Chlorhexidine and/or Metronidazole Plus FB301 Pre-treatment Trial

Open-label Safety and Efficacy Trial of Chlorhexidine and/or Metronidazole Pre-treatment Followed by FB301 in Women With Bacterial Vaginosis

The goal of this study is to evaluate how treatment with FB301 affects the balance of vaginal bacteria in women (aged 18-45) with bacterial vaginosis after pre-treatment with either a vaginal antiseptic wash (chlorhexidine), an oral antibiotic (metronidazole), or both.

The main question it aims to answer is:

Does treatment with FB301, with or without pre-treatment using a vaginal antiseptic (chlorhexidine) or an oral antibiotic (metronidazole), change the balance of vaginal bacteria, measured by the proportion of two key bacteria (Lactobacillus crispatus and Lactobacillus jensenii), between the start of treatment and follow-up visits over the next 10 weeks?

Researchers will compare participants randomly assigned to 4 different groups:

• Group 1 will receive FB301for 15 days with the antibiotic (metronidazole) for the first seven days. In the next menstrual cycle, they will receive just FB301 for an additional 15-days.
• Group 2 will receive FB301for 15 days. On the first day only, they will first undergo a vaginal cleanse with chlorhexidine (antiseptic solution). In the next menstrual cycle, they will receive just FB301 for an additional 15-days.
• Group 3 will receive FB301for 15 days with the antibiotic (metronidazole) for the first seven days. On the first day only, they will first undergo a vaginal cleanse with chlorhexidine (antiseptic solution). In the next menstrual cycle, they will receive FB301 for an additional 15-days following a vaginal cleanse with chlorhexidine (antiseptic solution) on the first day only.
• Group 4 will receive just FB301for 15 days. In the next menstrual cycle, they will receive just FB301 for an additional 15-days.

Participants will:

• Attend the study centre for up to 6 visits
• Provide vaginal swab samples at up to 6 visits
• Provide vaginal secretion samples using a menstrual disc at up to 4 visits
• Have blood samples taken at up to 6 visits
• Receive the study treatments for the randomly assigned group over two consecutive menstrual cycles.

Bacterial vaginosis is a dysbiosis of vaginal microbiota characterized by a shift from Lactobacillus dominance to that of communities of various mostly anaerobic bacteria. It is the most common vaginal disorder worldwide in women of childbearing age presenting with a range of clinical features from asymptomatic to an increase in vaginal discharge with or without the characteristic fishy odour. In addition, it is a risk factor for and/or associated with worse outcomes in sexually transmitted infections, reproduction and immune-driven diseases of the female reproductive tract.

During the trial, the participants will either receive, (1) FB301, a Live Biotherapeutic Product (LBP) comprising consortia of Lactobacillus strains, together with oral antibiotic treatment metronidazole, (2) FB301 following vaginal antisepsis with 0.5% chlorhexidine solution, (3) FB301 together with oral antibiotic treatment metronidazole following vaginal antisepsis with 0.5% chlorhexidine solution or (4) FB301. In addition, all participants will receive FB301in a second treatment cycle, either alone (Groups 1,2 and 4) or following a second vaginal antisepsis with 0.5% chlorhexidine solution in Group 3.

Treatment Group 1:

Oral metronidazole 500 mg twice daily for 7 days starting 1 day after menses, plus intravaginal FB301 once daily for 15 days, followed by a second course of intravaginal FB301 once daily for additional 15 days starting 1 day after menses.

Treatment Group 2:

Intravaginal antisepsis with a single dose of 0.5% chlorhexidine solution 1 day after menses, then intravaginal FB301 once daily for 15 days, followed by second course of intravaginal FB301 once daily for additional 15 days starting immediately after the next menstrual cycle.

Treatment Group 3:

Intravaginal antisepsis with a single dose of 0.5% chlorhexidine solution 1 day after menses, then oral metronidazole 500 mg twice daily for 7 days and intravaginal FB301 once daily for 15 days, followed by second intravaginal antisepsis with a single dose of 0.5% chlorhexidine solution then a second course of intravaginal FB301 once daily for additional 15 days 1 day after menses.

Treatment Group 4:

Intravaginal FB301 once daily for 15 days starting 1 day after menses, followed by second course of intravaginal FB301 once daily for additional 15 days 1 day after menses

The primary objective is to assess the impact on change in vaginal microbiome in terms of relative abundance of combined Lactobacillus species with chlorhexidine vaginal antisepsis (0.5%) and/or oral metronidazole pre-treatment followed by administration of FB301 in women with bacterial vaginosis.

Secondary objectives are to assess the safety and tolerability of FB301 with chlorhexidine vaginal antisepsis (0.5%) and/or oral metronidazole pre-treatment followed by administration of FB301 in women with bacterial vaginosis and to assess the impact on rate of cure of bacterial vaginosis with chlorhexidine vaginal antisepsis (0.5%) and/or oral metronidazole pre-treatment followed by administration of FB301 in women with bacterial vaginosis.

