Clinical trial NCT05788991
Conditions: Bacterial Vaginosis Vaginal Infection Vaginal Diseases
Keywords: bacterial vaginosis dequalinium chloride metronidazole vaginal infection treatment comparative study non inferiority
Sponsor: Medinova AG
Start date: 2021-07-26; Completion date: 2022-08-25
Enrollment: 151 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical trial is to show the efficacy and safety of dequalinium chloride in the treatment of bacterial vaginosis compared to metronidazole.

Detailed description:
Eligible patients who signed informed consent were randomized to receive treatment with either dequalinium chloride (+ oral placebo) or metronidazole (+ vaginal placebo) for up to 7 days. Primary objective was clinical cure rate at one week after start of treatment. Control visits to assess outcomes were done after end of treatment and after one month.

Arms: arm 1: Dequalinium chloride 10 mg vaginal tablets arm 2: Metronidazole 500 mg oral tablets
Interventions: intervention 1: Dequalinium Chloride intervention 2: Metronidazole Oral
Intervention descriptions: intervention 1: Fluomizin vaginal tablets (10 mg dequalinium chloride) used once a day for 6 days intervention 2: Metronidazole oral tablets (500 mg) taken twice a day for 7 days

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol  
 Version 2.0, 13-APR-2022  
Medinova AG  
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Confidential 
 
 
 
 
 
 
 
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Medinova AG 
 
CLINICAL STUDY PROTOCOL  
 
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 
Study number: 380119 
EudraCT Number: 2020-002489-15 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the 
extent necessary to obtain informed consent, may not be disclosed to another party unless 
law or regulations require such disclosure. Persons to whom the information is disclosed 
must be informed that the information is confidential and may not be further disclosed by 
them.  
Observational Product Name: 
Fluomizin® vaginal tablets (Medinova AG) 
Sponsor: 
Medinova AG 
Eggbühlstrasse 28 
CH-8050 Zurich / Switzerland 
 
Coordinating Investigator  
n/a 
Protocol Version: 
2.0 
Protocol Date: 
13 APR-2022 
 
 


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Amendments 
 
 
 
 
Nr. 
Description 
Date 
1. 
Changes in the statistical analysis of the 
primary endpoint (see section 9.4):  
x 
Primary analysis set has changed from 
mITT (exclusion of Nugent score ≤ 7) 
to ITT (all randomized patients), see 
section 9.3 
x 
Additional subgroup regarding the 
Nugent score at baseline.  
The amendment also affects the sample size 
(see section 9.1), because of a drop our rate 
adjustment. 
Minor changes in the statistical methods 
section (see 9.4), in the Nugent score category 
definition (see 7.2) and minor typing error 
13-APR-2022 
2. 
 
 
3. 
 
 


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APPROVAL SIGNATURES 
This study protocol has been reviewed and approved by the undersigned persons. It is 
confirmed that the information and guidance given in this protocol complies with scientific 
principles, the guidance of Good Clinical Practice, the Declaration of Helsinki in the latest 
relevant version and the applicable legal and regulatory requirements. 
 
Sponsor Protocol Signatures 
 
 
 
 
 
Name, Position 
Signature 
Date 
Sponsor or 
Sponsor’s 
authorized 
representative 
Dr. Philipp Grob, PhD 
Director, Global Scientific & Technical 
Affairs 
Eggbuehlstrasse 28, 8050 Zurich, 
Switzerland 
+41 44-306 1381 
grob.philipp@medinova.ch 
 
 
Medical Expert 
Anahí Hurtado-Chong, MD PhD 
Senior Manager, International Medical 
Affairs  
Eggbuehlstrasse 28, CH-8050 Zurich, 
Switzerland 
+41 44-306 1396 
hurtado.anahi@medinova.ch 
 
 
Coordinating 
Investigator 
Poland 
Dr. hab. n. med. Grzegorz Raba 
Prywatny Gabinet Ginekologiczno 
Położniczy ul. Jana Pawła II 3 37-710 
Żurawica, Poland 
 
 
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Investigator Protocol Signature 
 
By my signature, I agree to conduct this study according to this protocol and to make no 
additions or changes without the consent of the Sponsor. In addition, we agree that the study 
will be carried out in accordance with Good Clinical Practice (GCP), with the Declaration of 
Helsinki and with the laws and regulations of the country in which the study takes place. 
 
 
 
 
Name, Position, Affiliation 
Signature 
Date 
Investigator 
 
 
 
 
Sub-
Investigator 
 
 
 
 


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STUDY PERSONNEL 
Sponsor 
 
Medinova AG 
Eggbühlstrasse 28 
CH-8050 Zurich / Switzerland 
Tel.: +41 1 306 13 71 
Fax: +41 1 306 13 75 
 
Coordinating Investigator 
 
Dr. hab. n. med. Grzegorz Raba  
Prywatny Gabinet Ginekologiczno Położniczy  
ul. Jana Pawła II 3, 
37-710 Żurawica, Poland 
(Only applicable for Poland) 
 
Study Location 
 
Poland, Czech Republic, Slovakia 
Project Management 
 
Bea Wenskowski (Project Manager) 
GCP Service International Ltd. & Co. KG 
Anne-Conway-Strasse 2, 28359 Bremen 
Germany 
Tel +49 421 89 67 66 30 
Fax +49 421 43 48 659 
bwenskowski@gcp-service.com 
 
Data Management 
 
Data Management Department 
GCP Service International Ltd. & Co. KG 
Anne-Conway-Strasse 2, 28359 Bremen 
Germany  
dm@gcp-service.com 
 
Statistician 
 
Simona Botta 
GCP Service International Ltd. & Co. KG 
Anne-Conway-Strasse 2, 28359 Bremen 
Germany 
sbotta@gcp-service.com 
 
 
Monitoring 
 
GCP-Service International Ltd. & Co. KG 
Anne-Conway-Strasse 2, 28359 Bremen 
Germany 
+49 421 89676617 
 
Pharmacovigilance 
 
Product Vigilance Department  
GCP-Service International Ltd. & Co.KG 
Anne-Conway-Str. 2, 28359 Bremen 
Germany 
+49 421 8967 6636 
+49 421 1669 7547 
pv@gcp-service.com 
 
Central laboratory 
 
Spranger Laboratories 
Lindeberghstr. 9-13 
85051 Ingolstadt 
Germany 
Phone 0049 841 97 39 -40 
Fax 0049 841 97 39 -40  
clinical.trials@ingolab.de 
 


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TABLE OF CONTENTS 
APPROVAL SIGNATURES ................................................................................................................................ 3 
STUDY PERSONNEL ......................................................................................................................................... 5 
TABLE OF CONTENTS ..................................................................................................................................... 6 
List of Tables ...................................................................................................................... 9 
List of Figures ................................................................................................................... 10 
ABBREVIATIONS ............................................................................................................................................. 11 
1 
SYNOPSIS AND FLOWCHART ........................................................................................ 13 
2 
SCIENTIFIC BACKGROUND AND RATIONALE ......................................................... 16 
2.1 
Scientific Background .................................................................................... 16 
 
Bacterial Vaginosis ........................................................................................ 16 
 
Fluomizin (dequalinium chloride) Vaginal Tablets ......................................... 17 
 
Metronidazole ............................................................................................... 19 
2.2 
Rationale and Objectives ............................................................................... 19 
 
Rationale for Performing the Trial ................................................................. 19 
 
Trial Objectives ............................................................................................. 20 
 
Risk Benefit Assessment ................................................................................ 20 
3 
STUDY OBJECTIVES AND ENDPOINTS ....................................................................... 22 
3.1 
Primary Objective .......................................................................................... 22 
3.2 
Secondary Objectives .................................................................................... 22 
3.3 
Endpoints ...................................................................................................... 22 
4 
INVESTIGATIONAL PLAN ................................................................................................ 23 
4.1 
Clinical Trial methodology ............................................................................ 23 
 
Investigational plan description ..................................................................... 23 
4.2 
Methodological bias management ................................................................. 25 
 
Randomization .............................................................................................. 25 
 
Blinding ......................................................................................................... 25 
 
Site selection ................................................................................................. 25 
 
Patient recruitment ........................................................................................ 25 
4.3 
Periods and duration of the trial ................................................................... 25 
4.4 
Source data ................................................................................................... 25 
4.5 
Implemented measures due to COVID-19 pandemic ..................................... 25 
5 
STUDY POPULATION........................................................................................................ 27 
5.1 
Number of participants ................................................................................. 27 
5.2 
Inclusion Criteria ........................................................................................... 27 
5.3 
Exclusion Criteria .......................................................................................... 27 
5.4 
Other Eligibility Criteria Considerations ........................................................ 28 
5.5 
Early Patient Withdrawal ................................................................................ 28 
 
Voluntary discontinuation by a subject .......................................................... 28 
 
Incorrectly enrolled or randomized subjects ................................................. 28 
 
Procedures for discontinuation...................................................................... 29 
 
Dropouts and withdrawals ............................................................................. 29 
5.6 
Early Termination of the Study ...................................................................... 29 
6 
INVESTIGATIONAL PRODUCT ....................................................................................... 30 
6.1 
Description of Investigational Product(s) ....................................................... 30 
6.2 
Dose Justification .......................................................................................... 30 
6.3 
Comparator Justification ............................................................................... 30 
6.4 
Randomization .............................................................................................. 30 
6.5 
Administration .............................................................................................. 31 
6.6 
Product Labelling .......................................................................................... 31 


