Topical Metronidazole and Miconazole Co-formulated Vaginal Suppositories for Preventing Vaginal Infections in HIV-seronegative Women

Vaginal infections including bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), and
Trichomonas (T.) vaginalis are common and have been associated with increased risk of HIV
and other sexually transmitted infections (STIs) in multiple prospective studies. Effective
interventions for prevention of vaginal infections could substantially reduce the risk of
HIV and other STIs in women. A recently completed trial has demonstrated that monthly
periodic presumptive treatment (PPT) can reduce vaginal infections and promote Lactobacillus
colonization. However, the oral regimen of metronidazole 2 grams plus fluconazole 150 mg was
not sufficiently effective to warrant moving to Phase III HIV/STI prevention trials using
this intervention. The identification of more efficacious regimens for reducing vaginal
infections is a crucial step towards the development of inexpensive, female-controlled,
non-coitally dependent HIV/STI risk reduction interventions for women. There is growing
evidence that higher doses and longer courses may be more effective for treatment of vaginal
infections than single-dose therapy. The overall goal of this protocol is to conduct a
randomized, double-blind, placebo-controlled trial to test the efficacy of monthly PPT with
topical metronidazole 750 mg plus miconazole 200 mg (co-formulated suppositories) versus
matching placebo suppositories nightly for five nights each month for reducing the rates of
BV and VVC among HIV-seronegative women. This regimen could produce sufficient reductions in
vaginal infections to support its use in Phase III HIV and STI prevention trials. The study
participants will include 234 women who are sexually active (greater than or equal to 4
episodes of heterosexual intercourse during the past month), HIV-seronegative, 18 to 45
years old, with BV and/or VVC and/or T. vaginalis detected by laboratory testing at a
screening visit. There will be two study arms. The treatment arm (117 subjects) will receive
PPT with intravaginal metronidazole 750 mg plus miconazole 200 mg (co-formulated
suppositories) for five consecutive nights each month. The placebo arm (117 subjects) will
receive PPT with identical placebo intravaginal suppositories for five consecutive nights
each month. Individual participants will be in the study for one year.

Inclusion Criteria:

- Informed consent obtained and informed consent form (ICF) signed.

- Female, aged 18-45 years.

- Sexually active with greater than or equal to 4 episodes of sex with a male partner
during the past month.

- Human immunodeficiency virus (HIV)-seronegative on both HIV tests in parallel
screening.

- Presence of bacterial vaginosis (BV) and/or vulvovaginal candidiasis (VVC) and/or T.
vaginalis infection at screening:

1. BV: Microscopic criteria (Nugent's score greater than or equal to 7)

2. VVC: Fungal elements (pseudohyphae, blastoconidia, or both) on vaginal saline
wet mount plus a positive culture showing yeast on Sabouraud's agar.

3. T. vaginalis infection: Identification of motile trichomonads on vaginal saline
wet preparation.

- Able and willing to comply with study visit schedule and procedures during the
12-month period of follow-up.

- Able and willing to abstain from sex or to use non-latex condoms (provided) for 24
hours following insertion of each vaginal suppository.

- Willing to abstain from alcohol during, and for 48 hours after, treatment.

- Plan to remain in study area for the next year.

- Agree to not participate in other research studies involving drugs, medical devices,
or vaginal products for the duration of study.

Exclusion Criteria:

- Currently pregnant (positive urine Beta-Human Chorionic Gonadotropin (hCG) or
planning to conceive during the next 12 months (by self-report).

- Currently breastfeeding.

- Within first 3 months post-partum.

- Current menstruation - women who are currently menstruating may be enrolled following
the completion of menses.

- History of 4 or more episodes of treatment for any vaginal infection in the past 12
months. This would be a cumulative total, including any treatment for bacterial
vaginosis (BV) and/or vulvovaginal candidiasis (VVC) and/or Trichomonas vaginalis
(TV) and/or syndromic.

- History of medical condition that would contraindicate use of the study product

1. Porphyria

2. Epilepsy

3. Serious liver disease or signs and symptoms consistent with serious liver
disease including jaundice, ascites, esophageal varices, encephalopathy, and
bleeding disorders.

4. Renal failure

- History of adverse reaction to the study medications (intravaginal metronidazole or
miconazole).

- Current use of medication that may interact with the study drug (due to vaginal
absorption of study drug)

1. Warfarin

2. Phenytoin

3. Phenobarbital

4. Disulfiram

5. Cimetidine

6. Lithium

7. Astemizole

8. Terfenadine

- Current use of oral or intravaginal antifungal medication.

- Current use of oral or intravaginal metronidazole, tinidazole, or clindamycin.

- Current use of latex diaphragm.

- As determined by the investigator, a medical condition or situation exists such that
study participation would not be advisable.