1. Premenopausal women aged 18 to 45 years of age inclusive, at the time of signing the informed consent.
2. Participants with an untreated suspected or confirmed symptomatic BV presenting with characteristic vaginal discharge and/or fishy odor confirmed by Gram stain of the vaginal specimen having a Nugent Score of equal or above 7 at the screening visit.
3. Participant is otherwise in good physical and mental health, as determined by the investigator
4. BMI up to 37 kg/m2 (inclusive)
5. Premenopausal female patients Using oral, transdermal (patches), or injectable/implantable contraceptives or hormonal IUS (non-hormonal IUD is not allowed) within the last 3 months prior to screening must be willing not to change their method of contraception during the trial.OR Not using any hormonal method of contraception must be willing not to start any other method of contraception during the trial. They must use condoms after the period in which no sexual activity is allowed, i.e., following the primary evaluation timepoint
6. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
7. Regular predictable menstrual cycles or amenorrheic for at least 3 months due to use of a long-acting progestin or continuous use of oral contraceptives
8. Willing to be asked questions about reproductive/sexual activity and use of vaginal products.
9. Willing to provide and self-collect cervicovaginal secretions and vaginal swab samples at the clinic
10. Willing to undergo vaginal cleansing and treatment procedures, including selfadministration of IMP, where required, at home.
11. Willing to abstain from vaginal intercourse, following the first FB301 treatment until the primary evaluation timepoint
12. Willing to abstain from using insertive vaginal feminine products (i.e., tampons, menstrual cups, sex toys), vaginal cleansing products, spermicides, lubricants, or other vaginal products not approved by the Investigator following the first FB301 treatment until the primary evaluation timepoint
13. Willing and able to comply with trial procedures and attending scheduled visits.
14. No changes in medical conditions or prior/concomitant therapy also regarding adherence to sexual behavior and contraceptive/barrier requirements.

Exclusion Criteria:

1. Known immunodeficiency conditions, including drug induced.

2. Contraindication to metronidazole or chlorhexidine.

3. Any known condition requiring regular use of antibiotics, which would suggest the likely requirement for antibiotic treatment during the trial.

4. Any social, medical, or psychiatric condition that in the opinion of the Investigator would make it unlikely for the participant to comply with the trial requirements or might interfere with the objectives of the trial.

5. History of drug or alcohol abuse that in the opinion of the Investigator would make it unlikely for the participant to comply with the trial or would complicate interpretation of data from participation.

6. History of gynecological cancers, gynecological conditions, or surgical gynecological medical history which, in the opinion of the Investigator, precludes participation.

7. Abnormal finding on the physical examination or gynecological examination or any other condition which, in the opinion of the Investigator, precludes participation.

8. Patients with other infectious causes of vulvovaginitis (e.g., vulvovaginal candidiasis, Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, or active Herpes simplex [including PCR test positive]).

9. Patients with another vaginal or vulvar condition, which would confound the interpretation of clinical response.

10. Participants taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements) within 2 weeks or 5 half-lives (whichever is longer) before the start of trial treatment (unless, in the opinion of the Investigator and Sponsor, the medication will not interfere with the trial).

11. Receiving treatment involving investigational drugs. Any previous investigational drug must have been completed at least 30 days prior to screening in this trial.

12. Systemic and/or vaginally applied antibiotic use within the last 30 days prior to screening.

13. Participants who are currently receiving antibacterial therapy unrelated to BV.

14. Clinical laboratory test results which are clinically unacceptable at screening. Any clinically significant abnormal urinalysis should be repeated. If then confirmed abnormal and clinically significant, participant should be excluded. Any clinically significant out of range chemistry or hematology values should exclude the participant.

15. Positive serum HBsAg (other than vaccination related), HCV and HIV antibody tests at screening.

16. Positive test for Treponema pallidum (syphilis).

17. Clinically relevant abnormalities in blood pressure and pulse rate (as assessed by the Investigator).

18. Aural body temperature of < 35.5 or > 37.6°C at screening

19. Pregnant, breastfeeding, has been pregnant within the last 2 months, or wishes to become pregnant within the next 6 months. Egg donation during the trial is not permitted.

20. Use of a copper IUD (intrauterine device) within 12 weeks of screening. (Hormonal IUDs are permitted.)

21. Use of probiotics, prebiotics or symbiotics (supplements and products, oral or vaginal) within past 30 days. (NOTE: Oral yogurt with live cultures is allowed, as are fermented foods)

22. Donation of more than 100 mL whole blood or plasma within 4 weeks before start of treatment or more than 500 mL of whole blood 3 months before start of treatment or intended blood donation during the trial.

23. History of alcohol or substance dependency.

24. Employee of the Sponsor, the CRS Group, or other CRO involved in the clinical trial.

25. Any other conditions or factors which in the opinion of the Investigator may interfere with trial conduct.

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