Clinical trial NCT03894813
Conditions: Bacterial Vaginosis
Sponsor: Peking University Shenzhen Hospital
Start date: 2019-03-26; Completion date: 2020-12-30
Enrollment: 126 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The investigators are trying to determine if oral probiotics (Umeta-Miyue, Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14) (30 days)with metronidazole vaginal suppositories(7 days) is better than using metronidazole vaginal suppositories only in preventing the recurrence of bacterial vaginosis (BV).

Detailed description:
Studies have shown that oral probiotics can significantly promote the recovery of vaginal flora mainly because intestinal microbiota can migrate and affect vaginal microecology. This project aims to evaluate the efficacy of oral probiotics (Umeta-Miyue, Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14) (30 days) with metronidazole vaginal suppositories(7 days) in the treatment of bacterial vaginosis and to explore the correlation between vaginal flora and fecal flora by detecting the metagenomics of vaginal secretions and intestinal feces at the time of baseline phase, the first month after treatment, the third month after treatment and the sixth month after treatment.

Arms: arm 1: Probiotics: Oral probiotics(Umeta-Miyue, Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14) ) (qd, 30 days); Metronidazole: Metronidazole vaginal suppositories (qd,7 days) arm 2: Metronidazole vaginal suppositories(1 suppositories,qd,7 days )
Interventions: intervention 1: "Probiotics" and "Metronidazole" intervention 2: Metronidazole Vaginal
Intervention descriptions: intervention 1: Oral probiotics (Umeta-Miyue, Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14) (qd, 30 days)+Metronidazole Suppositories (qd, 7 days) intervention 2: Metronidazole Suppositories,qd, 7 days

Protocol documents:
Prot_SAP_000.pdf: 
 
Probiotics as Adjuvant Treatment for 
Bacterial Vaginosis 
 
NCT03894813 
 
2021-02-20 
 
 


Study Protocol with SAP 
This study was a single-centre, prospective, parallel-group, randomized, controlled 
study. Women who came to the gynaecological clinic of Peking University Shenzhen 
Hospital, China, between March 2019 and June 2019 with abnormal vaginal discharge 
symptoms were recruited, and eligible subjects were informed of the study protocol 
and enrolled in the study. The inclusion criteria were women aged between 18 and 65 
years old, premenopausal women, women with a history of sexual activity, and 
women with a Nugent’s Gram stain score of 7 or higher. The exclusion criteria were 
mixed vaginitis, such as vulvovaginal candidiasis (VVC), Trichomonas vaginalis 
(TV) infection, Chlamydia trachomatis (CT) infection or gonococcal vaginitis; 
planning for or being pregnant; breast-feeding; pelvic inflammatory disease; allergy to 
metronidazole; currently using antibiotics; long-term use of contraceptives or 
immunosuppressants or anaphylactic constitution; and a history of systemic organic 
diseases or psychiatric diseases. The study was conducted in accordance with the 
Declaration of Helsinki, was approved by the Medical Ethnic Committee of PKUSZH 
(with the Unique Protocol ID: PUshenzhenH2018-016) and was first posted on 
ClinicalTrials.gov (NCT03894813) on March 26, 2019. Informed consent was 
obtained from all subjects involved in the study. 
The sample size was calculated based on the non-inferiority test 
(https://www.cnstat.org/samplesize/12/), which referred to Gregor Reid et al, who 
carried out studies with the same Lactobacillus strains administered orally to women 
with bacterial vaginosis (BV). The relevant parameters were determined as follows: 
test level α=0.05, test power 1-β=0.80, Pt=0.90, Pc=0.75, Nt:Nc=1:1, boundary value 
Δ= -0.0.068 (excellent), and Fisher’s exact test. As a result, the sample size of each 
group was calculated as 50 patients, 100 patients in total. Considering a loss to 
follow-up rate of 20%, a sample size of 120 patients was finally determined, with 60 
patients in each group. 
After obtaining written informed consent, the participants were first asked to complete 
a questionnaire on demographic characteristics, reproductive health and sexual 
behaviour. They were subsequently randomly assigned to either the metronidazole 
group or the adjunctive probiotic group according to the random number table. The 
study was not blinded to the researchers or the patients. Starting from the enrolment 
day, the participants in the adjunctive probiotic group received orally administered 
probiotic drinks containing L. rhamnosus GR-1 and L. reuteri RC-14 (≥1 × 109 
CFU per day, for 30 days) and vaginally administered metronidazole suppositories 
(0.2 g per day, for 7 days), and the participants in the metronidazole group received 
metronidazole vaginal suppositories only. Clinical follow-up visits were scheduled at 
30 and 90 days after starting treatment. The intervention products were dispensed by 
the investigator at the initial visit, and the compliance of participants was assessed by 
counting returned containers and filling out a questionnaire. The feasibility, 
acceptability and adherence to the administered products; vaginal symptoms; and 