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6.7 
Unblinding .................................................................................................... 32 
6.8 
Handling and Storage of Study Drugs ........................................................... 32 
7 
STUDY ASSESSMENTS AND PROCEDURES ............................................................... 34 
7.1 
Study Schedule .............................................................................................. 34 
 
Screening ...................................................................................................... 34 
 
Treatment ..................................................................................................... 34 
 
Follow-up / End of Study ............................................................................... 34 
7.2 
Efficacy Assessment ...................................................................................... 34 
 
Patient Characteristics ................................................................................... 34 
 
Primary Parameter ......................................................................................... 35 
 
Secondary Parameters ................................................................................... 35 
7.2.3.1 
Clinical cure rate at follow-up (Amsel criteria) ........................................................ 35 
7.2.3.2 
Bacteriological cure rate at C1 and C2 ................................................................... 36 
7.2.3.3 
Therapeutic cure at C1 and C2 .............................................................................. 36 
7.2.3.4 
Evaluation of individual Amsel criteria ................................................................... 36 
7.2.3.5 
The development of the Nugent Score ................................................................... 36 
7.2.3.6 
Subjective assessment of efficacy .......................................................................... 36 
7.3 
Safety Assessments ....................................................................................... 37 
 
Adverse events .............................................................................................. 38 
 
Subjective assessment of tolerability ............................................................. 38 
 
Vital Signs ..................................................................................................... 38 
7.4 
Additional Aspects ........................................................................................ 38 
 
Assessment of treatment compliance through patients’ diary ....................... 38 
 
Time to Resolution of symptoms ................................................................... 38 
7.5 
Study Restrictions ......................................................................................... 38 
 
Confinement ................................................................................................. 38 
 
Concomitant Medication................................................................................ 38 
8 
SAFETY REPORTING ......................................................................................................... 40 
8.1 
Definitions and categories of Adverse Events ................................................ 40 
 
Adverse Events (AEs) ..................................................................................... 40 
 
Adverse Drug Reactions (ADR) ....................................................................... 40 
 
Unexpected Adverse Drug Reactions (UADR) ................................................. 40 
 
Serious Adverse Event (SAE) / Serious Adverse Reaction (SAR) ....................... 41 
 
Adverse Events of Special Interest (AESI) ....................................................... 41 
 
Adverse Event Intensity/Severity .................................................................... 41 
 
Assessment of association with the investigational products ........................ 42 
8.2 
Documentation of Adverse Events and Serious Adverse Events ..................... 42 
8.3 
Reporting of SAEs, SUSARs and AESIS ............................................................ 42 
8.4 
Pregnancy ..................................................................................................... 43 
8.5 
Data Safety Monitoring Board ........................................................................ 44 
8.6 
Development Safety Update Report ............................................................... 44 
9 
STATISTICAL METHODS ................................................................................................. 45 
9.1 
Determination of Sample Size ....................................................................... 45 
9.2 
Subject Disposition ....................................................................................... 46 
9.3 
Analysis Populations ..................................................................................... 46 
 
Intention To Treat (ITT) ................................................................................. 46 
 
Per protocol population (PP) .......................................................................... 46 
 
Safety Evaluation Set (SES) ............................................................................. 47 
 
Subgroups ..................................................................................................... 47 
9.4 
Statistical Analysis ........................................................................................ 47 
 
Descriptive statistics ..................................................................................... 47 
 
Demographics and baseline .......................................................................... 47 
 
Medical history .............................................................................................. 47 
 
Main analysis ................................................................................................. 48 
9.4.3.1 
Additional sensitivity analysis ............................................................................... 49 
 
Secondary Efficacy Analysis ........................................................................... 50 
9.4.4.1 
Clinical cure rate at C2 .......................................................................................... 50 


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9.4.4.2 
Bacteriological and therapeutic cure rate ............................................................... 50 
9.4.4.3 
Evaluation of Nugent Score ................................................................................... 50 
9.4.4.4 
Evaluation of individual Amsel criteria ................................................................... 50 
9.4.4.5 
Subjective assessment of efficacy .......................................................................... 51 
 
Safety Analysis .............................................................................................. 51 
9.4.5.1 
Adverse Events and Adverse Drug Reactions.......................................................... 51 
9.4.5.2 
Subjective assessment of tolerability ..................................................................... 51 
9.4.5.3 
Vital signs ............................................................................................................ 52 
 
Additional Analysis ........................................................................................ 52 
9.4.1.1 
Treatment compliance .......................................................................................... 52 
9.4.1.2 
Clinical symptoms ................................................................................................ 52 
9.5 
Statistical and Analytical Issues ..................................................................... 52 
 
Adjustment for Covariates ............................................................................. 52 
 
Handling of dropouts and missing data ........................................................ 52 
9.5.2.1 
Dropout rate ......................................................................................................... 52 
9.5.2.2 
Missing data ......................................................................................................... 52 
 
Interim Analysis ............................................................................................ 52 
 
Multicenter Studies ........................................................................................ 53 
10 
DATA MANAGEMENT AND QUALITY CONTROL ................................................... 54 
10.1 
Data Collection and Storage .......................................................................... 54 
10.2 
Data Management ......................................................................................... 54 
10.3 
Data Quality Assurance ................................................................................. 55 
 
Documentation .............................................................................................. 55 
 
Monitoring .................................................................................................... 55 
 
Audit/Inspection ........................................................................................... 56 
 
Investigator Responsibilities .......................................................................... 56 
11 
ETHICAL PRINCIPALS ....................................................................................................... 57 
11.1 
Basic Principals and Ethical Considerations ................................................... 57 
11.2 
Ethical Review Committee and Regulatory Authority ..................................... 57 
11.3 
Protocol Modifications .................................................................................. 57 
11.4 
Subject Information and Informed Consent ................................................... 57 
11.5 
Participant Confidentiality ............................................................................. 58 
11.6 
Investigator Qualification .............................................................................. 58 
12 
DATA HANDLING AND RECORD KEEPING ............................................................... 58 
12.1 
Study Monitoring and Source Data Verification ............................................. 59 
 
Used Subject and Medication Logs ................................................................ 59 
 
Protocol Compliance ..................................................................................... 59 
12.2 
Data Management ......................................................................................... 60 
 
Case Report Form .......................................................................................... 60 
12.3 
Record Keeping ............................................................................................. 61 
13 
FINANCE AND INSURANCE ............................................................................................ 61 
13.1 
Compensation to Subjects ............................................................................ 61 
13.2 
Insurance and Indemnity ............................................................................... 61 
13.3 
Investigators’ Fee .......................................................................................... 61 
14 
PUBLICATION POLICY ..................................................................................................... 62 
14.1 
Reporting and Publication ............................................................................. 62 
 
Reporting ...................................................................................................... 62 
 
Publication .................................................................................................... 62 
15 
REFERENCES ........................................................................................................................ 63 
16 
APPENDICES ........................................................................................................................ 66 
16.1 
Study schedule .............................................................................................. 66 
 


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List of Tables 
Table 1: Identity of Investigational Product .......................................................................... 30 
Table 2: Amsel Criteria for diagnosis ................................................................................... 35 
Table 3: Cure rate definition ................................................................................................ 35 
 
 


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List of Figures 
Figure 1: Schematics of the booklet with treatments ........................................................... 32 
Figure 2: Actual booklet ...................................................................................................... 32 
 
 


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ABBREVIATIONS 
Abbreviations 
Description of Abbreviations 
AE 
Adverse Event 
BfArM 
Bundesministerium für Arzneimittel und Medizinprodukte in Germany 
BV 
Bacterial Vaginosis 
C1 
Control 1 (first control examination) 
C2 
Control 2 (second control examination) 
CDMS  
Clinical Data Management System  
CRO 
Clinical Research Organization 
CTA 
Clinical Trial Authorisation 
Cu 
Unscheduled Control 
DCF 
Data Clarification Form 
DMP 
Data Management Plan 
DVP 
Data Validation Plan 
E 
Entry of the study 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
HPV 
Human papillomavirus 
HSV 
Herpes simplex virus 
ICH 
International Conference of Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
ITT 
Institutional Review Board 
Intention To Treat 
IUD 
Intrauterine Device 
LBG 
Lactobacillary Grade 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Maturation index 
MIC 
Minimum inhibition concentration 
PCR 
Polymerase Chain Reaction 
PP 
Per Protocol Analysis Set 
ePRO 
Electronic patient reported outcome/ diary 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SES 
Safety Evaluation Set 
SOP 
Standard Operating Procedure 
STD 
Sexually Transmitted Diseases 
TSS 
Total Symptoms Score 


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1 
SYNOPSIS AND FLOWCHART 
Title of study:  
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 
Name of sponsor:  
Medinova AG 
 
Eggbühlstrasse 28 
CH-8050 Zurich / Switzerland 
Tel.: +41 1 306 13 22 
Fax: +41 1 306 2126 
Investigational products: 
10 mg Dequalinium Chloride (Fluomizin) 
Study phase: 
Phase IV 
Indication: 
Bacterial vaginosis 
Number of study centres: 
15 
Study duration:  
up to 30 days with treatment period of 7 days 
Study Design: 
Multicentre, active-controlled, randomised, double-dummy study with parallel-
group design 
Study Objectives: 
 
