Development of Adherence Biomarkers for Multiple Microbicide and Multipurpose Prevention Technology (MPT) Dosage Forms

This is a Phase I, non-randomized, open label study in healthy, non-pregnant, HIV negative
women, who are not at risk of pregnancy, and are at low risk for STIs (sexually transmitted
infections). Participants will be assigned to use one of four placebo products: IVR
(intravaginal ring) (approximately 20 participants), and vaginal insert, film or HEC
universal placebo gel (approximately 10 participants each). Each woman will provide
pre-product use vaginal swabs. Participants assigned to vaginal insert, film or gel will use
products with and without timed intercourse with their male partner for a total of two doses
of the product, will provide vaginal swabs post product use, and will be seen over 4 visits.

Participants assigned to IVR do not have to be sexually active with a male partner. IVR
assigned participants will use a total of 3 IVRs, one at a time. IVR assigned participants
will use the first IVR (IVR1) for approximately 24 - 36 hours (no exposure to semen during
IVR1 use). IVR assigned participants will use a second IVR (IVR2) for approximately 7 - 10
days and a third IVR (IVR3) for approximately 28 - 32 days. During the use of IVR2 and IVR3,
participants may engage in sexual intercourse, but it is not required. Women assigned to IVR
use will be seen over 5 visits.

Once a woman completes the study cycle with one study product, she may elect to do another
cycle using a different product after a wash-out period of at least 7 days, if she can
comply with study product specific protocol requirements. She may elect to do up to four
cycles, each with a different study product. For each cycle, V1 screening procedures will be
repeated as indicated by symptoms and or participant history, as assessed by the
investigator and as outlined in the study manual. If re-screening procedures are not
indicated, the new cycle may start with Visit 2 (V2).

At Visit 1 (V1), volunteers will be consented and undergo procedures to confirm they are
eligible to continue in the study. Participants will be counseled to refrain from vaginal
activity, as applicable, for 48 hours prior to V2.

V2 should occur on days 3 - 10 of the menstrual cycle, or for participants who do not have
regular menstrual cycles, when the participant is not having heavy menstrual bleeding. Once
it has been confirmed that the participant meets all of the inclusion criteria and none of
the exclusion criteria, baseline pre-product use vaginal swabs will be taken. Participants
will be required to refrain from any vaginal activity until after Visit 3 (V3).

- Participants assigned to gel, film or insert, will insert one dose (Dose 1) vaginally
in the clinic. Vaginal swabs will be obtained in the clinic approximately 15 minutes
after product use. Participants will be given vaginal swabs for home use. Participants
will be instructed to obtain vaginal swabs, at bedtime daily, for 7 days, starting at
the first bedtime after V2. Vaginal swabs will be stored in the participant's
refrigerator and returned to the clinic at V3. V3 will occur 7 - 10 days after V2.

- For participants assigned to the IVR, the IVR1 will be inserted by the participant in
the clinic. The participant will leave IVR1 in place until V3, which will occur 24 - 36
hours after V2.

At V3:

- Participants assigned to gel, film or insert will return used vaginal swabs to the
clinic. Additional vaginal swabs will be obtained in the clinic. Participants will
vaginally insert one dose of their assigned product (Dose 2) in the clinic. Vaginal
swabs will be obtained in the clinic approximately 15 minutes after product use. The
participants will be instructed to have vaginal intercourse with her male sexual
partner within approximately 12 hours (± 4 hours) after insertion of the product. They
will obtain vaginal swabs, at bedtime daily, for 7 days, starting at the first bedtime
after V3 and after timed intercourse, as above. Participants will be instructed to
refrain from additional acts of vaginal intercourse or other vaginal activity until
Visit 4 (V4). Vaginal swabs will be stored in the participant's refrigerator and
returned to the clinic at V4. V4 will occur 7 - 10 days after V3.

- For participants assigned to the IVR, IVR1 will be removed at this visit. Post IVR1 use
vaginal swabs will be obtained in the clinic. The second IVR (IVR2) will be inserted by
the participant in the clinic. The participant will be instructed to leave the IVR2 in
place until V4, which will occur 7 - 10 days after V3. IVR Participants may have
vaginal intercourse (not required) during the use of IVR2 but should not have any other
vaginal activity during the use of IVR2.

At V4:

- Participants assigned to gel, film or insert will return used vaginal swabs to the
clinic. Additional vaginal swabs will be obtained in the clinic. Participants will be
exited from the study at this visit or they may elect to use a different study product.

- For participants assigned to the IVR, IVR2 will be removed at this visit. Post IVR2 use
vaginal swabs will be obtained in the clinic. The third IVR (IVR3) will be inserted by
the participant in the clinic. The participant will leave IVR3 in place until Visit 5
(V5), which will occur 28 - 32 days after V4. Participants may have vaginal intercourse
(not required) during the use of IVR3 but should not have any other vaginal activity
during the use of IVR3.

At V5 (For IVR only):

• IVR3 will be removed at this visit. Post IVR3 use vaginal swabs will be obtained in the
clinic. Participants will be exited from the study at this visit or they may elect to use a
different study product.

Volunteers must meet all of the following criteria prior to genital sampling at Visit 2:

- Age 18 to 50 years, inclusive

- General good health (by volunteer history and per investigator judgment) without any
clinically significant systemic disease (including, but not limited to significant
liver disease/hepatitis, gastrointestinal disease, kidney disease, thyroid disease,
osteoporosis or bone disease, and diabetes)

- History of Pap smears and follow-up consistent with standard medical practice as
outlined in the Study Manual or willing to undergo a Pap smear at V1

- Willing to give voluntary consent and sign an informed consent form

- Willing and able to comply with protocol requirements

- Protected from pregnancy by:

- hysterectomy

- reliable methods of contraception other than male or female condoms,
contraceptive IVR or male partner's vasectomy

- abstinence (IVR group only)

- or in a same sex relationship (IVR group only)

- For gel, insert or film assigned participants: Willing to engage in intercourse with
a male sexual partner without the use of male or female condoms as required in the
protocol

- For gel, insert or film assigned participants: In a mutually monogamous relationship
with a male partner who:

- Is at least 18 years old

- Is not known to be HIV positive

- Has no known risk for STIs

- Has not undergone a vasectomy

- Is not known to have azoospermia

- Is willing and able to comply with protocol requirements regarding sexual
activity/ abstinence

- Can engage with the participant in vaginal intercourse without condoms, as
specified in the protocol 8.2. Exclusion Criteria

Volunteers must not meet any of the following criteria prior to genital sampling at Visit
2:

- Currently pregnant

- Currently breastfeeding or planning to breastfeed during the course of the study

- History of sensitivity/allergy to any component of the vaginal products for either
the volunteer or her sexual partner, as applicable

- Use of vaginal douches, creams or gels, other than the study product, at any time
during the study, beginning 7 days prior to V2

- In the last six months, either the volunteer or her sexual partner (as applicable)
diagnosed with or treated for any STI. Note: Women with a history of genital herpes
who have been asymptomatic for at least six months may be considered for eligibility

- Positive test for Trichomonas vaginalis, Neisseria gonorrhea, Chlamydia trachomatis
or HIV

- Chronic or acute vulvar or vaginal symptoms (pain, irritation, spotting/bleeding,
discharge, etc.)

- Known current drug or alcohol abuse which could impact study compliance

- Participation in any other investigational trial within the last 30 days or planned
participation in any other investigational trial during the study

- Abnormal finding on laboratory or physical examination or a social or medical
condition in either the volunteer or her sexual partner (as applicable) which, in the
opinion of the investigator, would make participation in the study unsafe or would
complicate interpretation of data