adverse events (AEs) were also assessed by self-report in medication diaries and 
questionnaires at follow-up visits. Therapy was initiated after the enrolment visit and 
suspended when menstruation began and continued immediately when it finished. 
Patients were asked to avoid sexual intercourse and vaginal douching during the first 
7 days of treatment with metronidazole suppositories. 
General information and clinical signs and symptoms of BV, including homogeneous 
and thin vaginal discharge, unpleasant odour (such as a “fishy” smell) and vulvar 
discomfort (such as itching or burning), were recorded at 0 day, 30 days and 90 days. 
The efficacy outcome was evaluated by the cure rate according to per-protocol (PP) 
analysis, which was the percentage of participants who did not present with BV 
(defined by Nugent score < 7) at any of the follow-up visits. Those with a Nugent 
score ≥ 7 in the 30-day follow-up was excluded from the trail, but when we 
evaluate the overall recurrence rate of the 90-day follow-up, these participants were 
still included in. At each follow-up visit, patients were requested to report any 
unexpected symptoms during the study period. AEs were recorded in the case report 
form (Table S1). 
The diagnosis criteria of BV were based on Nugent Gram stain scoring of vaginal 
smears. The Gram-stained smear slides were examined microscopically, and the 
number of bacterial cells with different morphotypes was counted under 1000 × 
magnification. Each slide was identified according to Nugent score. A Nugent score 
of 0-6 was considered BV negative and of 7-10 was considered BV positive. The 
Gram stains were analysed in a double-blind manner by two experienced cytology 
technicians. 
This study was a single-centre randomized controlled trial with two arms allocated at 
a ratio of 1:1. SPSS 13.0 software was applied to generate a random number table, 
and the random order was assigned depending on the order of enrolment. 

ICF_001.pdf: 
Probiotics as Adjuvant Treatment for 
Bacterial Vaginosis 
 
NCT03894813 
 
2021-02-20 
 
 


Informed Consent 
 
We are going to carry out a study: Prospective, randomized controlled clinical study on the 
adjuvant treatment of bacterial vaginosis with probiotics. Your situation meets the enrollment 
conditions of this study. Therefore, we invite you to participate in this study. This informed 
consent form will introduce you to the purpose, steps, benefits and risks of this research. 
Please read it carefully and decide whether to participate. When the researchers explain and 
discuss the informed consent form to you, you can ask any questions at any time to make sure 
you are understanding. You can make a decision after discussing it with your family, friends, 
or your medical doctor. 
The project leader of this research is: Professor Fan Shangrong, Chief Physician, Peking 
University Shenzhen Hospital 
Project sponsor: BGI Precision Nutrition (Shenzhen) Technology Co., Ltd. 
 
1. Why is this research conducted? 
Bacterial vaginosis (BV) is a clinical syndrome caused by a dysbacteriosis of the vagina. It is 
a common disease in gynecological clinics and directly lead to many serious obstetrics and 
gynecological complications (such as premature delivery, postpartum endometritis, cervicitis, 
pelvic inflammatory disease et al). Radically treatment of BV can reduce the infection of 
patients with sexually transmitted diseases such as gonococcal infection, human 
papillomavirus (HPV), human immunodeficiency virus (HIV) infection risk. Currently, 
systemic or local administration of metronidazole is the gold standard program for the clinical 
treatment of BV. However, the recurrence rate was 52% in the 6-month follow-up and 68% in 
the 12-month follow-up test. New treatments are needed to prevent and reduce the recurrence 
of BV. 
 
2. How many people will participate in this research? 
This study is a preliminary test, with a sample size of 120 cases and 60 cases in each of the 
two observation groups. 
 
3. How was the research conducted? 
If your vaginal discharge is abnormal, you could be invited to screen for BV first, the 
following tests could be proceeded to determine whether you can participate in the study: 
(1) A cotton swab of the vaginal discharge will take and the pH value of vaginal secretions 
and Nugent score will be conducted to determine whether you can participate in the study.  
(2) If the test is indicated with BV, the researcher will ask about and record your medical 
history, and conduct a physical examination on you. 
(3) If you meet the included criteria and excluded criteria, you are asked to sign an informed 
consent. 
(4) Then you will be assigned to the control group or the test group according to a random 
number table in the order of entry time at a ratio of 1:1. 
(5) Starting from the enrolment day, the participants in the test group received orally 
administered probiotic drinks containing L. rhamnosus GR-1 and L. reuteri RC-14 (≥1 × 109 


CFU per day, for 30 days) and vaginally administered metronidazole suppositories (0.2 g per 
day, for 7 days), and the participants in the control group received metronidazole vaginal 
suppositories only.  
 
