Clinical Trial Results:
Comparative study of the efficacy and safety of vaginally applied Dequalinium Chloride (10 mg) and orally applied Metronidazole (2 x 500 mg) in the treatment of bacterial vaginosis
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Summary
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EudraCT number |
2020-002489-15 |
Trial protocol |
CZ SK |
Global end of trial date |
25 Aug 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
05 Dec 2024
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First version publication date |
05 Dec 2024
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Other versions |
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Summary report(s) |
Article |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
380119
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT05788991 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Medinova AG
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Sponsor organisation address |
Eggbühlstrasse 28, Zurich, Switzerland, 8050
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Public contact |
Anahí Hurtado Chong, Medinova AG, 0041 44306 1396, hurtado.anahi@medinova.ch
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Scientific contact |
Anahí Hurtado Chong, Medinova AG, 0041 44306 1396, hurtado.anahi@medinova.ch
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Jun 2023
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
25 Aug 2022
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Global end of trial reached? |
Yes
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Global end of trial date |
25 Aug 2022
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To evaluate whether vaginal tablets containing 10 mg dequalinium chloride (Fluomizin) are comparable in clinical efficacy to metronidazole 500 mg oral tablets in women suffering from bacterial vaginosis
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Protection of trial subjects |
The study was conducted in accordance with the protocol and the following:
• Consensus ethical principles derived from international guidelines including the Declaration of Helsinki 1996 and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines
• Applicable ICH Good Clinical Practice (GCP) Guidelines
• All applicable national and international laws, regulations, and standards
• EU directive 2005/28/EC
Data protection was handled in compliance with national/local regulations.
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Background therapy |
Metronidazole is is a nitroimidazole antibiotic and one of the first line recommended treatments for bacterial vaginosis with a posology of 500 mg twice daily for 7 days. Metronidazole is well tolerated in general, however after oral use, a bitter, metallic taste in the mouth and gastrointestinal adverse effects (abdominal cramps, nausea) are observed in up to 30% of the patients. In combination with alcohol, it is known to induce vomiting, heartburn, stomach pains, i.e. its typical (disulfiram) effect. According to some studies, Metronidazole is claimed not to be teratogenic in humans, even when used in the first trimester of pregnancy. Due to the difference in taste, it creates in milk, its use is not advised during lactation. Metronidazole is contraindicated in a first trimester (pregnancy category B) and breastfeeding is not possible since Metronidazole is excreted in milk. In general, Metronidazole has a good efficacy profile against all relevant BV associated pathogens. | ||
Evidence for comparator |
Fluomizin® is available as vaginal tablets, containing 10 mg Dequalinium chloride. It was first marketed in Germany in 1993 and is currently approved in 69 countries. Dequalinium chloride 10 mg vaginal tablet (Fluomizin®) has been developed as a directly compressed vaginal tablet to ensure fast disintegration of the tablet and rapid dissolution of the active substance. As soon as the vaginal tablet comes into contact with the vaginal secretion, it begins to disintegrate and Dequalinium chloride is released. After dissolution of the Dequalinium chloride 10 mg tablet in an estimated 2.5 – 5 ml of vaginal fluid, the Dequalinium chloride concentration is estimated at 2000 – 4000 μg/ml, assuming negligible absorption. This concentration is 4 to 8-fold higher than the minimal inhibitory concentration (MIC) of the least susceptible isolate (MIC = 512 μg/ml). The broad-spectrum antimicrobial activity covering all relevant pathogens for vaginal infections and the negligible systemic absorption are the key factors of dequalinium chloride that make it suitable for the treatment of most vaginal infections. The treatment of BV with a 6-day course of 10 mg Dequalinium chloride vaginal tablets had equal efficacy as a 7-day course of Clindamycin vaginal cream. The current formulation Dequalinium chloride 10 mg vaginal tablets (Fluomizin®) as 6-day therapy with its broad antimicrobial spectrum and excellent tolerability offers a safe and effective option for empiric therapy of different vaginal infections in daily practice. | ||
Actual start date of recruitment |
29 Jul 2021
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 71
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Country: Number of subjects enrolled |
Slovakia: 56
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Country: Number of subjects enrolled |
Czechia: 24
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Worldwide total number of subjects |
151
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EEA total number of subjects |
151
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
151
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients with symptomatic BV were recruited from July 29, 2021, to August 25, 2022, in Poland, the Czech Republic, and Slovakia from 11 gynecology practices and 1 hospital | ||||||||||||||||||
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Pre-assignment
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Screening details |
Premenopausal women 18 years or older with BV (defined as 4 positive Amsel criteria) were eligible to participate. Exclusion criteria were uterine/vaginal bleeding of unknown origin, ulcerations or erosions of the vaginal mucosa or cervix, candidiasis, aerobic vaginitis, sexually transmitted infections, hypersensitivity to a study medication | ||||||||||||||||||
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Period 1
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Period 1 title |
Entry visit (Day 0)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Dequalinium Chloride | ||||||||||||||||||
Arm description |
Dequalinium chloride 10-mg vaginal tablets (Fluomizin, Medinova AG). | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Dequalinium chloride
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Investigational medicinal product code |
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Other name |
Fluomizin
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Pharmaceutical forms |
Tablet + vaginal tablet
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Routes of administration |
Vaginal use
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Dosage and administration details |
