Phase 2a Study of Dapivirine Ring in Adolescent Females

MTN-023/IPM 030 is a Phase 2a, two-arm, placebo-controlled, double-blinded, multi-site,
randomized trial of dapivirine vaginal ring (VR) versus placebo VR. The clinical trial is
designed to assess the safety of dapivirine (25 mg) administered via a silicone vaginal ring
(primary objective) and evaluate the acceptability of the dapivirine or placebo VR in
sexually experienced, HIV-uninfected adolescent females, when inserted once every 4 weeks
during 12 weeks of study product use.

Approximately 96 participants will be randomized in a 3:1 ratio to receive either a silicone
elastomer vaginal ring containing 25 mg of dapivirine or a placebo VR. The ring will be
replaced every 4 weeks during the 12 week study product use period.

Use of a VR to provide sustained delivery of microbicides is a novel investigational method
for prevention of heterosexual transmission of HIV in women. This drug delivery method may
circumvent potential difficulties related to adherence to daily or coitally-dependent uses of
microbicide regimens.

Inclusion Criteria:

1. Age 15 through 17 years (inclusive) at Enrollment, verified per site SOPs

2. Able and willing to provide written informed assent/consent and able to obtain written
parental or guardian permission (as specified in site SOP) to be screened for and to
enroll in MTN-023/IPM 030

3. Able and willing to provide adequate locator information, as defined in site SOPs

4. Able to communicate in spoken and written English

5. Able and willing to comply with all study procedural requirements

6. Per participant report at Screening and Enrollment, willing to abstain from inserting
anything into the vagina for 72 hours prior to each follow-up visit, including
abstaining from penile-vaginal intercourse. Note: In the event the vaginal ring has
been expelled and requires reinsertion, repositioning the vaginal ring is permitted

7. In general good health as determined by the Investigator of Record (IoR)/designee at
Screening and Enrollment

8. Assessment of onset and progression of puberty, as measured by Tanner stage 4 or 5 at
Screening, per participant report and/or clinician assessment

9. HIV-uninfected based on testing performed at Screening and Enrollment (per protocol
algorithm in Appendix II)

10. Per participant report at Screening, history of sexual intercourse (at least one
episode in participant's lifetime)

11. Per participant report at Screening and Enrollment, agrees to use condoms for sexual
intercourse

12. Negative pregnancy test at Screening and Enrollment

13. 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 ring)

- intrauterine device (IUD)

- sterilization (of participant, as defined in site SOPs)

14. At Screening and Enrollment, participant states a willingness to refrain from
inserting the following vaginal products and/or objects into the vagina; spermicides,
diaphragms, contraceptive vaginal rings, menstrual cups, cervical caps (or any other
vaginal barrier method), douches, lubricants, for the 5 days prior to Enrollment
throughout the duration of study participation. Note: Neither the use of tampons or
sex toys, nor participant engagement in coitus is restricted.

15. 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 PSRT

Exclusion Criteria:

1. Per participant report at Screening, intends to do any of the following during the
study participation period:

1. become pregnant

2. relocate away from the study site

3. travel away from the study site for more than 4 consecutive weeks

2. Diagnosed with a urinary tract infection (UTI) and/or reproductive tract infection
(RTI) at Screening and/or Enrollment. Note: Otherwise eligible participants diagnosed
with UTI during Screening will be offered treatment and may be enrolled after
completing treatment and all symptoms have resolved. If treatment is completed and
symptoms have resolved within 56 days of obtaining informed consent for Screening, the
participant may be enrolled.

3. Diagnosed with pelvic inflammatory disease and/or an sexually transmitted infection
(STI) requiring treatment per current Centers for Disease Control and Prevention (CDC)
guidelines within 60 days of Enrollment (inclusive)

4. At Enrollment, has a clinically apparent Grade 2 or higher pelvic exam finding
(observed by study staff)** 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. If improvement to a non-exclusionary
grade or resolution is documented within 56 days of providing informed consent for
screening, the participant may be enrolled.

5. Participant report and/or clinical evidence of any of the following:

1. Known adverse reaction to any of the study products (ever)

2. Known HIV-infected partner

3. Non-therapeutic injection drug use in the 12 months prior to Screening

4. The use of HIV Post-exposure prophylaxis (PEP) and/or Pre-exposure prophylaxis
(PrEP) within the 6 months prior to Enrollment

5. Currently breastfeeding

6. Last pregnancy outcome within 90 days or less of Screening

7. Participation in any other research study involving drugs, medical devices,
vaginal products, or vaccines, within 60 days of Screening

8. Participant report of 3 or more penile-vaginal sexual partners in the month prior
to Screening

9. 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

6. Has any of the following Grade 1 or higher* laboratory abnormalities at Screening
Visit:

1. Aspartate aminotransferase (AST) or alanine transaminase (ALT)

2. Creatinine

3. Hemoglobin

4. Platelet count Note: Otherwise eligible participants with an exclusionary test
may be re-tested during the screening process. Please see the MTN-023/IPM 030 SSP
for additional details.

7. 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

- Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse
Events Version 1.0, December, 2004 (Clarification dated August 2009) **Female
Genital Grading Table for Use in Microbicide Studies Addendum 1 to the DAIDS
Table for Grading Adult and Pediatric Adverse Events, Version 1.0, December 2004
(Clarification dated August 2009)