   Primary 
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. 
   Secondary 
• 
To assess the clinical, bacteriological, and therapeutic cure rate on short-
term and/or long-term follow-up 
• 
To evaluate subjective assessment of efficacy and tolerability  
• 
To further explore the safety profile of Fluomizin in this patient population 
Study Population: 
236 
Eligibility criteria for 
 enrolment: 
1. 
Premenopausal woman ≥18 years 
2. 
Diagnosis of bacterial vaginosis (BV): (all 4 Amsel criteria positive, i.e. 1) 
greyish white thin discharge, 2) KOH test or ‘fishy’ smell, 3) microscopic 
presence of > 20% clue cells, 4) vaginal pH > 4.5) 
3. 
Signed Written Informed Consent to participate in this study. 
Efficacy Outcome 
Variables: 
Primary: Clinical cure rate at visit C1 (at 8 to 10 study days) based on three Amsel 
criteria (excluding vaginal pH > 4.5) 
Secondary:  
- 
Clinical cure rate at follow-up (at C2 = at 24 to 30 study days) 
- 
Bacteriological cure rate at C1 and C2  
- 
Therapeutic cure rate at C1 and C2  
- 
Evaluation of individual Amsel criteria at E, C1 and C2 
- 
The development of the Nugent Score within 3 categories, i.e. (1) 
cured, (2) intermediate, and (3) BV positive at E, C1 and C2 
- 
Subjective assessment of efficacy 
Safety Parameters: 
1. 
Adverse events (AEs) and serious adverse events (SAEs) 
2. 
Subjective assessment of tolerability 


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3. 
Vital signs 
Other Parameters: 
Treatment compliance 
- 
Treatment compliance shall be assessed based on the patient diary 
with regard to number doses taken and treatment duration. 
Resolution of symptoms 
- 
Based on patient diary the time until resolution of symptoms shall be 
analysed. 
Statistical methods: 
The differences in clinical cure rate between Fluomizin and Metronidazole will be 
analysed in a confirmatory manner using a one-sided Farrington-Manning test on a 
2.5% significance level with following hypothesis: 
 H0: ȧF – ȧM  ≤ -δ  
 H1: ȧF – ȧM ˃ -δ 
 
 
It is evaluated whether the observed difference is greater than the non-inferiority 
margin - δ. The test statistic is based on the asymptotic normality of the score 
statistic. 
Efficacy will be analysed based on the ITT and repeated as sensitivity analysis for 
the PP population. The Farrington-Manning test will provide a p-value for the 
outcome variable, on which the decision will be based.  
If non-inferiority can be shown, data can furthermore be tested for superiority of 
Fluomizin over the leading therapy option Metronidazole. The Farrington-
Manning test is also providing a confidence interval for this purpose, which will 
be specified with 0.95 (95%). The hypotheses tested for the evaluation of possible 
superiority are the following: 
H0: ȧF – ȧM  ≤ δ 
H1: ȧF – ȧM  ˃ δ 
If Fluomizin exceeds Metronidazole, and the null hypothesis can be rejected, then 
Fluomizin is considered superior to Metronidazole with respect to efficacy. 
There is no multiplicity problem to be considered since this analysis corresponds 
to a closed hierarchical test procedure.  
For primary and secondary endpoints, at least summary statistics will be provided 
in the following way: 
x 
Quantitative Parameters will be presented in terms of mean, standard 
deviation, median, Q1, Q3, extreme values, number of patients and 
missing data. 
x 
Qualitative parameters will be presented in terms of number and 
percentage of each modality as well as number of patients and missing 
data. 
A Statistical Analysis Plan (SAP) will be written by the study statistician, containing 
a more detailed explanation of methods used, as well as a list of the output that 
will be generated when the data is provided. The SAP will be finalized and 
approved prior to the interim analysis. 
Sample size: 
The minimum number n, of evaluable patients necessary for each treatment 
groups is determined by the following equation: 
݊ൌʹ൫ݖଵିఈ൅ݖଵିఉ൯
ଶȧெሺͳ െȧெሻ
ߜଶ
 
Assuming incidences of treatment successes for both groups of 0.8 (80%), a 
clinical relevant difference of 0.15 (15%), a power of 0.8 (80%) and a one-sided 


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type one error rate of 0.025 (2.5%), the minimum number of evaluable patients 
per treatment group is 112. Assuming a drop-out rate of 5 %, a total of 118 
patients per treatment group is planned.  
 
 
 
 
 


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2 
SCIENTIFIC BACKGROUND AND RATIONALE 
2.1 
Scientific Background 
 Bacterial Vaginosis  
Bacterial vaginosis (BV) is a synergistic polymicrobial syndrome characterized by depletion of 
Lactobacillus spp., especially those that produce hydrogen peroxide and lactic acid, and an 
intense increase in the quantity of commensally vaginal anaerobic bacteria to 100- to 1000-
fold above normal levels [Marrazzo, 2006]. BV is the most common vaginal disorder in 
reproductive-age women [Kenyon et al., 2013], causing about 20-40% of all vaginal infections 
[Sobel, 1997]. BV increases the risk of acquisition and transmission of sexually transmitted 
infections and is associated with pregnancy complications [Nasioudis et al., 2017]. 
BV is not called vaginitis because of the absence of inflammation - there are no toxic 
leucocytes, pain, itching, dyspareunia, redness of the vulva or vagina - only microbial shift to 
anaerobic pathogens [Donders, 2010]. It is still unknown whether the loss of lactobacilli 
precedes or follows the upheaval of flora [Srinivasan and Fredricks, 2008]. Although the 
composition of the bacteria in BV varies between individuals, Gardnerella, Atopobium, 
Mycoplasma, Prevotella, Bifidobacterium, Megasphaera, Leptotrichia, Sneathia, Dialister, and 
Clostridium species are found most frequently [Srinivasan et al., 2012]. The development of 
bacterial vaginosis results in the aforementioned quantitative and qualitative shift from 
normally occurring lactobacilli species: L. crispatus, L. gasseri, L. jensenii, and L. iners to a 
mixed flora dominated by anaerobic bacteria [Larsson and Forsum, 2005; Ravel et al., 2011]. 
Diagnostic criteria of BV established by Amsel have been proved remarkably simple and useful 
in clinical practice: a) a vaginal pH higher than 4.5; b) the presence of clue (vaginal epithelial) 
cells in the vaginal fluid; c) a thin, grey or white homogenous discharge; d) a positive KOH 
"whiff" test (the release of an amine [fishy] odour upon the addition of 10% potassium 
hydroxide to the vaginal fluid) [Amsel et al., 1983]. Typically, bacterial vaginosis is diagnosed 
if 3 of the 4 Amsel criteria are present. The presence of clue cells is the single most reliable 
predictor of BV [Eschenbach et al., 1988]. The four Amsel criteria are usually regarded as the 
gold standard for diagnosis and clinical cure of BV [Sweet, 2000].  
Bacterial vaginosis has been consistently associated with numerous adverse sequelae related 
to the upper genital tract, including pelvic inflammatory disease and post-surgical infection in 
the setting of invasive gynaecologic procedures. Pregnant women with bacterial vaginosis 
experience a high rate of preterm delivery and low-birth-weight infants [Marrazzo, 2006], 
seven studies (two case-control and five cohort studies) reporting this [Oleen-Burkey and 
Hillier, 1995]. 
Concerning the BV therapy, anti-infectives with activity against anaerobes are indicated, but 
routine treatment of sexual partners is usually not recommended [Mehta, 2012]. The mainstay 
recommended treatments are oral metronidazole or topical clindamycin, both with comparable 
80-90% efficacy [Livengood, 2009] However, three months after the end of therapy the 
recurrence rate is usually 30% or higher [Bradshaw, Tabrizi, et al., 2006]. There are several 
disadvantages associated with these two therapies [Mendling et al., 2016]: A significant 
proportion of patients do not achieve an adequate response, recurrence of BV is frequent, drug 
resistance may develop, and there is a risk of post-treatment candidosis.  
The Bacterial Vaginosis Working Group of the Centre for Disease Control and Prevention (CDC) 
recommends regimens for the treatment of bacterial vaginosis: metronidazole 500 mg orally 
twice a day x 7 days, or metronidazole gel 0,75%, one full applicator (5 g) intravaginally once 
a day x 5 days, or Clindamycin cream 2% one full applicator (5 g) intravaginally at bedtime x 
7 days (MMWR, 2002). The effectiveness of CDC recommended therapies at 3–4 weeks is about 
80%, the  recurrence rate within 1 month after therapy being as high as 20% [Joesoef et al., 
1999; Koumans and Kendrick, 2001].  