Vaginal tablets (containing either 10 mg dequalinium chloride or placebo) were applied once a day for 6 days
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Arm title
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Metronidazole | ||||||||||||||||||
Arm description |
Metronidazole, 500-mg oral tablets | ||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||
Investigational medicinal product name |
Metronidazole
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Oral tablets (containing 500 mg metronidazole or placebo) were taken twice a day for 7 days
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Period 2
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Period 2 title |
Visit 1 (Day 7-11)
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Is this the baseline period? |
No | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Assessor | ||||||||||||||||||
Blinding implementation details |
Double-dummy medication kits prepared by an independent contractor contained vaginal and oral tablets, with placebo and active medication. The randomization sequence was prepared by an independent statistician using block randomization with variable block sizes stratified by center. An interactive randomization tool in the electronic case report form provided the medication kit number, ensuring allocation concealment. Patients, investigators, and outcome assessors were blinded.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Dequalinium Chloride | ||||||||||||||||||
Arm description |
10-mg vaginal tablets (Fluomizin, Medinova AG). | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Dequalinium chloride
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Investigational medicinal product code |
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Other name |
Fluomizin
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Pharmaceutical forms |
Tablet + vaginal tablet
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Routes of administration |
Vaginal use
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Dosage and administration details |
Vaginal tablets (containing either 10 mg dequalinium chloride or placebo) were applied once a day for 6 days
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Arm title
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Metronidazole | ||||||||||||||||||
Arm description |
Metronidazole, 500-mg oral tablets | ||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||
Investigational medicinal product name |
Metronidazole
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
500 mg twice a day for 7 days
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Period 3
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Period 3 title |
Visit 2 (Day 20-40)
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Is this the baseline period? |
No | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Assessor | ||||||||||||||||||
Blinding implementation details |
Double-dummy medication kits prepared by an independent contractor contained vaginal and oral tablets, with placebo and active medication. The randomization sequence was prepared by an independent statistician using block randomization with variable block sizes stratified by center. An interactive randomization tool in the electronic case report form provided the medication kit number, ensuring allocation concealment. Patients, investigators, and outcome assessors were blinded.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Dequalinium Chloride | ||||||||||||||||||
Arm description |
10-mg vaginal tablets (Fluomizin, Medinova AG). | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Dequalinium chloride
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Investigational medicinal product code |
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Other name |
Fluomizin
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Pharmaceutical forms |
Tablet + vaginal tablet
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Routes of administration |
Vaginal use
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Dosage and administration details |
Vaginal tablets (containing either 10 mg dequalinium chloride or placebo) were applied once a day for 6 days
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Arm title
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Metronidazole | ||||||||||||||||||
Arm description |
Metronidazole, 500-mg oral tablets | ||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||
Investigational medicinal product name |
Metronidazole
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
500 mg twice a day for 7 days
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Baseline characteristics reporting groups
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Reporting group title |
Dequalinium Chloride
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Reporting group description |
Dequalinium chloride 10-mg vaginal tablets (Fluomizin, Medinova AG). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Metronidazole
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Reporting group description |
Metronidazole, 500-mg oral tablets | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
ITT
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The ITT population included all randomized and treated patients allocated according to their randomization.
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Subject analysis set title |
PP
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The PP population included patients without major protocol violations.
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Subject analysis set title |
Safety
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The safety population included patients who took at least 1 dose of study medication.
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End points reporting groups
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Reporting group title |
Dequalinium Chloride
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Reporting group description |
Dequalinium chloride 10-mg vaginal tablets (Fluomizin, Medinova AG). | ||
Reporting group title |
Metronidazole
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Reporting group description |
Metronidazole, 500-mg oral tablets | ||
Reporting group title |
Dequalinium Chloride
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Reporting group description |
10-mg vaginal tablets (Fluomizin, Medinova AG). | ||
Reporting group title |
Metronidazole
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Reporting group description |
Metronidazole, 500-mg oral tablets | ||
Reporting group title |
Dequalinium Chloride
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Reporting group description |
10-mg vaginal tablets (Fluomizin, Medinova AG). | ||
Reporting group title |
Metronidazole
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Reporting group description |
Metronidazole, 500-mg oral tablets | ||
Subject analysis set title |
ITT
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The ITT population included all randomized and treated patients allocated according to their randomization.
