Microbicide Safety and Acceptability in Young Men

Microbicides are products that can be applied in the vagina or rectum to decrease the
chances of transmission of sexually transmitted infections (STIs) including HIV. In the US,
one of the most vulnerable groups for acquiring HIV infection is young men, especially young
Black and Latino men who have sex with men (MSM). This study will be conducted with a young
18-30 year-old ethnically diverse sample of HIV-negative MSM who report engaging in
receptive anal intercourse (RAI) using condoms inconsistently or not at all. Our goal is to
test whether patterns of use of a placebo rectal gel prior to RAI suggest that the product
would be used correctly and consistently in real life circumstances and whether this highly
vulnerable population could safely use tenofovir gel, a microbicide candidate. In Version
3.0 of this multicentered protocol, a cohort of 40 male and transgender female sex workers
were added to Stages 1A and 1B in order to determine the feasibility of recruitment and
retention of men who have sex with men (MSM) with high risk sexual behavior, such as sex
workers, for microbicide studies, and their likelihood to use noncondom based HIV prevention
strategies. This study will be conducted by the University of Pittsburgh in collaboration
with researchers at the HIV Center for Clinical and BehavioralStudies at Columbia
University; the Fenway Community Health in Boston; and the University of Puerto Rico
Clinical Trial Unit in San Juan, Puerto Rico. Subjects will be enrolled at the University of
Pittsburgh, Fenway Community Health, and the University of Puerto Rico. This is a two-stage
longitudinal study including a clinical and behavioral evaluation (Stage 1A) with an
acceptability and adherence trial (Stage 1B), followed by a Phase 1 randomized,
double-blind, multi-site, placebo-controlled trial (Stage 2). Participants who complete
Stage 1A are eligible to be selected for enrollment into Stage 1B; a similar transition
occurs between Stage 1B and Stage 2.

- In Stage 1A, approximately 280 MSM between the ages of 18-30 will be enrolled,
including a subset of 40 sex workers and will undergo a baseline medical evaluation and
a detailed Web-based baseline behavioral assessment.

- In Stage 1B, approximately 140 participants from Satge 1A, including a subset of 20 sex
workers, will be asked to apply a placebo gel (HEC) rectally prior to each episode of
RAI over a 3-month period, reporting each use via a phone reporting system. At the end
of the 3 months, participants will complete a Web-based questionnaire and take part in
a video teleconference.The first 42 eligible participants, excluding the mal and
transgender female sex worker cohort, (approximately 14 at each site) completing Stage
1B with a reported adherence of 80% or greater will be invited to enroll in Stage 2.

- In Stage 2, approximately 24 eligible participants from Stage 1B will progress to Stage
2 and be randomized at a 1:1 ratio to tenofovir 1% gel or HEC placebo gel.Following a
baseline visit, participants will return to the clinic, where a single dose of the
study gel will be administered. Within approximately 30 minutes, rectal swab, stool,
and rectal biopsy specimens will be obtained via anoscopy. After a one-week recovery
period participants will return to the clinic for assessment. If no significant adverse
events(AEs) are reported they will begin to self-administer once-daily outpatient doses
of the study gel for 7 days, after which they will return to the clinic for evaluation
and specimen collection.

Inclusion Criteria for Participants in Stage 1A (non sex-workers):

1. Willing and able to provide written informed consent to take part in the study

2. Willing and able to communicate in English or Spanish

3. Must agree not to participate in other drug trials

4. Biologically male and identifies as male

5. Age 18-30 years at screening

6. HIV-1 status antibody negative or unknown per patient report

7. Understands and agrees to local STI reporting requirements

8. Able and willing to provide adequate information for locator purposes

9. Availability to return for all study visits, barring unforeseen circumstances

10. A history of consensual RAI at least once in past month

11. Reporting at least one occasion of unprotected RAI in the prior year* In order to
identify participants at increased risk for acquiring HIV

Inclusion Criteria for Participants in Stage 1A (sex-workers):

1. Willing and able to provide written informed consent to take part in the study

2. Willing and able to communicate in English or Spanish

3. Must agree not to participate in other drug trials

4. Biologically male, including male-to-female transgender women

5. Age 18-30 years at screening

6. HIV-1 status antibody negative or unknown per patient report

7. Understands and agrees to local STI reporting requirements

8. Able and willing to provide adequate information for locator purposes

9. Availability to return for all study visits, barring unforeseen circumstances

10. A history of consensual RAI at least once in past month

11. Reporting at least one occasion of unprotected RAI in the prior year*

12. Reporting at least two occasions of RAI as part of transactional sex (i.e., having
received money or other goods/services in exchange for sex) in the prior 2 months*

