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

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.

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])