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Subject analysis set title |
PP
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The PP population included patients without major protocol violations.
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Subject analysis set title |
Safety
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The safety population included patients who took at least 1 dose of study medication.
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End point title |
Clinical cure rate | |||||||||
End point description |
Resolution of the abnormal vaginal discharge, negative whiff test, and less than 20% clue cells
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End point type |
Primary
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End point timeframe |
One week
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Attachments |
Untitled (Filename: Primary analysis.tiff) |
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Statistical analysis title |
Primary endpoint- non inferiority | |||||||||
Statistical analysis description |
The difference in proportions between groups (with 95%CIs) for clinical cure, bacteriologic cure, and therapeutic cure were analyzed using a Farrington-Manning test with a 1-sided significance level of α = .025 and a noninferiority margin of 15 percentage points
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Comparison groups |
Metronidazole v Dequalinium Chloride
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Number of subjects included in analysis |
143
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | |||||||||
P-value |
≤ 0.025 [1] | |||||||||
Method |
Farrington-Manning | |||||||||
Parameter type |
Difference in proportion | |||||||||
Confidence interval |
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level |
95% | |||||||||
sides |
1-sided
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lower limit |
15 | |||||||||
upper limit |
- | |||||||||
| Notes [1] - 1 sided significance level |
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End point title |
Clinical cure rate | |||||||||
End point description |
Clinical cure was defined as the resolution of abnormal vaginal discharge, whiff test, and clue cells (ie, all 3 criteria must be negative)
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End point type |
Secondary
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End point timeframe |
1 month
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| No statistical analyses for this end point | ||||||||||
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End point title |
Bacteriological cure rate | |||||||||
End point description |
Bacteriologic cure was defined as a Nugent score of 3 or less.
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End point type |
Secondary
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End point timeframe |
1 week
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| No statistical analyses for this end point | ||||||||||
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End point title |
Bacteriologic cure rate | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
1 month
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| No statistical analyses for this end point | ||||||||||
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End point title |
Clinical improvement | |||||||||
End point description |
Clinical improvement was defined as 2 or more negative Amsel criteria at both visits.
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End point type |
Secondary
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End point timeframe |
1 month
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| No statistical analyses for this end point | ||||||||||
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End point title |
Tolerability (assessed by the patient) | |||||||||||||||||||||
End point description |
Subjective tolerability to the treatment were rated by patients as very good, good, moderate, or poor.
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End point type |
Secondary
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End point timeframe |
1 month
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Standard Amsel Criteria | |||||||||
End point description |
The standard Amsel criteria define BV as the presence of 3 or more criteria.5 Conversely, 2 or more negative criteria are considered BV negative.
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End point type |
Post-hoc
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End point timeframe |
1 week
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| No statistical analyses for this end point | ||||||||||
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End point title |
Standard Amsel Criteria | |||||||||
End point description |
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End point type |
Post-hoc
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End point timeframe |
1 month
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| No statistical analyses for this end point | ||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events within 24 days of randomization were defined as treatment emergent.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.1
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Reporting groups
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Reporting group title |
Dequalinium Chloride
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Reporting group description |
10-mg vaginal tablets (Fluomizin, Medinova AG). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Metronidazole
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Reporting group description |
Metronidazole, 500-mg oral tablets | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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13 Apr 2022 |
One protocol amendment (v2.0 13-April-2022) was made to change the analysis sets definition. The
analysis set mITT was restricted to subjects who were treated and had the Nugent score value at
baseline ≥7 and was going to be used for the main efficacy analysis. The mITT was replaced with the
ITT, i.e. all patients randomized and treated, regardless of the Nugent score value. A clarification to
describe exactly when a subject is considered treated was also added, to avoid any ambiguity. Nugent
scores results were only received after several days at which time the subject was already enrolled in
the study. Considering the unexpectedly high rate of low Nugent score values, there was a risk of lack
of power in the analysis because the primary analysis was planned on the mITT analysis set, although
the primary endpoint bacterial vaginosis status was based on the Amsel Criteria and not on the Nugent
score values. Therefore, it seemed more meaningful to consider the Nugent score in a sensitivity
analysis than in the primary analysis. With this change, the analysis set for the primary endpoint changed
from the mITT to the new ITT analysis set defined. To include a differentiation dependent on the Nugent
score value in the analysis as was originally intended, subjects were categorised into subgroups by
Nugent score value at baseline, and the primary and secondary endpoint analyses were performed also
by subgroup.
The change in the analysis set population for the primary endpoint also affected the drop-out rate
considered from 30% to 5%, and consequently the planned global sample size was reduced from 160
to 118 patients per treatment arm. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| The limitations of the study are the short follow-up; the reduced sample size, which hindered subgroup analyses; and the patient population limited to White European individuals | |||||||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/38696172 |
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