Evaluating the Safety of and Adherence to a Vaginal Matrix Ring Containing Dapivirine and Oral Emtricitabine/Tenofovir Disoproxil Fumarate in an Adolescent and Young Adult Female Population

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety of and adherence to a vaginal matrix ring (VR) containing dapivirine and oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) in adolescent and young adult females.

Detailed Description
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This study will evaluate the safety of and adherence to a vaginal matrix ring (VR) containing dapivirine and oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) in adolescent and young adult females. The study will enroll healthy, HIV-uninfected adolescent and young adult females between 16 and 21 years of age. Participants will be randomized to one of two sequences of one VR containing 25 mg of dapivirine to be inserted monthly for 24 weeks and one 200 mg FTC/300 mg TDF oral tablet taken daily for 24 weeks. After completing the randomized sequence of two study product use periods, participants will then select between the two study products to use in the final 24 weeks of the trial. Participants will be able to choose either or neither study product during the third product use period. The study includes approximately 76 weeks of follow-up per participant. Participants will attend monthly study visits, which may include behavioral assessments/counseling; physical and pelvic examinations; and blood, urine, and pelvic sample collection.

Official Title
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A Phase 2a Crossover Trial Evaluating the Safety of and Adherence to a Vaginal Matrix Ring Containing Dapivirine and Oral Emtricitabine/Tenofovir Disoproxil Fumarate in an Adolescent and Young Adult Female Population

Conditions
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HIV Infections

Intervention / Treatment
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* Device: Dapivirine vaginal ring
* Drug: FTC/TDF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 16 through 21 years (inclusive) at Enrollment, verified per site standard operating procedures (SOPs). Able and willing to provide informed consent, and if under the legal age of consent be able to provide informed assent and obtain parental or guardian permission/consent, to be screened for and to enroll in MTN-034 (as specified in site SOP). Able and willing to provide adequate locator information, as defined in site SOPs. Able and willing to comply with all study procedural requirements. Per participant report at Screening, post-menarche. HIV-uninfected based on testing performed at Screening and Enrollment (per protocol algorithms found in the study protocol). Per participant report at Screening, history of at least one episode of sexual intercourse in participant's lifetime. Negative pregnancy test at Screening and Enrollment. Per participant report, use of an effective method of contraception for at least two months 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). Note: Participant must be on the same contraception method for at least the two months prior to Enrollment. Per participant report at Screening, willing to abstain from inserting anything into the vagina for 72 hours prior to each study visit, including receptive intercourse. Note: In the event the VR has been expelled and requires reinsertion, repositioning the VR is permitted. Note: Participant use of tampons is permitted at any time during the study. At Screening and Enrollment, agrees not to participate in other research studies involving drugs, medical devices, vaginal products, or vaccines for the duration of study participation, unless approved by the Protocol Safety Review Team (PSRT). Exclusion Criteria: Per participant report at Screening and Enrollment, intends to do any of the following during the study participation period: become pregnant. access and/or use oral PrEP outside the context of study participation. relocate away from the study site. travel away from the study site for a time period that would interfere with product resupply and study participation. At Screening or Enrollment, has a positive HIV test. Diagnosed with urinary tract infection (UTI), pelvic inflammatory disease (PID), sexually transmitted infection (STI) or reproductive tract infection (RTI) requiring treatment per World Health Organization (WHO) guidelines at Screening or Enrollment. Note: Otherwise eligible participants diagnosed during screening with a UTI, PID or STI/RTI requiring treatment per WHO guidelines - other than asymptomatic bacterial vaginosis (BV) and asymptomatic candidiasis - are offered treatment consistent with WHO recommendations. If treatment is completed and symptoms have resolved within 70 days of obtaining informed assent/consent for screening, the participant may be enrolled. Genital warts requiring treatment also must be treated prior to enrollment. Genital warts requiring therapy are defined as those that cause undue burden or discomfort to the participant, including bulky size, unacceptable appearance, or physical discomfort. At Enrollment, has a clinically apparent Grade 2 or higher pelvic exam finding. 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 Investigator of Record (IoR)/designee is considered expected non-menstrual bleeding and is not exclusionary. Note: Otherwise eligible participants with exclusionary pelvic exam findings may be enrolled/randomized after the findings have improved to a non-exclusionary severity grading or resolved. If improvement to a non-exclusionary grade or resolution is documented within 70 days of providing informed assent/consent for screening, the participant may be enrolled. Participant report and/or clinical evidence of any of the following: Known adverse reaction to any of the study products (ever). Known adverse reaction to latex and polyurethane (ever). Symptoms suggestive of acute HIV infection at Screening or Enrollment. Non-therapeutic injection drug use in the 12 months prior to Enrollment. Use of HIV PEP and/or PrEP within the 3 months prior to Enrollment. Currently breastfeeding. Last pregnancy outcome within 8 weeks or less of Enrollment. Participation in any other research study involving drugs, medical devices, vaginal products or vaccines within 60 days of Enrollment. At Enrollment, as determined by the IoR/designee, has any significant uncontrolled active or chronic cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, endocrine, respiratory, immunologic disorder or infectious disease. Has any of the following laboratory abnormalities at Screening Visit: Positive for hepatitis B surface antigen (HBsAG). Hemoglobin Grade 2 or higher. Calculated creatinine clearance less than 60 mL/min by the Schwartz Equation. Note: Otherwise eligible participants with an exclusionary test may be re-tested during the screening process; re-testing procedure details can be found in the MTN-034 Study Specific Procedures (SSP) Manual. If improvement to a non-exclusionary grade or resolution is documented within 70 days of providing informed assent/consent for screening, the participant may be enrolled. Has any other condition that, in the opinion of the IoR/designee, would preclude informed assent/consent, make study participation 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: 16 Years
Maximum Age: 21 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: Sequence A: Dapivirine vaginal ring + FTC/TDF<br>Participants will receive one 25 mg dapivirine vaginal ring inserted vaginally each month for 24 weeks, followed by one FTC/TDF oral tablet taken by mouth daily for 24 weeks, followed by participant's choice of either or neither study product for 24 weeks. | Device: Dapivirine vaginal ring<br>* Vaginal ring containing 25 mg of dapivirine<br>Drug: FTC/TDF<br>* Tablet containing 200 mg FTC/300 mg TDF<br>* Other names: Emtricitabine/Tenofovir Disoproxil Fumarate; Truvada;|
| Experimental: Sequence B: FTC/TDF + Dapivirine vaginal ring<br>Participants will receive one FTC/TDF oral tablet taken by mouth daily for 24 weeks, followed by one 25 mg dapivirine vaginal ring inserted vaginally each month for 24 weeks, followed by participant's choice of either or neither study product for 24 weeks. | Device: Dapivirine vaginal ring<br>* Vaginal ring containing 25 mg of dapivirine<br>Drug: FTC/TDF<br>* Tablet containing 200 mg FTC/300 mg TDF<br>* Other names: Emtricitabine/Tenofovir Disoproxil Fumarate; Truvada;|

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 (AEs) | During participants' first year on study (i.e., during first and second product use periods) participants were randomized to use either the dapivirine vaginal ring for 6 months followed by FTC/TDF for 6 months or vice versa. All AEs were reported as per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. AEs that were graded as at least Grade 2 (i.e., moderate or higher) were classified into the two periods based on reported date of AE onset, with AEs occurring between the participant's randomization date and the date 30 days after their Week 24 visit classified into Period 1, and AEs occurring between their Week 24 visit and the date 30 days after their Week 48 visit classified into Period 2. AEs occurring within 30 days of the Week 24 visit were counted in both periods. This is the number of participant-periods with at least one grade 2 or higher AE by product (combining the two product use periods). | Study periods 1 and 2 | 
| Number of Participant-Visits With No Product Use | During the study period where participants were randomized to use FTC/TDF they were assessed for FTC/TDF adherence by dried blood spot (DBS) at monthly visits. Results that were below the lower limit of detection (< 16.6 fmol/punch) were classified as no use of FTC/TDF during the preceding month, and detectable results (>= 16.6 fmol/punch) classified as at least some FTC/TDF use. During the study period where participants were randomized to use the dapivirine vaginal ring (VR) they were assessed for ring adherence by residual drug levels in returned VRs. Results that were less than or equal to a rate of 0.9mg dapivirine released per month were classified as no use of the VR during that month, and results greater than 0.9mg dapivirine release per month classified as at least some VR use. | Study periods 1 and 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participant-Visits Reporting Acceptability of Study Product | During the study period where participants were randomized to use FTC/TDF they were asked to rate how much they liked using the tablets for HIV prevention (3 and 6 months after initiating the product). During the study period where participants were randomized to use the dapivirine vaginal ring they were asked to rate how much they liked using the ring for HIV prevention (3 and 6 months after initiating the product). | Study periods 1 and 2 | 
| Number of Participant-Visits With No Product Use | During the study period where participants chose which product they used (i.e., Weeks 49-72) they were assessed for FTC/TDF adherence by dried blood spot (DBS) and/or dapivirine vaginal ring adherence by residual drug levels in returned VRs at monthly visits, depending on which product they chose. Results that were below the lower limit of detection (< 16.6 fmol/punch) were classified as no use of FTC/TDF during the preceding month, and detectable results (>= 16.6 fmol/punch) classified as at least some FTC/TDF use. Results that were less than or equal to a rate of 0.9mg dapivirine released per month were classified as no use of the VR during that month, and results greater than 0.9mg dapivirine release per month classified as at least some VR use. | Study period 3 (Weeks 49-72) | 
| Number of Participants Selecting Each Study Product | During the third study product use period (i.e., Weeks 49-72) participants chose whether to use the dapivirine VR, FTC/TDF oral tablets, or neither product, and could change their decision throughout the 6 month period. Participants were categorized into one of four categories based on their selection pattern: always chose dapivirine VR, always chose FTC/TDF oral tablets, switched at least once (including switching to or from no product), and never chose either product. | Study period 3 (Weeks 49-72) | 
| Percentage of Participants Reporting Preference for Dapivirine VR as Compared to FTC/TDF Oral Tablets | Participants were asked would you prefer to use the ring or the tablets for HIV prevention? at their enrollment, Month 12, and product use end visit (Month 18) visits. | All three study periods (enrollment, month 12, and month 18 study visits) |