Recurrent Bacterial Vaginosis (BV)
Conditions
Brief summary
The MOTIF@ FRESH trial will assess the safety and efficacy of "vaginal microbiome transplantation" (VMT). Healthy females will be enrolled to donate vaginal fluid which will be processed and transplanted in females with a history of recurrent bacterial vaginosis (BV), treated with antibiotics.
Detailed description
The proposed randomized, double-blinded, placebo-controlled trial is to evaluate the safety of vaginal microbiota transplantation (VMT) in women with recurrent bacterial vaginosis (BV). The study is based in South Africa, at the FRESH (Females Rising through Education, Support, and Health) Clinical Research Site (CRS) located in the Umlazi Township of Durban. The aim of the trial is to assess the ability of antibiotic treatment plus VMT to establish a Lactobacillus-dominant vaginal community. The underlying hypothesis is that the VMT will lead to less inflammation and higher prevalence of vaginal Lactobacillus compared to antibiotics alone. The transplant material will be vaginal fluid collected from healthy donors (also known as Donors) using a disposable menstrual cup. Donors are defined as participants with Nugent scores \<4. Over a 16-week period, donors will provide vaginal fluid via softcups (referred to as "donations"). All donations will undergo extensive testing for sexually transmitted infections (STIs) and other infections. Donations that test negative for specified infections will be processed to generate vaginal microbial transplantation (VMT) doses for recipients. Recipients are defined as participants with Nugent scores ≥4. Because the HPV vaccine is not routinely administered in South Africa, all recipients without documented proof of prior HPV vaccination will receive the HPV vaccine at least 30 days prior to the intervention. The intervention includes the standard of care for bacterial vaginosis in both the U.S. and South Africa: oral metronidazole (MTZ), administered twice daily for seven days. Following completion of the MTZ course, recipients will receive three VMT doses administered over approximately 1.5 weeks. Recipients will be randomized in a 2:1 ratio to receive either VMT or placebo and will be followed for six months post-intervention.
Interventions
BIOLOGICALVaginal Microbiome Transplantation (VMT)
Vaginal fluid from healthy donors
Metronidazole 400 mg PO every 12 hours for 7 days is the concomitant medication. This antibiotic course is the standard Bacterial Vaginosis (BV) treatment which effectively eliminates microbes associated with BV for a limited time.
1mL of sterile saline solution
Sponsors
Douglas Kwon
Massachusetts General Hospital
Bill and Melinda Gates Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Participants will be randomized 2:1 to VMT vs. placebo
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 25 Years
Healthy volunteers
No
Inclusion criteria
* Premenopausal females between 18 to 25 years of age who are enrolled in the FRESH study * Nugent score ≥ 4 * Confirmation of use of effective contraceptive method by all study recipient participants (referred to as recipients) of child-bearing potential, which includes use of at least one of the following: Hormonal method, such as birth control pills, patches, injections, vaginal rings, or implants; Barrier method, such as a condom or diaphragm used with a spermicide (a foam, cream, or gel that kills sperm); Intrauterine device (IUD) - non-levonorgestrel containing * Ability and willingness to give written informed consent.
Exclusion criteria
* History of clinically significant vaginal, cervical, or uterine disease including but not limited to cancer of the female reproductive tract, prior hysterectomy, high grade cervical dysplasia (CIN III), or diagnosed with cervicovaginal infection (with the exception of bacterial vaginosis or yeast) within the 30 days prior to the procedure * Allergy to metronidazole * Use of investigational therapies or investigational vaccines within 90 days prior to study screening * Has not received the HPV vaccine and is not willing to be vaccinated * Metabolic syndrome, e.g. diabetes, pre-diabetes, glucose intolerance * Use of any immunomodulatory agents within 30 days prior to study enrollment * Participants taking any of the following medications: systemic steroids (inhaled or nasal steroid therapy is permitted), interleukins, systemic interferons, or systemic chemotherapy * History of coronary artery disease, myocardial infarction, COPD, chronic renal failure, decompensated cirrhosis, or any other condition that in the opinion of the investigator will compromise ability to participate in the study * Pap smear result of LSIL, HSIL, AGUS * Insertion of levonorgestrel-containing IUD within 90 days prior to study enrollment * Either breastfeeding, pregnant, or trying to conceive within 24 weeks prior to study enrollment; or becomes pregnant during study period * Use of probiotics and prebiotics (supplements and products, oral or vaginal) within 30 days of the study \- NOTE: Oral yogurt with live cultures and fermented foods are allowed. * Routine use of oral antibiotics i.e., daily use for acne, Hiradenitis suppurativa, or regular use for post-coital urinary tract infection prophylaxis within the past 30 days * Taken non-metronidazole antibiotics in last 30 days * Taken metronidazole within the last 2 weeks * BMI \> 40 * Positive for any of the STIs listed below or on treatment for any of them. * Neisseria gonorrhoeae * Chlamydia trachomatis * HIV * Trichomonas vaginalis * Syphilis * Mycoplasma genitalium * Currently employed at, or professionally affiliated with the FRESH clinical research site, UKZN's HIV Pathogenesis Program (HPP), or the Ragon Institute of Mass General Brigham, MIT and Harvard (referred to as "the Ragon/MGH" in this document). * Screens positive for TB by symptomatic questionnaire
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the safety of VMT | for 23 weeks after intervention | The primary outcome of the study is to evaluate if VMT increases the proportion of women with a Lactobacillus crispatus-dominant microbiota at any time within the 4 weeks after the first dose as measured by sequencing of the microbial community where Lactobacillus crispatus make up \> 50% of detected microbes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Determine whether VMT will result in a durable change in vaginal microbiota | 2, 12, and 24 weeks after intervention | Secondary outcome will measure Lactobacillus crispatus dominance across follow-up weeks. The hypothesis is that antibiotic plus VMT therapy will increase the proportion of women with a Lactobacillus crispatus-dominant microbiota from 5-10% to 50-60%. The safety, toxicity, and tolerability of VMT will also be assessed via a) follow up pelvic assessments to assess for rash, irritation or infection calls, b) patient symptom questionnaires to assess self-reported symptoms of vulvovaginal discomfort, and c) adverse event reporting. |
| Characterize the host clinical and subclinical mucosal inflammatory response before and after VMT | 24 weeks after intervention | Additional secondary, exploratory analyses will be done to evaluate mechanisms for increased Lactobacillus prevalence, or lack thereof. This will include measuring proportions of individual Lactobacillus species (e.g., L. crispatus, L. iners, L. jensenii, L. gasseri), assessing vaginal microbial community type, microbial community diversity measures, individual taxa associated with treatment group, and host mucosal inflammatory immune response. (e.g., vaginal concentration of IL1beta, IL1alpha, IL1RA, IL6, IL8, TNFa, IFNg) |
Countries
South Africa
Contacts
CONTACTSarah M Eisa, MPH
CONTACTEyerusalem T Alemu, BA
PRINCIPAL_INVESTIGATORDouglas S Kwon, MD, PhD
Ragon Institute of MGB, MIT, and Harvard
PRINCIPAL_INVESTIGATORCaroline Mitchell, MD, MPH
Massachusetts General Hospital
PRINCIPAL_INVESTIGATORKrista Dong, MD
Ragon Institute of MGB, MIT, and Harvard
Outcome results
None listed