- In order to identify participants at increased risk for acquiring HIV

Inclusion Criteria for Participants in Stage 1B (both sex workers and non sex-workers):

1. Completed Stage 1A

2. HIV-1 uninfected at screening based on HIV rapid test results

3. Reports unprotected RAI in the prior three months on at least one occasion* In order
to obtain acceptability data from individuals most likely to benefit from microbicide
availability

4. Availability to return for all Stage 1B visits, barring unforeseen circumstances

Inclusion Criteria for Participants in Stage 2:

1. Completed study stage 1AB

2. HIV-1 uninfected at screening based on HIV rapid test results

3. Availability to return for all Stage 2 visits, barring unforeseen circumstances

Exclusion Criteria for Participants in Stage 1A (both sex workers and non sex-workers):

1. Any condition or prior therapy that, in the opinion of the investigator, would make
study participation unsafe, make the individual unsuitable for the study or unable to
comply with the study requirements. Such conditions may include, but are not limited to,
current or recent history of severe, progressive, or uncontrolled substance abuse, or
renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, or
cerebral disease

Exclusion Criteria for Participants in Stage 1B (both sex workers and non sex-workers):

1. Clinical or laboratory diagnosis of active rectal infection requiring treatment per
current CDC guidelines. Infections requiring treatment include Chlamydia (CT),
gonorrhea (GC), syphilis, active HSV lesions, chancroid, genital sores or ulcers, and
if clinically indicated, genital warts. Note that an HSV-2 seropositive diagnosis
with no active lesions is allowed, since treatment is not required

2. Positive Hepatitis B surface antigen test indicating hepatitis B infection

3. Allergy to methylparaben, propylparaben, or latex

4. History of significant drug allergy or recurrent urticaria

5. History of inflammatory bowel disease

6. Currently engage or plan to engage in unprotected RAI with HIV-infected partners

7. By participant report planning to receive another investigational drug while
participating in this study

8. Any other condition or prior therapy that, in the opinion of the investigator, would
make study participation unsafe, make the individual unsuitable for the study or
unable to comply with the study requirements. Such conditions may include, but are
not limited to, current or recent history of severe, progressive, or uncontrolled
substance abuse, or renal, hepatic, hematological, gastrointestinal, endocrine,
pulmonary, neurological, or cerebral disease

Exclusion Criteria for Participants in Stage 2:

1. Meet any of the exclusion criteria for Stage 1B

2. Reporting a history of transactional sex (i.e., having received money or other
goods/services in exchange for sex) in the prior 6 months

3. Undergoing or completed gender reassignment

4. Grade 2 or higher liver function, creatinine, coagulation, electrolyte, or hematology
abnormality in accordance with DAIDS toxicity table values (normal values based on
site specific laboratory criteria) at screening (or Visit 2 PT/INR for coagulation),
and confirmed by retest/and or redraw

5. History of significant gastrointestinal bleeding

6. History of inflammatory bowel disease

7. Abnormalities of the rectal mucosa, or significant rectal symptom(s), which in the
opinion of the clinician represents a contraindication to biopsy (including but not
limited to presence of any unresolved injury, infectious or inflammatory condition of
the local mucosa, and presence of symptomatic external hemorrhoids

8. Per participant report, anticipated use and/or unwillingness to abstain from the
following medications during the period of Stage 2 study participation:

1. Heparin, including Lovenox®

2. Warfarin

3. Plavix® (clopidogrel bisulfate)

4. Aspirin >81 mg per day

5. Non-steroidal anti-inflammatory drugs (NSAIDS)

6. Any other drugs that are associated with increased likelihood of bleeding
following rectal biopsy

9. By participant report, use of systemic immunomodulatory medications within the 4
weeks prior to the Stage 2 Enrollment Visit and throughout study participation

10. By participant report, use of rectally administered medications, rectally
administered products (including condoms) containing N-9, or any investigational
products within the 2 weeks or 10 half-lives of the drug, whichever is longer, prior
to the Stage 2 Enrollment Visit, or is planning to receive another investigational
drug while participating in this study

11. Any other condition or prior therapy that, in the opinion of the investigator, would
make study participation unsafe, make the individual unsuitable for the study or
unable to comply with the study requirements. Such conditions may include, but are
not limited to, current or recent history of severe, progressive, or uncontrolled
substance abuse, or renal, hepatic, hematological, gastrointestinal, endocrine,
pulmonary, neurological, or cerebral disease -