like bleeding at the time of the Enrollment visit* or expected menses-like bleeding within 14 days of the Enrollment visit (*Women who have vaginal bleeding at the scheduled Enrollment visit may return at a different date to be re-examined and possibly enrolled provided they are still within the screening window and meet all criteria.) Any condition that, in the opinion of the Investigator, would preclude provision of consent, make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives

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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: High Eudragit MK-2048 vaginal film<br>Single use of 2 x 2 vaginal film containing 30 mg of MK-2048 and 68.1 mg of ammonio methacrylate copolymer type B (Eudragit®). | Combination Product: MK-2048 High Eudragit Vaginal Film<br>* 2 x 2 vaginal film containing 30 mg of MK-2048 and either 68.1 mg of ammonio methacrylate copolymer type B (Eudragit®)<br>|
| Active Comparator: Low Eudragit MK-2048 vaginal film<br>Single use of 2 x 2 vaginal film containing 30 mg of MK-2048 and 41.5 mg of ammonio methacrylate copolymer type B (Eudragit®). | Combination Product: MK-2048 Low Eudragit Vaginal Film<br>* 2 x 2 vaginal film containing 30 mg of MK-2048 and 41.5 mg of ammonio methacrylate copolymer type B (Eudragit®)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade 2 or Higher Adverse Events | Number of participants who experience Grade 2 or higher adverse events | Through study completion, approximately 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration Versus Time Curve of MK-2048 | Area under the plasma concentration versus time curve of MK-2048 reported as pg x day/mL. MK-2048 plasma concentration was measured at 0, 3, 5, 7, 10, 14, and 28 days after film insertion. | Through study completion, approximately 28 days | 
| Area Under the Cervical Tissue Homogenate Concentration Versus Time Curve of MK-2048 | Area under the cervical tissue homogenate concentration versus time curve of MK-2048 reported as pg x day/mL. MK-2048 concentration was measured at 0, 3, 5, 7, 10, 14, and 28 days after film insertion. | Through study completion, approximately 28 days | 
| Area Under the Cervicovaginal Lavage Fluid Concentration Versus Time Curve of MK-2048 | Area under the cervicovaginal lavage fluid concentration versus time curve of MK-2048 reported as pg x day/mL | Through study completion, approximately 28 days | 
| Area Under the Rectal Swab Eluent Concentration Versus Time Curve of MK-2048 | Area under the rectal swab eluent concentration versus time curve of MK-2048 reported as pg x day/mL | Through study completion, approximately 28 days | 
| Area Under the Vaginal Swab Eluent Concentration Versus Time Curve of MK-2048 | Area under the vaginal swab eluent concentration versus time curve of MK-2048 reported as ng x day/mL. MK-2048 concentration was measured at 0, 3, 5, 7, 10, 14, and 28 days after film insertion. | Through study completion, approximately 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vagina, Film, Extended Release