Medication plan: 
Intervention group: Metronidazole suppository (200mg), 1 capsule/day, vaginally 
administered for 7 consecutive days; starting from the first day of treatment, metronidazole 
suppository, take Umi-Miyue probiotics on an empty stomach every morning, menstruation 
During this period, take it continuously for 30 days. 
Control group: Metronidazole suppository (200mg), 1 capsule/day, vaginally administered for 
7 consecutive days. 
(6) Clinical follow-up visits were scheduled at 30 and 90 days after starting treatment. You 
will receive a series tests and report a questionnaire. 
 
4. What are the inclusion criteria and exclusion criteria? 
The inclusion criteria were women aged between 18 and 65 years old, premenopausal women, 
women with a history of sexual activity, and women with a Nugent’s Gram stain score of 7 or 
higher. The exclusion criteria were mixed vaginitis, such as vulvovaginal candidiasis (VVC), 
Trichomonas vaginalis (TV) infection, Chlamydia trachomatis (CT) infection or gonococcal 
vaginitis; planning for or being pregnant; breast-feeding; pelvic inflammatory disease; allergy 
to metronidazole; currently using antibiotics; long-term use of contraceptives or 
immunosuppressants or anaphylactic constitution; and a history of systemic organic diseases 
or psychiatric diseases.  
 
5. How long will this study last? 
The follow-up period of this study was 3 months after the start of treatment and the adverse 
events will be monitored for 6 months after the enrollment. 
 
6. What are the risks of participating in this study? 
Studies have reported that transient abdominal distension and flatulence are rare said affects 
in taking the probiotics. Any adverse reactions related to the study product during the 
observation period will be treated in time. Occasionally, a small amount of bleeding from the 
cervix occurs during the sampling of vaginal secretions, which is mostly related to the 
patient’s own reproductive tract infection.  
 
7. What are the benefits of participating in this study? 
Participate in this study, you will receive standardized diagnosis and medication treatment 
with BV. The treatment may improve symptoms and obtain a cure. Oral probiotics can 
regulate the balance of your intestinal flora and genital tract flora, improve systemic 
immunity, and prevent disease recurrence. 
 
 8. Is it necessary to participate in and complete this research? 
Whether you participate in this study is entirely voluntary. If you are unwilling, you can 
refuse to participate at any time. This will not have any negative impact on your current or 


future medical care. Even after you agree to participate, you can change your mind at any 
time and tell the investigator to withdraw from the study. Your withdrawal will not affect your 
access to normal medical services. 
 
After your drop out, your information in the previous study will not be used and will finally 
be destroyed. However, in rare cases, it is necessary to use this information. For example, 
when government regulatory agencies conduct supervision, inspection, and statistics, they 
will request to view all research information, which will include relevant information about 
your participation in the research at that time. 
 
9. Fees and compensation for participating in the study 
The medicine for your bacterial vaginosis treatment is provided by the sponsor, and the 
examination of vaginal secretions for each person during the follow-up period will be paid by 
the sponsor. There is no compensation for transportation expenses, lost work expenses, etc. in 
this study. This research is unpaid. 
 
10. How to deal with research-related injuries? 
When your health is harmed by participating in this study, please inform the investigator 
immediately. 
 
11. Will my information be kept confidential? 
If you decide to participate in this research, your participation and your personal information 
will be kept confidential. Your secretion specimen will be identified by the study number 
instead of your name. Your files will be kept in a locked filing cabinet, which is only 
accessible to researchers. To ensure that the research is conducted in accordance with the 
regulations, when necessary, members of the government management department or the 
ethics committee can consult your personal data in the research unit according to the 
regulations. When the results of this research are published, no personal information about 
you will be disclosed. 
 
12. Who should I contact if I have questions or difficulties? 
If you have any questions, you can contact the Clinical Research Ethics Committee of Peking 
University Shenzhen Hospital with the TEL: 0755-83923333-8809. 
 
13. Signature 
Researcher’s Statement 
   I have explained the study (a prospective, randomized controlled clinical trial on the 
adjuvant treatment of bacterial vaginosis with probiotics) to the subject, she have realize the 
background, purpose, procedures, risks and benefits of this study, and gave her enough time 
to read the informed consent form and discuss with others; I told the subject’s contact 
information when they encountered research-related problems; I told the subject that she 
could do anything during the research period There is no need for any reason to withdraw 
from this study. 
 


Investigator’s signature:                
Date:               
 
Subject’s statement 
   The researcher explained the study (a prospective, randomized controlled clinical study of 
probiotics for adjuvant bacterial vaginosis) to me and I have known the background, purpose, 
procedures, risks and benefits of the study. I have enough time and opportunity to ask 
questions. I know who I should contact when I have questions. I read this informed consent 
form and decided to participate in this research. I know that I can withdraw from this research 
at any time during the research period without any reason. I was told that I would get a copy 
of this informed consent form, which contained my signature and the researcher’s signature. 
 
 
Subject’s signature:                 
Date: