Phase II/III Study on the Non-Inferiority of Metronidazole/Neomycin Sulfate/Nystatin Pessaries Versus Tergynan in Treating Bacterial Vaginosis and Vulvovaginal Candidiasis
- Trial ID
- 2024-518862-28-00
- Protocol
- NNMAIS 01/2021
- Sponsor
- Antibiotice S.A.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of Metronidazole/Neomycin Sulfate/Nystatin pessaries compared to Tergynan® vaginal tablets in achieving therapeutic cure, both clinical and microbiologic/mycological, after a 10-day treatment in female patients with bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC). This comparison is clinically relevant as it aims to establish the non-inferiority of the pessaries, potentially offering an alternative treatment option for these common vaginal infections.
Secondary objectives include:
- Comparing the safety and tolerability profiles of Metronidazole/Neomycin Sulfate/Nystatin pessaries and Tergynan® vaginal tablets.
- Assessing the impact of bacterial vaginosis and vulvovaginal candidiasis on patients' Quality of Life (QoL).
Participants
The clinical trial involves **female patients** diagnosed with either **bacterial vaginosis (BV)** or **vulvovaginal candidiasis (VVC)**. The study population consists of post-menarche women aged between 18 and 50 years, who are in general good health as determined by medical history, physical examination, vital signs, and pelvic examination. Participants are required to have regular menstrual cycles, with intervals between 21 to 35 days. The trial does not include male subjects or vulnerable populations. Participants must agree to abstain from sexual intercourse during the first 10 days of the study and use non-lubricated condoms thereafter. They must also refrain from alcohol consumption during the treatment period and for one day afterward, and avoid using intra-vaginal products throughout the study. Women of childbearing potential are required to have a negative pregnancy test upon entry and must practice reliable contraception from 28 days before enrollment through 30 days following treatment. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed as a **phase II/III multi-centre, open-label, parallel group study** to evaluate the non-inferiority of the safety and efficacy of Metronidazole/Neomycin Sulfate/Nystatin pessaries compared to Tergynan vaginal tablets in the treatment of specific and non-specific vaginitis, including **bacterial vaginosis (BV)** and **vulvovaginal candidiasis (VVC)**. The trial will commence with an initial phase II, involving an interim analysis of the first 80 evaluable subjects to determine the sample size for phase III. The study aims to establish the clinical cure rate for each treatment arm, with a non-inferiority margin set at 10%. The trial is expected to start recruitment on November 1, 2024, and conclude by July 1, 2026.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as diagnosis of BV or VVC, age between 18 and 50 years, and general good health. The screening will include a medical history review, physical examination, and laboratory tests. Following the screening, participants will be randomized into one of the two treatment arms. The treatment period will last for 10 days, during which participants will be required to abstain from sexual intercourse and alcohol consumption, and refrain from using intra-vaginal products.
Follow-up visits will be scheduled to assess the primary and secondary endpoints, including clinical and microbiological/mycological cure rates, adverse events, and symptom relief. The primary endpoint is the proportion of participants achieving a clinical cure, defined by specific criteria for BV and VVC. Secondary endpoints include microbiological/mycological cure rates and the incidence of adverse events. The end-of-study visit will evaluate the sustainability of therapeutic cure and any additional treatment needs.
Participant involvement is expected to last from the initial screening through the final follow-up visit, with the total duration depending on individual response to treatment and the need for additional follow-up. Conditions that may lead to early termination from the study include non-compliance with study protocols, withdrawal of consent, or the occurrence of serious adverse events. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure participant safety and data integrity.
Treatment
The clinical trial involves the evaluation of two treatments for the management of specific and non-specific **vaginitis**. The experimental medication is a combination product consisting of **Metronidazole**, **Neomycin sulfate**, and **Nystatin**. This formulation is presented as a pessary, with each unit containing 500 mg of Metronidazole, 65,000 IU of Neomycin sulfate, and 100,000 IU of Nystatin. The pessaries are intended for **vaginal use** and are administered once daily. The maximum treatment period is 10 days, with a maximum daily dose of 500 mg. The product is manufactured by Antibiotice SA and is not a pediatric formulation. Participant compliance with the dosing schedule is monitored throughout the study.
The comparator treatment in this study is Tergynan, a vaginal tablet also containing the active substances **Metronidazole**, **Neomycin sulfate**, and **Nystatin**. The pharmaceutical form is a vaginal tablet, and it is administered via the same route, **vaginal use**. The dosage and treatment duration are identical to the experimental medication, with a maximum daily dose of 500 mg and a treatment period of up to 10 days. Tergynan is produced by Bouchara Recordati. This comparator serves as the standard-of-care therapy against which the experimental medication's safety and efficacy are measured.
Efficacy
The efficacy of the clinical trial will be assessed by comparing the therapeutic cure rates of two treatment regimens for specific and non-specific vaginitis. The primary endpoint is the proportion of participants achieving a clinical cure at Visit 2 (V2) in both the bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC) groups for each treatment arm. Clinical cure is defined as a score of zero for any sign and symptom scored as 1-2 at baseline, or a score of 0-1 for any sign and symptom scored as 3 at baseline, without the need for further treatment as determined by the research clinician. For BV, the absence of all three Amsel criteria is required.
Secondary endpoints include the proportion of participants achieving a microbiological/mycological cure at V2, defined as a Nugent score of 0-3 for BV and a negative Candida culture for VVC. The therapeutic cure is a combination of clinical and microbiological/mycological cures. Additional secondary endpoints involve the proportion of participants reporting urogenital adverse events (AEs) and serious adverse events (SAEs) considered product-related, the proportion of participants experiencing symptom relief, and the need for additional treatment as per physician opinion. The median time to symptom relief and the sustainability of therapeutic cure from V2 to V3 will also be evaluated.