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Successful treatment of Bacterial vaginosis with both standard drugs metronidazole and 
clindamycin poses risks for developing vulvovaginal candidiasis. In one study, 8.5% of the 
patients treated with clindamycin vaginal cream developed a secondary candidiasis [Fischbach 
et al., 1993]. In another clinical study, 14.8% of the patients developed candidiasis after 
clindamycin vaginal cream and 12.5% after oral metronidazole [Ferris et al., 1995].  
Increasing resistance against metronidazole and clindamycin has been reported by several 
investigators [EJ et al., 1993; Goldstein et al., 2002; Austin et al., 2005; Nagaraja, 2008]. So 
far, true acquired antimicrobial resistance occurring in vaginal infections has not been 
observed as a major problem in clinical practice [Sobel, 2000, 2001]. Nevertheless, misuse of 
the over-the-counter (OTC) antimycotics, as well as widespread use of systemic oral azoles, 
could result in the spread of azole-resistant Candida albicans, and even more likely it could 
lead to an increase in non-albicans Candida species with intrinsic azole resistance [Sobel, 
2001; Ferris et al., 2002].  
Thus, despite the current knowledge of BV many questions regarding treatment remain 
unanswered - all current therapies have disadvantages and gaps [Donders et al., 2014]. The 
most important challenges are the need for new drugs with better cure rates, possibility to 
prevent recurrence and to avoid pregnancy complications. For this reason, other promising 
treatment approaches need to be evaluated. The purpose of the current study is to compare 
the efficacy and tolerability of such a treatment option, Fluomizin, with the current standard 
therapy. 
Although antibiotics are selective and effective antimicrobials, it is nevertheless still necessary 
and desirable to broaden the therapeutic possibilities [Mendling et al., 2016]. As alternative 
therapy, broad-spectrum antimicrobial agents, such as dequalinium chloride (DQC), are used 
to treat vaginal infections. Typical representatives are phenyl derivates (e.g. chlorhexidine, 
hexetidine), acids (e.g. salicylic acid), halogens (e.g. povidone-iodine), and quaternary 
ammonium compounds (e.g. dequalinium chloride). Less specific antimicrobial agents have 
the advantage that (1) the resistance of pathogenic microorganisms is not expected due to  
their multiple mechanisms of action, (2) they can also be used for mixed vaginal infections 
because of their broad antimicrobial spectrum, as well as (3) for pre- and post-operative 
prophylaxis [Mendling et al., 2016]. 
 Fluomizin (dequalinium chloride) Vaginal Tablets  
Fluomizin is available as vaginal tablets, containing 10 mg dequalinium chloride [1,1'-(decane-
1,10-diyl)bis(4-amino-2-methylquinolinium) dichloride], an antiseptic and anti-infective agent 
belonging to the class of quaternary ammonium compounds [D'Auria et al., 1989].  
Fluomizin is approved for the treatment of bacterial vaginosis in Switzerland and 23 countries 
of the European Union, including Czech Republic, Hungary, Slovak Republic and Romania. 
Fluomizin in its current formulation has been marketed since 1993.  
Dequalinium chloride, the drug substance of Fluomizin, has a wide range of antimicrobial 
activity encompassing Gram positive, Gram negative bacteria, protozoa and fungi. Its 
mechanism of action is directed toward the cytoplasmatic membrane where dequalinium 
chloride causes damage and consequently releases cellular components [D'Auria et al., 1989].  
As for other surface-active compounds, the primary mode of action of dequalinium chloride is 
the enhancement of cell permeability and the subsequent loss of enzymatic activity, causing 
cell death [Mendling et al., 2016]. The bactericidal and fungicidal effect of dequalinium 
chloride has been demonstrated to occur within 30 to 60 minutes [D'Auria et al., 1989]. Della 
Casa and colleagues demonstrated the in vitro antimicrobial activity of dequalinium chloride 
against different pathogens that are relevant for vaginal infections, including anaerobic 
bacteria (Gardnerella vaginalis, Bacteroides spp., Peptostreptococcus spp., etc.), aerobic 
bacteria (staphylococci, streptococci, Escherichia coli, etc.), Candida species (C. albicans, C. 
glabrata, etc.) and Trichomonas vaginalis [Della Casa et al., 2002]. The antimicrobial activity 


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of dequalinium chloride against Candida spp. is comparable with clotrimazole and ciclopiroxol 
amine [Della Casa et al., 2002]. A recent in vitro study has also demonstrated a high 
susceptibility of Atopobium vaginae to dequalinium chloride and confirmed that dequalinium 
chloride has bactericidal activity [Lopes dos Santos Santiago et al., 2012]. No development of 
resistance of micro-organisms to dequalinium chloride has been reported in laboratory studies 
or clinical trials. Resistance of pathogens is unlikely due to the multiple modes of action of 
dequalinium chloride.  
In fact, multidrug resistance to single quaternary cationic anti-infectives is associated rather 
with hypersensitivity to compounds containing two quaternary cations, including dequalinium 
chloride [Turner et al., 1997].  
In a recently published multicentre, controlled study, Weissenbacher and colleagues compared 
the efficacy of dequalinium chloride 10 mg vaginal tablets (Fluomizin) once daily for 6 days to 
clindamycin vaginal cream 2% for 7 days in the treatment of BV [Weissenbacher et al., 2012]. 
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. At week 4, the overall clinical 
cure rates observed were 79.5% with 10 mg dequalinium chloride and 77.6% with clindamycin, 
demonstrating that the efficacy of dequalinium chloride was as good as clindamycin 
(statistically significant), also after a long-term follow-up. The number of women with positive 
cultures of Candida spp. (‘colonisation’) at week 4 was slightly higher in the clindamycin group 
(14.6%) than in the dequalinium chloride group (9.3%); however, due to small figures the data 
was statistically not significant. Consistent with these results, symptomatic vulvovaginal 
candidosis at second follow-up was half as common with dequalinium chloride (2.7%) than 
with clindamycin (5.8%). No serious adverse drug reactions (ADRs) were observed.  
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 [Mendling et al., 2016]. 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) [Hugo and Frier, 1969]. 
An in vivo anti-infective effect is generally obtained if the concentration of the active substance 
at the site of action is 2 to 4 times higher than the MIC for 20 minutes up to 2 hours [Della 
Casa et al., 2002].  
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 [Mendling et al., 2016]. 
Within clinical studies, different vaginal dequalinium chloride preparations have been used to 
treat more than 3000 women with various vaginal infections [Mendling et al., 2016]. The 
overall share of ADRs was with 2.4 % very low, showing excellent local tolerance of vaginally 
administered dequalinium chloride.  
A total of 181 pregnant women have been intentionally treated with vaginal dequalinium 
chloride in four clinical studies, and no adverse effects on pregnancy or on the health of the 
foetus/new-born child (based on pH, Apgar scale, and follow up until 1 year) have been 
observed [Mendling et al., 2016].  
In conclusion, 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.  
 
 


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 Metronidazole 
Metronidazole [1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole] is a nitroimidazole antiinfective 
that has been used in clinical practice for over 25 years [Freeman et al., 1997]. Its original 
indication was the treatment of Trichomonas vaginalis-infections, but over the years it has 
been discovered to be useful in treatment of anaerobic infections, especially (BV). 
Metronidazole is available for oral or vaginal treatment. The best-known brand is Flagyl, but 
many generics are marketed as well. Metronidazole could be used orally 500 mg twice daily 
for 5 or 7 days or as a 2g in a single dose (”one shot”);  applied intravaginally as 0.75% vaginal 
gel once to twice daily for 5 days; or as a vaginal ovula 500 mg once daily for 10 days. 
Metronidazole (5-nitroimidazole derivative) is an antiprotozoal and an antibacterial agent with 
both antibacterial and antitrichomonal activity. 
If absorbed systemically (oral use) metronidazole is metabolized in the liver. The half-life of 
metronidazole is 6-11 hours. Major metabolites of metronidazole are excreted in urine.  
Main indications in gynaecology are: (1) (BV) due to anaerobic bacteria and Gardnerella 
vaginalis, and (2) Trichomonas vaginitis due to Trichomonas vaginalis.  
In head to head trials, metronidazole and clindamycin (both so-called “gold standard” 
treatments recommended by CDC and other guidelines) have equal efficacy with cure rates of 
60-90% [Larsson and Forsum, 2005; Bradshaw, Morton, et al., 2006], as shown after 1 week 
and after 1 month. Furthermore, no difference in treatment failures was seen after 1 week or 
1 month when oral versus local applications were compared. Resistance has been described. 
Metronidazole is generally 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 10% of the patients [Donders, 2010]. In combination with alcohol it is known 
to induce vomiting, heartburn, stomach pains, i.e. its typical (disulfiram) effect. It is not known 
whether such general side effects also ensue when used vaginally. 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. 
During systemic application many adverse effects have been reported [Donders, 2010] 
(gastrointestinal, candidosis haematological, immunological, psychiatric, neuropathies, 
gastrointestinal, liver, kidney, eye watering). Patients with chronic diseases and thus already 
using other drugs (Alcohol, Warfarin, Disulfiram, Phenobarbital, Cimetidine, Lithium, 
Ciclosporin, 5-FU, Busulfan) has limited use of metronidazole due to interactions. Vaginal 
application is not compatible with contraceptive latex products. 
Metronidazole is contraindicated in a first trimester (pregnancy category B) and breastfeeding 
is not possible since metronidazole appears in milk. 
In general, metronidazole has a good efficacy profile against all relevant BV associated 
pathogens [Freeman et al., 1997]. 
 
2.2 
Rationale and Objectives 
 Rationale for Performing the Trial 
According to the US Food and Drug Administration (FDA) guidelines, clinical cure is 
recommended as primary efficacy endpoint as follows: resolution of the abnormal discharge, 


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a negative KOH "whiff" test, and the presence of the clue cells at less than 20 percent of the 
total epithelial cells on microscopic examination of the saline wet mount. (Guidance for 
industry: Bacterial vaginosis; Developing Antimicrobial Drugs for treatment, 2019, 
www.fda.gov).  
Since the effectiveness of the current recommended therapies at 3–4 weeks is about 60 -80% 
depending on product and study design and the BV  recurrence rate within 1 month after 
therapy varies between 9-57% [Arredondo et al., 1992; Koumans and Kendrick, 2001; Larsson 
and Forsum, 2005], new approaches to BV therapy are required. Moreover, successful therapy 
of bacterial vaginosis with both standard drugs metronidazole and clindamycin poses risks for 
developing vulvovaginal candidosis. 
Metronidazole is the leading therapy option used in treatment of BV, and the oral method is 
more common than the vaginal. The comparison against metronidazole and demonstration of 
cure rates based on Nugent score should be demonstrated.  
Vaginal dequalinium chloride has been shown to have equal clinical efficacy as clindamycin in 
the treatment of BV and to be well-tolerated with negligible systemic effects [Weissenbacher 
et al., 2012]. It has the major advantage that its broad antimicrobial activity makes it 
appropriate for the treatment of mixed vaginal infections and in case of an uncertain 
diagnosis. Moreover, resistance of pathogens is unlikely due to its multiple modes of action, 
and vaginal dequalinium chloride also provides a reduced risk for post-treatment vaginal 
infections of different aetiology that is quite frequent after specific antibacterial or antimycotic 
treatment.  
The test drug is a broad-acting anti-infective agent which also exhibits good efficacy against 
different Candida species with no known resistances so far. Thus, the current study 
investigates the efficacy and tolerability of Fluomizin, compared to the current standard 
therapy, and evaluates whether patients benefit from the test drug and have reduced rate of 
secondary candidosis in comparison to metronidazole oral therapy.   
 Trial Objectives 
The general aim of this study is to evaluate whether vaginal tablets containing 10 mg 
dequalinium chloride (Fluomizin) are comparable in clinical efficacy to orally 2x500mg/day for 
7 days metronidazole in patients suffering from bacterial vaginosis. 
 Risk Benefit Assessment 
The efficacy and safety of treatment with Fluomizin has already been substantiated in clinical 
studies, and its safety has been proven in these clinical studies as well as from more following 
10 years of post-marketing experience. The mode of action of dequalinium chloride bears a 
clinical advantage of therapeutic activity because the development of resistance to 
dequalinium chloride has not been reported. The safety profile of Fluomizin is very favourable; 
mainly local adverse drug reactions with a low incidence have been observed. 
Metronidazole 500mg tablets is one of the internationally acknowledged standard therapies 
for bacterial vaginosis and is approved in all participating countries for the treatment of 
bacterial vaginosis.  
Metronidazole 500mg once daily orally for 7 days represents a standardised regimen in the 
therapy of bacterial vaginosis which is indicated in the approved Summary of Product 
Characteristics in the participating countries. Since only severe cases of bacterial vaginosis 
(based on Amsel criteria) will be enrolled in the study, the treatment period of 7 days has been 
selected over the shorter one ensuring the best clinical efficacy, and thus is justified. 


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Current treatment of BV with both standard drugs metronidazole and clindamycin has the 
following disadvantages: In clinical studies, recurrence rates – 1 month after therapy – have 
been observed in the range of 10% to 50%; subsequent development of vulvovaginal 
candidiasis has been observed in 10% to 25% of the treated patients. 
These observations demonstrate the need for efficient alternatives. Fluomizin with its broad 
antimicrobial activity could reduce the risk of development of vulvovaginal candidosis, 
probably some recurrences, and especially drug resistances. 
If the results of this study are as good as expected and efficient, as demonstrated in previous 
clinical comparative study with Fluomizin and clindamycin [Weissenbacher et al., 2012], the 
alternative therapy will be strongly supported, from which future patients will benefit,  as the 
risk for development of vulvovaginal candidosis and resistances is reduced. 
 
 
 


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3 
STUDY OBJECTIVES AND ENDPOINTS 
The general aim of this study is to evaluate whether vaginal tablets containing 10 mg 
dequalinium chloride (Fluomizin) are comparable in clinical efficacy to orally 2x500mg/day for 
7 days metronidazole in patients suffering from bacterial vaginosis. 
3.1 
Primary Objective 
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. 
3.2 
Secondary Objectives 
 
To assess the clinical, bacteriological, and therapeutic cure rate on short-term and/or long-
term follow-up 
 
To evaluate subjective assessment of efficacy and tolerability  
 
To further explore the safety profile of Fluomizin in this patient population 
3.3 
Endpoints 
The primary efficacy variable is the clinical cure rate at C1 (8 to 10 days after randomization) 
defined as all Amsel criteria (greyish white thin discharge; KOH test or ‘fishy’ smell; presence 
of > 20% clue cells; vaginal pH > 4.5) are negative excluding the pH.  
 
The secondary endpoints are: 
1. Clinical cure rate at follow-up (at C2 = at 24 to 30 days after randomization) 
2. Bacteriological cure rate at C1 and C2  
3. Therapeutic cure rate at C1 and C2  
4. Individual Amsel criteria at C1 and C2 
5. The development of the Nugent Score within 3 categories, i.e. (1) cured, (2) 
intermediate, and (3) BV positive  
6. Subjective assessment of efficacy 
7. Incidence of adverse events 
8. Subjective assessment of tolerability 
 
 


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4 
INVESTIGATIONAL PLAN 
4.1 
Clinical Trial methodology  
The effectiveness of the current recommended therapies at 3–4 weeks is about 60 - 80%, and 
the recurrence rate of BV within 1 month after therapy varies between 9 - 57% with both 
numbers depend mainly on study design [Arredondo et al., 1992; Koumans and Kendrick, 
2001; Larsson and Forsum, 2005; Bohbot et al., 2010]. The present study is a phase IV study 
in which the efficacy and safety of Fluomizin in bacterial vaginosis (BV) will be assessed in 
comparison to one of. recommended standard therapies. 
 Investigational plan description  
This is an international, multi-centre, active-controlled, randomized, double-dummy, phase IV 
study with parallel group design in outpatients suffering from bacterial vaginosis. 
Study participants will be recruited from the group of patients consulting a gynaecologist due 
to the study-specific indication.  
The patients will first be asked by the investigators for a general interest to participate in a 
clinical trial. If they agree, the Informed Consent procedures described in section 11.4 will be 
followed and afterwards, the screening visit procedures will be performed. 
 
Screening visit (E) 
1. Obtaining patient written Informed Consent before any study specific procedures are 
performed 
2. Diagnosis of BV according to 4 Amsel criteria  
3. Sampling of vaginal secretion for bacteriological status for Nugent score 
4. Assessing clinical signs & symptoms 
5. Urine pregnancy test  
6. Reviewing exclusion criteria 
7. Documenting demographic data 
8. Recording medical history 
9. Measuring vital signs 
10. Documenting concomitant diseases and concomitant medication (anamnesis) 
11. Creating new subject entry in electronic case report form (eCRF) and randomization of 
subject. 
12. Dispensing study medication according to kit number provided, and instructing the 
patient on how to use it 
13. Instructing the patient to keep the packaging of the used/unused study medication 
and to return it at the next visit 
14. Providing link to the online diary/questionnaire and instructing the patient on the use 
of it 
15. Scheduling the next visit within 8 to 10 days after screening/entry visit 
 
C1 - First Control Examination (8 to 10 days after Entry Visit):  
Patients will visit the investigator site and then following procedures will be done: 
1. Checking the results of the laboratory tests for Nugent score  
2. Evaluating the BV clinical status based on Amsel criteria  
3. Sampling of vaginal secretion for bacteriological status for Nugent score 
4. Assessing clinical signs & symptoms 
5. Recording (any new) concomitant medication 
6. Checking patient diary & questionnaire (ViedocME) for compliance 


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7. Recording adverse events  
8. Assessing subjective efficacy by investigator  
9. Assessing subjective tolerability by investigator  
10. Scheduling control visit 2 (C2) 24 to 30 days after entry visit 
 
C2 - Second Control Visit (24 to 30 days after Entry Visit):  
1. Evaluating the BV clinical status based on Amsel criteria  
2. Sampling of vaginal secretion for bacteriological status for Nugent score 
3. Assessing clinical signs & symptoms 
4. Recording concomitant medication 
5. Urine pregnancy test  
6. Checking patient diary (ePRO) for compliance  
7. Recording adverse events 
8. Assessing subjective efficacy by investigator  
9. Assessing subjective tolerability by investigator  
 
Unscheduled Visits (Cu) 
Unscheduled visits may take place for a number of reasons, including and not limited to the 
following: 
• 
Patient contacts the investigator with complaints of a worsening of the symptoms 
• 
AE occurred 
• 
Patient may desire to withdraw 
 
In case the patient drops-out early from the study, the following procedures will be performed: 
1. Evaluating the BV clinical status based on Amsel criteria   
2. Sampling of vaginal secretion for bacteriological status for Nugent score 
3. Assessing clinical signs & symptoms 
4. Recording concomitant medication 
5. Checking patient diary (ePRO) for compliance  
6. Recording adverse events  
7. Assessing subjective efficacy by investigator  
8. Assessing subjective tolerability by investigator  
 
 


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4.2 
Methodological bias management  
 Randomization  
At the entry visit all eligible patients will receive either Fluomizin® (investigational product) 
with placebo or comparator with placebo based on double-dummy design. 
The medication is numbered and used consecutively. If a patient discontinues the study, the 
subject number will not be reused, and the patient will not be allowed to re-enter the study. 
The study medication will be dispensed at entry by the physician according to the allocated 
study medication after randomization. 
 Blinding  
As this is a double-blind double dummy study each subject will receive identical medication 
kit containing both vaginal and peroral medication from which one will be placebo and the 
second active substance. There are no laboratory or clinical assessments or specific AEs that 
could unblind the subject. 
 Site selection  
Study will be run at approximately 15 sites in 3 countries. Only sites equipped for and skilled 
in microscopic examination of native vaginal smear will be included in the study. 
 Patient recruitment  
There will be a competitive patient recruitment.   
4.3 
Periods and duration of the trial  
The duration of the study for participating subjects is up to 30 days with a treatment period 
of 7 days.  
4.4 
Source data  
Source data are all the information in original records and certified copies of original records 
of clinical findings, observations, or other activities in the study, which are necessary for the 
reconstruction and evaluation of the study. The investigator will permit trial-related 
monitoring, audit(s), IEC review(s) and regulatory inspection(s), providing direct access to 
source data/records. 
4.5 
Implemented measures due to COVID-19 pandemic 
Due to the ongoing pandemic of COVID-19, measures will be implemented to ensure the safety 
and well-being of the subjects. These will be chosen and implemented in accordance with the 
local regulations and in alignment with the most current version of EMA’s Guidance on the 
management of clinical trials during the COVID-19 pandemic, and recommendations by 
national competent authorities. Sponsor will monitor the situation closely and continuously 
and adjust these measures if necessary and communicate these changes to the respective 
investigators to make sure they will follow these measures and precautions. 
Bare minimum of precautions implemented at study sites should be as follows: 
x 
Providing hand-sanitizers at the entrance 


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x 
Inquiry regarding subjects’ health status and potential COVID-19 symptoms 
x 
Maintaining safe distance from others 
x 
Both subjects and site staff should always wear face masks at the study site when 
possible 
x 
Number of subjects and patients present at the study site should be maintained with 
respect to the safe distance between individuals and subjects should be warned not to 
bring family or friends to the appointment 
This is not an exhaustive list and study sites may have different practical solutions for 
implementation of these precautions. Nevertheless, study sites should adhere to the local 
regulations and the current knowledge to prevent or minimize risk of SARS-COV-2 
transmission.  
 
 
 


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5 
STUDY POPULATION 
5.1 
Number of participants 
236 subjects will be enrolled in approximately 15 sites. 
5.2 
Inclusion Criteria 
To be eligible for the study, subjects must fulfil the following criteria:  
1. Premenopausal woman ≥18 years 
2. Diagnosis of bacterial vaginosis (all 4 Amsel criteria positive, i.e. 1) greyish white thin 
discharge, 2) KOH test or ‘fishy’ smell, 3) microscopic presence of > 20% clue cells, 4) 
vaginal pH > 4.5) 
3. Signed Written Informed Consent to participate in this study 
 
5.3 
Exclusion Criteria 
The following excludes the patient from the study: 
1. Pregnancy and/or lactation based on urine Pregnancy test (women with 
childbearing potential should use any contraception excluding vaginal methods 
like vaginal ring, etc.) 
2. Uterine bleeding (including menstruation) or vaginal bleeding of unknown origin 
3. Ulcerations/erosions of vaginal mucosa or cervix uteri 
4. Patients with clinical symptoms and findings of Candida vulvovaginitis and/or 
Aerobic vaginitis 
5. Clinically manifest or suspicion of STIs (Neisseria gonorrhoeae, Chlamydia 
trachomatis, or Trichomonas vaginalis) based on signs, symptoms, and anamnesis 
6. Use of any antimicrobial treatment (local or systemic) 14 days before entry the 
study  
7. Use of any vaginal medication or vaginal douching 7 days before entry the study  
8. Unwillingness to refrain from alcohol consumption during treatment, and 48 hours 
after treatment  
9. Severe systemic diseases (HIV, cancer, tuberculosis, autoimmune diseases, 
diabetes mellitus, severe psychiatric conditions, etc.), including diseases treated 
with immunosuppressive therapies, systemic corticosteroids, or warfarin  
10. Known or suspected hypersensitivity to one of the study medications, inclusive of 
their excipients 
11. Inability to follow the procedures of the study, e.g. due to language problems, 
psychological disorders, dementia, etc. of the participant (including inability to fill-
in electronic patient diary) 
12. Participation of patient in another investigational drug study concomitantly or 
within 30 days prior to entry in the study 
13. Patient is relative of, or staff directly reporting to, the investigator 
 
 
 


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5.4 
Other Eligibility Criteria Considerations 
NA 
5.5 
Early Patient Withdrawal 
In accordance with the current revision of the Declaration of Helsinki and other applicable 
regulations, a patient has the right to withdraw from the study at any time and for any reason 
without prejudice to his or her future medical care from the physician or the institution. 
Reasons for removal of the patient from investigational product or observation might include: 
• 
Serious Adverse Events (SAEs) 
• 
Intolerable side effects (Adverse Drug Reactions) 
• 
The patient does not adhere to study rules and procedures 
• 
Worsening of the initial findings  
• 
At the request of the patient (withdrawal of consent) 
• 
In the investigator’s opinion it is in the patient’s best interest to terminate participation  
• 
Lost to follow-up 
When a patient decides to withdraw from the study, all efforts will be made to complete and 
report the observations as thoroughly as possible. If possible, an examination scheduled for 
early dropouts at the time of the patient's withdrawal will be performed. The reason for 
discontinuation of therapy will be recorded in any case in the eCRF.  
 Voluntary discontinuation by a subject 
Subjects are free to discontinue their participation in the study at any time without giving any 
reason, and without prejudice to further treatment. Subjects who discontinue their 
participation in the study should always be asked about the reason(s) for their discontinuation 
and about the presence of any adverse events. If possible, they should be seen and assessed 
by the investigator(s). Adverse events should be followed up and any diary cards and study 
medication should be returned. 
 Incorrectly enrolled or randomized subjects 
Incorrectly enrolled or randomized subjects will continue to receive study treatment and 
assessments if, in the opinion of the investigator and/or study team, this is not considered to 
involve any risk or discomfort for the subject. Otherwise, those subjects will be discontinued 
from further study treatment and assessments. 
 
 


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 Procedures for discontinuation 
The reason for discontinuation and the date of discontinuation from the study must be 
documented on the eCRF provided. The effect of discontinuation will be considered in the 
analysis to minimize potential bias. For all discontinuations, the assessments that are specified 
either at the end of the study period or for the early dropouts should be carried out wherever 
possible.  
 Dropouts and withdrawals 
Patients dropping out after inclusion into the clinical study will not be replaced. The subjects 
are not allowed to re-enter the study. 
5.6 
Early Termination of the Study 
The end of this study is defined as the date of the last visit of the last patient undergoing this 
study. 
The sponsor reserves the right to discontinue this study at a single site at any time for different 
reasons, such as: 
x 
Successful completion of the study at the centre 
x 
The required number of subjects for the study has been reached 
x 
Failure of the investigator to comply with the protocol, the sponsor’s procedures or GCP 
guidelines 
x 
Safety concerns 
x 
Inadequate recruitment of subjects by the investigator. 
 
The sponsor reserves the right to discontinue the whole study at any time. Reasons may 
include: 
x 
The discovery of any unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study. 
x 
Successful completion of the whole trial. 
 
 
 
 


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6 
INVESTIGATIONAL PRODUCT  
6.1 
Description of Investigational Product(s) 
Information about the dosage form, manufacturer and batch number for the investigational 
product is given in Table 1.  
 
Fluomizin and matching placebo: each 6 vaginal tablets 
Metronidazole and matching placebo: each 14 oral tablets 
 
Table 1: Identity of Investigational Product 
 
Investigational product 
Comparator 
Name 
Dequalinium chloride 
vaginal tablets 
(Fluomizin) 
Metronidazole tablets 
Dosage form and 
strength 
Blister containing 6 
vaginal tablets (10 mg) 
Blister containing 14 oral tablets 
(500mg) 
Manufacturer / Supplier 
Medinova AG, Switzerland 
/ IL-CSM 
IL-CSM 
Manufacturer of the 
clinical study medication  
Rottendorf Pharma 
IL-CSM 
6.2 
Dose Justification  
The dose and mode of administration of Fluomizin® - 1 vaginal tablet 10 mg dequalinium 
chloride daily, before going to sleep, for 6 days is based on the approved Summary of Product 
Characteristics in the participating countries. Additionally, placebo oral tablets should be 
applied by patient twice daily for 7 days based on double-dummy design (Group 1).  
Comparator 500mg Metronidazole oral tablets should be taken twice daily for 7 days. 
Additionally, placebo vaginal tablets should be applied by the patient for 6 days based on 
double-dummy design (Group 2). 
The total treatment duration in both groups is 7 days.  
6.3 
Comparator Justification 
Metronidazole is one of two leading and recommended therapy options used in treatment of 
BV, and the oral method for metronidazole is more common than vaginal. The comparability 
of Fluomizin against clindamycin the second recommended therapy has already demonstrated 
non-inferiority. Thus, the comparison to oral metronidazole is justified.  
6.4 
Randomization 
At the entry visit all eligible patients will receive either Fluomizin® (investigational product) 
with placebo or comparator with placebo based on double-dummy design. 
The medication is numbered and used consecutively. If the subject dropouts from the study, 
the subject number will not be reused, and the patient will not be allowed to re-enter the study. 
The study medication will be dispensed at entry by the physician according to the allocated 
study medication after randomization. 
 
 


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6.5 
Administration 
One tablet of the investigational product, i.e. Fluomizin vaginal tablets (10 mg Dequalinium 
chloride) will be administered intravaginally daily, before going to sleep, for 6 days. 
The comparator Metronidazole 500mg tablets will be administrated orally twice daily for 7 
days. 
Treatment has not to be initiated during menstruation and in 7 days before the expected 
period of menstrual bleeding. If unexpected significant vaginal bleeding occurs, the vaginal 
treatment must be interrupted and resumed afterwards, while the oral treatment continues 
without interruption. Patients must return all partially used and unused medication, as well as 
empty containers to the investigator at the end of therapy. Treatment compliance will be 
assessed by the investigator by asking the patients about administrating the study medication 
as prescribed and recording the drug accountability, by reviewing diary entries and by 
calculating compliance of the investigational product. 
6.6 
Product Labelling  
The study medication will be supplied in wallets: containing 6 vaginal tablets for patients 
allocated to Fluomizin and 14 oral tablets Metronidazole Placebo and vice versa. Schematics 
are depicted in Figure 1, actual photos then in Figure 2. Placebo vaginal and oral tablets will 
be provided based on double-dummy design requirements. 
The labels will contain at least the following information: route of administration, number of 
doses per day, study code, subject number, batch no., expiry date, as well as the following 
instructions for use: for clinical study use only, keep out of the reach of children, store at room 
temperature and not above 30°C, return at the next visit all partially used / unused study 
medication. The labelling can be adapted according to national regulations. 
Dosage adjustments during the study are not planned. 


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6.7 
Unblinding 
Breaking of the blinding of individual subjects is only permitted in case of a serious or 
unexpected adverse event or other medical event, when knowledge of the type of 
investigational drug given is required for therapeutic decisions for this event. 
6.8 
Handling and Storage of Study Drugs 
Investigational products and placebo tablets must be kept in a secure place under appropriate 
storage conditions. All study drugs will be stored at room temperature and not above 30°C in 
their original containers, until dispensed to subjects. Study medication must not be frozen. 
A drug dispensing log will be kept current by the investigator, detailing the dates and 
quantities of investigational medicinal product dispensed to each subject. The inventory will 
be available to the monitor to verify drug accountability during the study. Any unused reusable 
Figure 1: Schematics of the booklet with treatments 
Figure 2: Actual booklet 


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investigational medicinal product, either not dispensed or returned by the subject, including 
empty containers will be accounted for and returned to the sponsor. 
When required/allowed by local policies, unused supplies may be destroyed at the study 
centre. The investigator will ensure that such disposition does not expose subjects to risks 
from the investigational medicinal product. The investigator will maintain records of any such 
alternative disposition to permit an accurate drug accountability. Destruction of any unused 
medication must only be performed after the final drug accountability by the monitor has been 
done and the concerned medication has been marked for destruction. Documentation of 
destruction (which IMP, batch numbers, date of destruction etc) must be provided and filed.  
 
 
 


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7 
STUDY ASSESSMENTS AND PROCEDURES  
7.1 
Study Schedule 
 Screening 
Screening is based on the diagnostic criteria of BV: a) a vaginal pH higher than 4.5; b) the 
presence of clue (vaginal epithelial) cells in the vaginal fluid; c) a thin, grey or white 
homogenous discharge, d) a positive KOH "whiff" test (the release of an amine [fishy] odour 
upon the addition of 10% potassium hydroxide to the vaginal fluid).  
 Treatment 
The treatment duration for both groups is 7 days. 
One tablet of the investigational product, i.e. Fluomizin vaginal tablets (10 mg Dequalinium 
chloride) or matching placebo will be administrated intravaginally daily, before going to sleep, 
for 6 days. The comparator Metronidazole 500mg tablets or matching placebo will be 
administrated orally twice daily for 7 days.  
 Follow-up / End of Study 
After the patients have left the study, there will be no special treatment which differs from the 
normal treatment of the study indication. The investigator must decide if a continuation of 
medical treatment is necessary and how it will look like. For the follow-up of adverse events 
after patients have left the study see Section 8. 
7.2 
Efficacy Assessment 
Variables are assessed either clinically by the evaluation of symptoms or using vaginal 
secretion for microscopy and Nugent score.  
There will be a total of 3 vaginal samples: 
1. Vaginal sampling, and assessment of pH and Amine test 
2. Vaginal sampling for microscopy (native smear with 0.9% NaCl) 
3. Vaginal sampling for laboratory examination: Nugent score 
 
The sample of the vaginal secretion will be taken from the posterior vaginal vault with a plastic 
or wooden Ayre’s spatula (no cotton swabs) and spread onto glass slides.  
Sample 1:  
KOH 10% solution will be later added to one of the slides for “whiff” (Amine) test.  
Sample 2:  
One drop of 0.9% NaCl solution will be placed on the second slide for the 
immediate microscopic (phase contrast 400-fold magnification) evaluation 
(number of clue cells, presence of Candida, exclusion of Trichomonas vaginalis).  
Sample 3: 
This sample of the vaginal secretion is used for Gram staining in the central 
laboratory for Nugent scoring.  
 
 
 Patient Characteristics 
The following variables will be collected in the eCRF and the patient’s record:  
- 
Month and year of birth, race, date of last menstruation, number of births and/or 
pregnancies, body height 


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- 
Vital signs: weight, heart rate, systolic and diastolic blood pressure will be measured. 
Resting blood pressure and heart rate should be measured after 5 minutes sitting 
- 
Number of vaginal infections occurred during the last 12 months; number of bacterial 
vaginosis occurred during the last 2 years 
- 
Concomitant medication, concomitant diseases 
 
 Primary Parameter 
The primary efficacy variable is the clinical cure rate at visit C1 based on the Amsel criteria 
(vaginal pH > 4.5, presence of clue cells, KOH test, greyish white, malodorous discharge, as 
seen in Table 2), where clinical cure is defined as: 3 criteria negative, excluding pH (Table 3). 
Table 2: Amsel Criteria for diagnosis 
Greyish white, thin, malodorous discharge 
yes 
    no 
 
Presence of clue cells: > 20% of the total epithelial cells on 
microscopic examination of the saline wet mount 
yes 
    no 
 
A fishy odour of the vaginal discharge with a drop of 10% KOH 
yes 
    no 
 
Vaginal pH > 4.5 
yes 
    no 
 
 
Table 3: Cure rate definition  
Greyish white, thin, malodorous discharge 
No 
Presence of clue cells: > 20% of the total epithelial cells on 
microscopic examination of the saline wet mount 
No 
A fishy odour of the vaginal discharge with a drop of 10% KOH 
No 
 
 
 Secondary Parameters 
The secondary efficacy parameters are: 
1. Clinical cure rate at follow-up (at C2 = at 24 to 30 study days) 
2. Bacteriological cure rate at C1 and C2  
3. Therapeutic cure rate at C1 and C2  
4. Evaluation of individual Amsel criteria at C1 and C2 
5. The development of the Nugent Score within 3 categories, i.e. (1) cured, (2) 
intermediate, and (3) BV positive  
6. Subjective assessment of efficacy 
7.2.3.1 Clinical cure rate at follow-up (Amsel criteria) 
The clinical cure rate based on the Amsel criteria (vaginal pH > 4.5, presence of clue cells, KOH 
test, greyish white, malodorous discharge), where clinical cure is defined as: 3 criteria 
negative, excluding pH. The cure rate will be assessed as secondary efficacy variable at visit 
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7.2.3.2 Bacteriological cure rate at C1 and C2 
The bacteriological status will be determined by the Nugent score. The Nugent score includes 
the evaluation of:  
x 
Gram positive bacteria (Lactobacillus), with classes from zero to four, where zero 
stands for more than 30 bacteria/field of view and four for no bacteria. 
x 
Gram negative or gram-labile bacteria (e.g. Gardnerella, Prevotella and Bacteroides), 
with classes from zero to four, where numbers increase with increasing bacteria 
numbers. 
x 
and gram-labile bacteria (Mobiluncus), with classes from zero to two, where numbers 
increase with increasing bacteria numbers. 
These single scores are then summed to the overall Nugent score, that ranges between 
zero and ten, where a score of 
x 
0-3 is a normal flora and indicates no bacterial vaginosis, 
x 
4-6 is intermediate flora and indicates that a bacterial vaginosis should be 
considered with regard to the clinical symptoms, 
x 
and from 7-10 is considered bacterial vaginosis 
Bacteriological cure is defined as Nugent score ≤ 3. 
7.2.3.3 Therapeutic cure at C1 and C2 
The therapeutic cure rate is defined as a combination of clinical and bacteriological cures, 
i.e. patient has to meet the criteria of both. 
7.2.3.4 Evaluation of individual Amsel criteria 
a) Clue cells 
The number of clue cells will be determined by phase contrast microscopy using a 400u 
magnification. The proportion of clue cells as compared to the total number of epithelial cells 
without adherent bacteria is reported semi-quantitatively. The presence of clue cells is 
considered positive if t 20% of the total epithelial cells of the wet mount are clue cells. 
b) KOH test for volatile amines 
A positive KOH test for volatile amines involves the presence of a fishy amine odour on mixture 
of secretions with 10% KOH (due to the volatilisation of the amine products of anaerobic 
bacterial metabolism). 
c) Vaginal pH 
The pH of the vaginal secretion will be measured using pH strips Merck, colour scale 4.0-7.0 
with a measurement interval of about 0.3. The pH should not be measured at the cervix, but 
at the lateral vaginal wall in the upper third of the vagina. 
d) Abnormal vaginal discharge 
The BV-specific discharge and the specific type of smell will be evaluated as present or 
absent. 
The development of the individual Amsel criteria will be analysed over time.  
7.2.3.5 The development of the Nugent Score 
The development of the 3 Nugent Score categories (1) Normal (score 0 - 3), (2) intermediate 
(score 4 - 6), and BV positive (score 7 - 10) will be analysed over time.  
7.2.3.6 Subjective assessment of efficacy 


