Clinical trial NCT03670355: Pharmacokinetic and Safety Study of a 90 Day Intravaginal Ring Containing Tenofovir
Official title: A Phase 1, Randomized Pharmacokinetic and Safety Study of a 90 Day Intravaginal Ring Containing Tenofovir
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Infections
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2018-09-13
Enrollment: 49
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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 \[Dated November 2007\])

Primary outcomes:
measure: Measurement of TFV levels in plasma
timeFrame: Measured through Day 92
measure: Measurement of TFV levels in cervicovaginal fluid (CVF)
timeFrame: Measured through Day 92
measure: Measurement of TFV levels in rectal fluid
timeFrame: Measured through Day 92
measure: Measurement of TFV levels in cervical tissue
timeFrame: Measured through Day 92
measure: Measurement of tenofovir diphosphate (TFV-DP) levels in cervical tissue
timeFrame: Measured through Day 92
measure: Proportion of participants with Grade 2 or higher genitourinary adverse event
timeFrame: Measured through Day 92
measure: Proportion of participants with Grade 3 or higher adverse event
timeFrame: Measured through Day 92
Secondary outcomes:
measure: Frequency of study IVR removal/expulsions (voluntary and involuntary)
timeFrame: Measured through Day 92
measure: Duration without IVR in vagina
timeFrame: Measured through Day 92
measure: Frequency of IVR use initiation and persistence
timeFrame: Measured through Day 92
measure: Degree (on a scale of 1 to 10) to which participants like or dislike using the IVR
timeFrame: Measured through Day 92
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama CRS
state: Alabama
city: San Francisco
country: United States
facility: Bridge HIV CRS
state: California
city: Pittsburgh
country: United States
facility: University of Pittsburgh CRS
state: Pennsylvania
Study officials:
affiliation: San Francisco Department of Public Health
name: Albert Liu, MD, MPH
role: STUDY_CHAIR
References:
citation: Hawley I, Song M, Scheckter R, McClure T, Piper J, Chen BA, Hoesley C, Liu AY, van der Straten A. Users' Preferred Characteristics of Vaginal Rings for HIV Prevention: A Qualitative Analysis of Two Phase I Trials. AIDS Res Hum Retroviruses. 2022 Apr;38(4):313-326. doi: 10.1089/AID.2021.0077. Epub 2022 Feb 11.