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

Study Overview
=================
Brief Summary
-----------------
This research study is about vaginal infections such as bacterial vaginosis, yeast infections, and trichomoniasis. Usually, these infections can be treated with medication, but sometimes they come back after treatment. Researchers want to know if using vaginal suppositories can decrease the risk of vaginal infections. Participants will include 234 women who are sexually active (greater than or equal to 4 episodes of sex with men during the past month), HIV-negative, 18 to 45 years old, with bacterial infection [vaginosis and/or vulvovaginal candidiasis (VVC) and/or Trichomonas vaginalis] detected by laboratory testing at a screening visit. Women will receive vaginal suppositories containing drug or inactive ingredients (placebo). Participation in the study will be about 12 months. Study procedures include: urine and blood tests, physical exams, and questionnaires.

Detailed Description
-----------------
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.

Official Title
-----------------
A Double-Blind, Randomized Trial of Monthly Treatment With Topical Metronidazole and Miconazole Co-formulated Vaginal Suppositories Versus Placebo for Preventing Vaginal Infections in HIV-seronegative Women

Conditions
-----------------
Bacterial Vaginosis, Candidiasis, Trichomoniasis

Intervention / Treatment
-----------------
* Drug: Neo-Penotran® Forte (active ingredient Metronidazole & Miconazole Nitrate)
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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: BV: Microscopic criteria (Nugent's score greater than or equal to 7) VVC: Fungal elements (pseudohyphae, blastoconidia, or both) on vaginal saline wet mount plus a positive culture showing yeast on Sabouraud's agar. 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 Porphyria Epilepsy Serious liver disease or signs and symptoms consistent with serious liver disease including jaundice, ascites, esophageal varices, encephalopathy, and bleeding disorders. 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) Warfarin Phenytoin Phenobarbital Disulfiram Cimetidine Lithium Astemizole 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Intravaginal metronidazole 750 mg plus miconazole 200 mg (co-formulated suppositories) nightly for 5 consecutive nights each month; 117 Subjects. | Drug: Neo-Penotran® Forte (active ingredient Metronidazole & Miconazole Nitrate)<br>* Neo-Penotran® Forte (active ingredient Metronidazole & Miconazole Nitrate), co-formulated vaginal suppositories containing metronidazole 750 mg with miconazole 200 mg and excipients (Witepsol S 55). Witepsol S 55 is a hard fat suppository base. Such bases consist mainly of triglyceride esters of the higher saturated fatty acids along with varying proportions of mono- and diglycerides. 117 subjects receive nightly for 5 consecutive night each month.<br>|
| Placebo Comparator: Arm 2<br>Placebo suppositories nightly for five consecutive nights each month; 117 Subjects. | Drug: Placebo<br>* Placebo vaginal suppositories, identical in appearance to the active product; contains Witepsol S 55, Titanium Dioxide and D+C yellow #10 with no metronidazole or miconazole.117 subjects receive nightly for 5 consecutive nights each month.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of Monthly Periodic Presumptive Treatment (PPT) Using Metronidazole With Miconazole Intravaginal Suppositories Versus Matching Placebo Nightly for Five Nights Each Month for Preventing Vulvovaginal Candidiasis (VVC). | Percentage of follow-up visits (Months 2, 4, 6, 8, 10, 12) positive for VVC based on the presence of fungal elements (pseudohyphae, blastoconidia, or both) on vaginal saline wet mount plus a positive culture showing yeast on Sabouraud's agar. | Months 2, 4, 6, 8, 10, and 12. | 
| Efficacy of Monthly Periodic Presumptive Treatment (PPT) Using Metronidazole With Miconazole Intravaginal Suppositories Versus Matching Placebo Nightly for Five Nights Each Month for Preventing Bacterial Vaginosis (BV). | Percentage of follow-up visits (Months 2, 4, 6, 8, 10, 12) positive for BV as determined by applying standard microscopic scoring criteria (Nugent's criteria) to vaginal Gram stained slides. BV is diagnosed when the score is greater than or equal to 7. | Months 2, 4, 6, 8, 10, and 12. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of Monthly Periodic Presumptive Treatment (PPT) Using Metronidazole With Miconazole Intravaginal Suppositories Versus Placebo for Preventing Any Vaginal Infection (a Combined Endpoint Including BV, VVC, and Trichomonas Vaginalis Infection). | Percentage of follow-up visits (Months 2, 4, 6, 8, 10, 12) positive for any of three vaginal infections (BV, VVC, Trichomonas vaginalis infection). | Months 2, 4, 6, 8, 10, and 12. | 
| Efficacy of Monthly Periodic Presumptive Treatment (PPT) Using Metronidazole With Miconazole Intravaginal Suppositories Versus Matching Placebo Nightly for Five Nights Each Month for Preventing BV by Clinical Criteria (Amsel's Criteria). | Percentage of follow-up visits (Months 2, 4, 6, 8, 10, 12) positive for BV by clinical criteria (Amsel's criteria). | Months 2, 4, 6, 8, 10, and 12. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Bacterial vaginosis, metronidazole, miconazole, vulvovaginal candidiasis, trichomonas vaginalis, women, Kenya