The study will utilize a phase II/III multi-centre, open-label, parallel group design to establish the non-inferiority of the test product (Metronidazole/Neomycin Sulfate/Nystatin pessaries) compared to the reference product (Tergynan® vaginal tablets). The non-inferiority margin is set at 10%. An interim analysis will be conducted after the initial phase II with 80 evaluable subjects to determine the sample size for phase III. The clinical cure rate will be established separately for the BV and VVC groups, and sample size calculations will be performed accordingly.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Diagnosis of bacterial vaginosis (BV) based on the presence of at least three of the following Amsel criteria: a. Homogeneous vaginal discharge (off white, yellowish, milky or grey, thin), b. positive KOH (whiff test), c. vaginal secretions pH of > 4.5, d. clue cells > /= 20 percent of vaginal squamous epithelial cells on saline "wet mount" or Gram coloration The BV diagnosis will be confirmed by a Nugent score equal or higher than seven on bacteriological analysis of vaginal samples.
- Diagnosis of vulvovaginal candidiasis (VVC) based on the presence of hyphae or pseudohyphae on KOH or saline preparation; with a vaginal pH less than or equal to 4.5 and clinically must have at least two or more of the following signs and symptoms of VVC, each rated based on severity* with minimum composite score of 2. Signs include vulvovaginal edema, erythema, and/or excoriation. Symptoms include vulvovaginal itching, burning, and/or irritation. *Severity will be graded on a scale of 0-3 (absent = 0; mild = 1; moderate = 2; severe = 3).
- Post-menarche women, between 18 and 50 years old;
- Participant is in general good health based on medical history, physical examination, vital signs, and pelvic examination.
- Subjects who have regular menstrual cycles (Subjects with regular menstrual cycles with intervals between 21 to 35 days)
- Subject is willing and able to provide written informed consent prior to any study related procedures being performed.
- Women of child bearing potential must have a negative high sensitivity urine pregnancy test or negative serum pregnancy test result upon entry into the study.
- Women of childbearing potential must agree to practice reliable contraception* for the 28-day period before enrollment through 30 days following treatment. * Acceptable birth control methods for the purposes of this study may include, but are not limited to, abstinence from intercourse with a malepartner, monogamous relationship with vasectomized partner, barrier methods to include non-lubricated condoms and diaphragms, intrauterine devices, and licensed hormonal methods. NuvaRing® contraceptive use will be prohibited from this study since the device can alter vaginal secretions.
- Any Pap test performed in the prior 3 years must be normal or ASCUS Human papillomavirus (HPV) negative.
- Subjects must agree to abstain from sexual intercourse throughout the first 10 days of the study. Following the first 10 days, subjects must agree to use a non-lubricated condom when engaging in sexual intercourse.
- Subjects must be willing to abstain from alcohol ingestion during the 10 days treatment period and for 1 day afterward.
- Subjects must agree to refrain from the use of intra-vaginal products throughout the study (e.g., douches, feminine deodorant sprays, spermicides, lubricated condoms, tampons, and diaphragms).
- Subject is willing and able to cooperate to the extent and degree required by this protocol at the discretion of the investigator.
Exclusion Criteria
- Subjects with clinical manifestation of other active vaginal infections, such as infection by Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Herpes simplex type 2 (HSV-2, or genital herpes) or known infection with HPV, or another vaginal or vulvar condition, that in opinion of the Investigator might confuse interpretation of response to study product. (e.g.- erosive lichen planus, desquamative interstitial vaginitis, contact dermatitis involving the vulvar epithelium, allergy. The above-mentioned infections are detected during clinical examination, as per Investigator’s opinion and experience
- Subjects diagnosed with cervical intraepithelial neoplasia) class 2 or class 3 (CIN 2 or 3) or carcinoma of the cervix;
- Subjects who have undergone gynaecological procedures in the month prior to inclusion (such as cauterization of the cervix, cervical biopsy, high-frequency surgery);
- Subjects who received intravaginal or systemic antimicrobial or antifungal therapy one-month prior randomization;
- Subjects on immunosuppressive medications (such as corticosteroids, cyclosporine, etc.);
- Knowledge of positive test result for human immunodeficiency virus or viral hepatitis B or C;
- Active disease or history of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinoma of the skin which is considered cured with minimal risk of recurrence
- Diabetes Mellitus Type I or Type II;
- Subjects diagnosed with Pelvic Inflammatory Disease;
- Participation in any experimental study or ingestion of any experimental drug 12 months before the start of this study;
- Consumes excessive amounts of alcohol, abuses drugs, or has any condition that would compromise compliance;
- Subjects who in Investigator's opinion would be non-compliant or Subjects with other vaginal or vulvar conditions, which in the investigator's opinion may confound interpretation of clinical response;
- Female subjects that are pregnant or lactating or planning to become pregnant during the study period;
- Virgin female subjects.
- Subjects who have a known hypersensitivity to components of the formula.
- Menstruating at the time of diagnosis or expected to menstruated during the course of the treatment (10 days)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Romania | Not Yet Recruiting | 01 Nov 2024 | 80 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Metronidazole/Neomycin sulfate/Nystatin 500 mg/65000 IU/100000 IU, pessaries | Test | PESSARY | VAGINAL USE | 500 | 10 | PRD11661410 |
TERGYNAN, comprimé vaginal | Comparator | COMPRIMÉ VAGINAL | VAGINAL USE | 500 | 10 | PRD1600970 |