Protocol Full Title:A randomized double-blind, placebo-controlled, parallel multicenter phase III study to evaluate the effectiveness and safety of Probiotic on the clinical and biological parameters of women with urinary tract infection  

Phase of Development:Phase III

Name of the Investigational product:Probiotic 

STUDY OBJECTIVE(S) :Primary Objective:To evaluate effectiveness of Probiotic on the clinical and biological parameters of menopausal women with urinary tract infection  

Secondary Objective : To evaluate safety of Probiotic  on the clinical and biological parameters of menopausal women with urinary tract infection  

STUDY DESIGN:A randomized double-blind, placebo-controlled parallel multicenter phase 3 clinical trial

STUDYCENTER(S):Multicenter

SAMPLE SIZE:The sample size required for this study was estimated to be 60 patients (30 patients per treatment group). This number was based on the results in an earlier unpublished study. The assumed study parameters would provide 80% power for a 2-sided t test at a significance level of 0.05. 

STUDY DURATION:06 month

PLANNED DURATION OF TREATMENT: 90 days 

STUDY ENROLLMENT AND WITHDRAWAL CRITERIA:Inclusion criteria:Patients with meeting all of the following criteria will be considered for enrollment in the study:• Women between the ages of 17 and 70.

• Have a history of recurrent UTIs, defined as ≥ 3 episodes in the past year, of which two were approximately in the past 6 months immediately prior to their screening visit (Visit 1), at the discretion of the investigator. At least one episode must be diagnosed medically and treated by a health care professional, the remaining two may be self-reported.• Voluntarily participating in the clinical study, fully understanding and being fully informed of the study, and having signed the Informed Consent Form (ICF).• Willingness and capability to complete all the study procedures.

Exclusion criteria:Patients with history or significant presence of the following will be excluded from participation/enrollment in the study trial:•Immunosuppressed•Known allergies to investigational product or its excipients•Known vaginal infection other than bacterial vaginosis (BV) or yeast infection at time of screening•Women who have needed changes to medical intervention or in-office procedures in the last 3 months•Women who wear a pessary•Women who use catheters regularly•Women with an obstruction or neurogenic bladder causing incomplete bladder emptying. Individuals who have taken oral antibiotics (or topical antibiotics in their urogenital area) within the previous 30 days. •Individuals that have a significant acute or chronic coexisting illness such as renal diseases (renal failure, nephrolithiasis), anatomical urinary tract abnormalities, intestinal disease, severe uncontrolled metabolic or cardiovascular disease (such as diabetes or hypertension), anticoagulant therapy, cancer. •Medical conditions or diseases that may affect subject safety or confound study results in the opinion of the investigator

(Need to be provided by  sponsor) :• The investigational product (IP) is a Probiotic which will be supplied by Sponsor.•The placebo contained only excipient, maltodextrin (1.00 g).

The test group –(n = 30) will Probiotic (______) billion colony-forming unit activity powder (carrier maltodextrin) thrice a day.  (details to be provide by sponsor)Control (placebo) group – (n = 30) will receive maltodextrin with similar dosing schedule. The packaging and labeling for both the products were same except the coded batch numbers used for differentiation.

EVALUATION SCHEDULE:The patients will be followed up during the Day 1, Day 45 and Day 90. All patients were required to log their compliance in the provided forms given to them throughout the study. 

Incidence rate of symptomatic UTI To evaluate in healthy women who experience recurrent UTIs, the effect of 6 months of daily supplementation of the investigational product on incidence rate of symptomatic UTIs.90 days duration of studyChange in vaginal pH The vaginal pH will be assessed using a colorimetric paper strip at baseline, 3 months, and Day 90. This outcome examines numeric changes in pH over time. Baseline to 90 days 

Frequency of UTI The mean number of UTIs experienced per participant during the 6-month study period will be compared between control and experimental arms. 90 days  duration of study

Hematological and hepatic biomarkers were analyzed following the standard medical test protocols at screening (baseline) and end of treatment (Day 90)•Fasting Blood sugar level •HbA1c•Lipid profile •C-reactive protein 

Vital signs measurement and physical examination will be carried out at Screening, Day1, Day 45 and Day 90. All adverse events will be reported during the entire duration of study. 

STUDY ENDPOINTS:Primary End Point: Incidence rate of symptomatic UTI 

Secondary End Point:•Change in the vaginal pH from baseline to Day 90 (end of study)  •The mean number of UTIs experienced per from baseline to Day 90 (end of study)  •Change in the Fasting Blood sugar level from baseline to Day 90 (end of study)  •Change in the HbA1c level from baseline to Day 90 (end of study)  •Change in the FSH from baseline to Day 90 (end of study)  •Change in the LH  from baseline to Day 90 (end of study) •Change in the Serum estradiol levels from baseline to Day 90 (end of study)  •Change in the Serum testosterone levels from baseline to Day 90 (end of study)  •Change in the C-reactive protein (mg/L) levels from baseline to Day 90 (end of study)  •Change in the lipid profile parameters [triglycerides (mmol/L), total cholesterol (mmol/L), low density lipoprotein cholesterol (mmol/L), and high density lipoprotein cholesterol (mmol/L)] from baseline to Day 90 (end of study)  •Change in the antral follicle count from baseline to Day 90 (end of study)  •Change in the ovarian volume from baseline to Day 90 (end of study)  

•Number of participants who Experienced at least one Adverse Event during the study duration

•Number of participants who discontinued study drug due to an Adverse Event during the study

STATISTICAL ANALYSIS:The statistical evaluation will be performed using appropriate statistical tests. The details of statistical analysis to be performed will be described in Statistical Analysis Plan (SAP). Statistical analysis will be performed using the latest version of SAS® system software (SAS Institute Inc., USA).

Symptoms considered were bloating and cramping, abdominal pain, diarrhoea and constipation, stomach rumbling, nausea, vomiting, headache, and anxiety. Intergroup mean difference [(Test) – (Placebo)] for all the symptoms was analyzed through ANOVA and 95% confidence interval (CI) estimation.

Safety analyses were based on the safety population, which was defined as all randomized patients who received study treatment, and were summarized by the actual treatment received.

Significant levels will be set at p<0.05. All analyses will be based on the intention-to-treat principle. Missing values will be handled by the modern imputation methods which will be accomplished using a set of repeated imputations created by predictive models based on the majority of participants with complete data. Demographic characteristics and other baseline values will be described using descriptive statistics for each group. Continuous variables with normal distribution will be expressed as the means with SD; for abnormally distributed variables, the data will be expressed as medians with a centile range (such as the 25th and 75th centiles). Numbers and proportions will be used to describe the categorical variables. Between-group differences in primary and secondary outcomes will be tested using repeated measures analyses of variance. 

ETHICAL CONSIDERATIONS:The study will be conducted as per the National Ethical Guidelines for Biomedical and Health Research involving Human participants ICMR (2017), ICH (Step 5) ’Guidance on Good Clinical Practice’, New Drugs and Clinical Trials Rules 2019 G.S.R. 227(E) dated 19 Mar 2019, ’Good Laboratory Practice’, ‘Good Clinical Practices for Clinical Research in India’ Guidelines, Good Clinical Laboratory Practice (GCLP) and Declaration of Helsinki (Fortaleza, October 2013).