Pharmacokinetic and Safety Study of a 90 Day Intravaginal Ring Containing Tenofovir

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the pharmacokinetics (PK) and safety of a 90-day intravaginal ring (IVR) containing tenofovir (TFV).

Detailed Description
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This study will evaluate the pharmacokinetics (PK) and safety of a 90-day intravaginal ring (IVR) containing tenofovir (TFV) in healthy, HIV-uninfected individuals assigned female sex at birth. Participants will be randomly assigned to receive an IVR containing either 1.4 g TFV or placebo. The IVR will be inserted at the enrollment visit (Day 0) and used continuously for approximately 91 days. Additional study visits will occur at Days 1, 7, 14, 28, 42, 56, 91, and 92. Study visits may include behavioral assessments, physical examinations, blood and urine collection, and pelvic and rectal specimen collection.

Official Title
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A Phase 1, Randomized Pharmacokinetic and Safety Study of a 90 Day Intravaginal Ring Containing Tenofovir

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Tenofovir (TFV) IVR
* Drug: Placebo IVR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Assigned female sex at birth Note: Participants who are female at birth, who now identify as male, will not be excluded so long as they are not on female-to-male transition therapy. Age 18 through 45 years (inclusive) at Screening, verified per site standard operating procedures (SOPs) Able and willing to provide written informed consent to be screened for and enrolled in MTN-038 Able and willing to provide adequate locator information, as defined in site SOPs Able to communicate in spoken and written English Available for all visits and able and willing to comply with all study procedural requirements Willing to abstain from receptive vaginal or anal sexual activities for 72 hours prior to each clinical visit and for 72 hours after biopsy collection Willing to use male condoms for penile-vaginal and penile-rectal sexual intercourse for the duration of study participation Per participant report, using 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 vaginal ring) intrauterine device (IUD) sterilization (of participant or partner, as defined in site SOPs) having sex exclusively with individuals assigned female sex at birth sexually abstinent as defined by abstaining from penile-vaginal intercourse for 90 days prior to Enrollment, and intending to remain abstinent for the duration of study participation In general good health as determined by the Investigator of Record (IoR)/designee at Screening and Enrollment HIV-uninfected based on testing performed at Screening and Enrollment (per protocol algorithm in the study protocol) Per participant report at Screening, regular menstrual cycles with at least 21 days between menses Note: This criterion is not applicable to participants who report using a progestin-only method of contraception at Screening (e.g., Depo-Provera or levonorgestrel-releasing IUD) nor to participants using continuous combination oral contraceptive pills, as the absence of regular menstrual cycles is an expected, normal consequence in this context. Per participant report at Screening and Enrollment, states a willingness to refrain from inserting any non-study vaginal and rectal products or objects into the vagina or rectum including, but not limited to spermicides, female condoms, diaphragms, intravaginal rings, vaginal or rectal medications, menstrual cups, cervical caps, douches, lubricants, and sex toys (vibrators, dildos, etc.) for the 24 hours preceding the Enrollment Visit and for the duration of study participation. Note: Use of tampons is permitted except for 24 hours prior to clinic visits in which CVF samples are scheduled to be collected. Participants 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 At Screening and Enrollment, agrees not to participate in other research studies involving drugs, medical devices, vaginal or rectal products, or vaccines after the Screening Visit and for the duration of study participation Exclusion Criteria: Pregnant at Screening or Enrollment or plans to become pregnant during the study period Note: A documented negative pregnancy test performed by study staff is required for inclusion; however, a self-reported pregnancy is adequate for exclusion from the study. Diagnosed with symptomatic urinary tract infection (UTI) or reproductive tract infection (RTI) at Screening or Enrollment Otherwise eligible participants diagnosed with UTI/RTI during screening will be offered treatment. If treatment is complete and symptoms have resolved within the 45 day screening window, eligible participants may be enrolled. Note: Asymptomatic BV and candidiasis are not exclusionary. Diagnosed with an acute sexually transmitted infection (STI) requiring treatment per current Centers for Disease Control and Prevention (CDC) guidelines (http://www.cdc.gov/std/treatment/) at Screening or Enrollment such as gonorrhea, chlamydia, trichomonas, pelvic inflammatory disease, and/or syphilis Note: Genital warts requiring treatment and frequent recurrence of HSV are considered exclusionary; however, infrequent HSV outbreaks are not. Genital warts requiring treatment are defined as those that cause undue burden or discomfort to the participant, including bulky size, unacceptable appearance, or physical discomfort. See MTN-038 Study-Specific Procedures (SSP) Manual for additional information. Has a clinically apparent Grade 2 or higher pelvic exam finding (observed by study staff) at Screening or Enrollment. * Note: Cervical 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. 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 within 45 days of providing informed consent for screening. Participant report and/or clinical evidence of any of the following: Known adverse reaction to any of the study products (ever), including polyurethane Chronic and/or recurrent vaginal candidiasis Non-therapeutic injection drug use in the 12 months prior to Enrollment Last pregnancy outcome less than 90 days prior to Enrollment Gynecologic or genital procedure (e.g., tubal ligation, dilation and curettage, piercing) 45 days or less prior to Enrollment Note: Colposcopy and cervical biopsies for evaluation of an abnormal Pap test as well as IUD insertion/removal are not exclusionary. Currently breastfeeding or planning to breastfeed during the study Participation in any other research study involving drugs, medical devices, vaginal or rectal products, or vaccines, in the 60 days prior to Enrollment Use of pre-exposure prophylaxis (PrEP) for HIV prevention and/or post-exposure prophylaxis (PEP) for potential HIV exposure within the 3 months prior to Enrollment, and/or anticipated use and/or unwillingness to abstain from PrEP during trial participation Has any of the following laboratory abnormalities at Screening Visit: Grade 1 or higher Aspartate aminotransferase (AST) or alanine transaminase (ALT)* Grade 1 or higher Hemoglobin* Calculated creatinine clearance less than 60 mL/min by the Cockcroft-Gault formula Positive Hepatitis B surface antigen result Note: Otherwise eligible participants with an exclusionary laboratory result may 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. Has any other condition that, in the opinion of the IoR/designee, would preclude informed consent, make study participation unsafe, complicate the interpretation of study outcome data, or otherwise interfere with achieving the study objectives including any significant uncontrolled active or chronic medical condition. (*) Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected Version 2.1, July 2017 and/or Addendum 1 (Female Genital Grading Table for Use in Microbicide Studies [Dated November 2007])

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: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tenofovir (TFV) Intravaginal Ring (IVR)<br>The TFV IVR will be inserted during the enrollment visit (Day 0) and used continuously for approximately 91 days. | Drug: Tenofovir (TFV) IVR<br>* Contains 1.4 g TFV<br>|
| Placebo Comparator: Placebo IVR<br>The placebo IVR will be inserted during the enrollment visit (Day 0) and used continuously for approximately 91 days. | Drug: Placebo IVR<br>* Contains placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of TFV levels in plasma | As assessed by pharmacokinetic sampling and analysis | Measured through Day 92 | 
| Measurement of TFV levels in cervicovaginal fluid (CVF) | As assessed by pharmacokinetic sampling and analysis | Measured through Day 92 | 
| Measurement of TFV levels in rectal fluid | As assessed by pharmacokinetic sampling and analysis | Measured through Day 92 | 
| Measurement of TFV levels in cervical tissue | As assessed by pharmacokinetic sampling and analysis | Measured through Day 92 | 
| Measurement of tenofovir diphosphate (TFV-DP) levels in cervical tissue | As assessed by pharmacokinetic sampling and analysis | Measured through Day 92 | 
| Proportion of participants with Grade 2 or higher genitourinary adverse event | As defined by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, and/or Addendum 1 (Female Genital [Dated November 2007] Grading Table for Use in Microbicide Studies) | Measured through Day 92 | 
| Proportion of participants with Grade 3 or higher adverse event | As defined by the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 | Measured through Day 92 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of study IVR removal/expulsions (voluntary and involuntary) | Assessed by self-report | Measured through Day 92 | 
| Duration without IVR in vagina | Assessed by self-report | Measured through Day 92 | 
| Frequency of IVR use initiation and persistence | Assessed by whether the IVR is in place when participants come to the clinic for their study visits | Measured through Day 92 | 
| Degree (on a scale of 1 to 10) to which participants like or dislike using the IVR | Assessed by self-report | Measured through Day 92 |