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The subjective assessment of therapy efficacy will be subjectively assessed as the overall 
satisfaction with the treatment by both the investigators and the patients. At each control, the   
subjective assessment of efficacy will be rated using 4 categories: 
* 
very good 
* 
good 
* 
moderate 
* 
poor 
7.3 
Safety Assessments 
Safety assessments will consist of recording and monitoring of: 
1. Adverse events (AEs) and serious adverse events (SAEs) 
2. Subjective assessment of tolerability 
3. Vital signs 
 
 


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 Adverse events 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product, and which does not necessarily have a causal 
relationship with this treatment. 
AEs will be elicited by a standard non-leading question like "How did you feel since last visit?" 
All AEs encountered during the study will be recorded in the detail indicated in the CRF, 
regardless of their relationship to the investigational medicinal product as assessed by the 
investigator. 
See Chapter 8 Safety reporting for more details.  
 Subjective assessment of tolerability 
The subjective assessment of tolerability shall be performed by both the investigator and the 
patients.  
The subjective assessment of tolerability will be rated using 4 categories: 
* 
very good 
* 
good 
* 
moderate 
* 
poor 
 Vital Signs 
The following vital signs will be measured: Weight, heart rate, systolic and diastolic blood 
pressure. Resting blood pressure and heart rate should be measured after 5 minutes sitting. 
7.4 
Additional Aspects 
 Assessment of treatment compliance through patients’ diary 
Treatment compliance shall be assessed based on the patient diary with regard to number 
doses taken and treatment duration.  
 Time to Resolution of symptoms 
Based on patient diary the time until resolution of symptoms shall be analysed. 
7.5 
Study Restrictions 
The use of the following medications is not allowed: 
- 
Use of any antimicrobial treatment (local or systemic) during the study  
- 
Use of any vaginal medication or vaginal douching during the study  
- 
Immunosuppressive therapy during the study 
- 
Alcohol consumption during treatment, and 48 hours after the treatment 
 Confinement 
NA 
 Concomitant Medication 


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Subjects should receive medical treatment for their condition as per standard of care. 
Medication history and concomitant medications will be taken at the randomization and 
recorded on the eCRF. 
 
 
 


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8 
SAFETY REPORTING 
8.1 
Definitions and categories of Adverse Events 
 Adverse Events (AEs) 
An adverse event (AE) is any untoward medical occurrence (i.e. any unfavourable and 
unintended sign (including abnormal laboratory findings), symptom or disease) in a patient or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
A surgical procedure that was planned prior to the start of the study by any physician treating 
the subject should not be recorded as AE (however, the condition for which the surgery is 
required should be documented in the medical history section or may even be reported as an 
AE). 
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal e.g. physical examination findings, symptoms, diseases, or laboratory test 
results. 
- 
Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (e.g. seasonal allergy without acute complaints). 
- 
Conditions that started before signing of informed consent and for which symptoms 
or treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g. allergic pollinosis). 
- 
Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events. 
Overdose and its subsequent symptoms shall be documented as AE. 
The following events are not considered to be adverse events: 
- 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion). However, the disorders, which led to the procedures, are AEs, if they did 
not exist before or if they worsened during or after administration of the investigational 
medicinal product. 
- 
Pre-existing diseases or conditions, which do not worsen during or after administration 
of the investigational medicinal product. 
- 
The disease under study or signs and symptoms associated with the disease, unless 
more severe than expected for the subject’s condition according to the opinion of the 
investigator. 
 Adverse Drug Reactions (ADR) 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions. The phrase "responses to medicinal products" means that 
a causal relationship between a medicinal product and an adverse event is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out.  
 Unexpected Adverse Drug Reactions (UADR) 


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An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator's Brochure for an unapproved investigational medicinal 
product).  
 Serious Adverse Event (SAE) / Serious Adverse Reaction (SAR) 
Serious adverse event (SAE) or serious adverse drug reaction (SADR) is classified as any 
untoward medical occurrence that at any dose (including overdose) meets at least one the 
following criteria:  
- 
results in death  
- 
is life-threatening  
- 
requires inpatient hospitalization or prolongation of existing hospitalization  
- 
results in persistent or significant disability or incapacity  
- 
is a congenital anomaly or birth defect  
- 
is an important medical event (e.g. requires medical treatment to avoid one of the 
above-mentioned conditions)  
In this trial SAE reporting period will start with randomization and last until end of study.  
Medical and scientific judgment should be exercised in deciding whether a medically important 
event or an adverse event is serious in other situations. Important adverse events that are not 
immediately life-threatening or do not result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above, should also be considered serious. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or drug 
abuse. Laboratory abnormalities may only be classified as SAE if deemed clinically significant 
by the investigator. Suspected Unexpected Serious Adverse Reaction (SUSAR). 
 Adverse Events of Special Interest (AESI) 
Adverse events of special interest (AESI) are events that have by character a special meaning 
or importance for the particular drug. An AESI might have a serious or non-serious character. 
In this study the following is determined as an AESI: 
- 
Vulvovaginal candidosis 
 Adverse Event Intensity/Severity 
Severity of AEs will be assessed according to the following definitions: 
x 
Mild: sign or symptom of the AE is apparent but is easily tolerated by the subject. 
x 
Moderate: the AE interferes somewhat with the subject’s usual activities (disturbing). 
x 
Severe: the AE prevents the subject from working or performing his/her usual 
activities (unacceptable).  
Note: Severity is not seriousness. An AE may be severe but not serious, as in a severe 
headache, while an SAE may be mild, as in a mild myocardial infarct. 


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 Assessment of association with the investigational products 
Careful medical judgment should be exercised to determine if there is a causal relationship 
between an AE and the investigational product. The following guidance is provided:  
 
x 
Certain: A clinical event, including laboratory test abnormality, occurs in a plausible 
time relationship to drug administration, and which cannot be explained by concurrent 
disease or other drugs or chemicals. The response to withdrawal of the drug (de-
challenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, using a satisfactory re-challenge procedure if 
necessary.  
x 
Probable: A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to concurrent 
disease or other drugs or chemicals, and which follows a clinically reasonable response 
on withdrawal (de-challenge). Re-challenge information is not required to fulfil this 
definition.  
x 
Possible: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, but which could also be explained by 
concurrent disease or other drugs or chemicals. Information on drug withdrawal may 
be lacking or unclear.  
x 
Unlikely: A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship improbable, and 
in which other drugs, chemicals or underlying disease provide plausible explanations.  
x 
Unrelated: A clinical event, including laboratory test abnormalities, for which a causal 
association between the study drug and the event can be excluded. 
8.2 
Documentation of Adverse Events and Serious Adverse Events 
Adverse events and all information regarding SAEs, whether reported by the subject or 
observed by the investigator/study personnel, must be documented in the subject’s medical 
record, and recorded on the Adverse Event/Serious Adverse Event Forms in the eCRF. 
One of the aims of the study is to assess the safety and tolerability of the study drug. The 
investigator is responsible for recording and reporting AEs observed from randomization until 
end of study. 
Medical events occurring during the screening period (i.e. after obtaining the subject’s written 
consent, but before randomization) will not be recorded as AE but on the Medical History page 
in the eCRF, except those resulting from a protocol-mandated procedure, which should be 
reported on the Adverse Event/Serious Adverse Event Forms. 
All AEs and SAEs will be followed until resolution, until the condition stabilizes if irreversible, 
until the event is otherwise explained, or until the patient is lost to follow-up. Once resolved, 
the appropriate AE/SAE eCRF sections will be updated. The investigator will ensure that follow-
up includes any supplemental investigations as may be indicated to elucidate the nature 
and/or causality of the AE or SAE. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals. 
At any time after the end of study, if an investigator learns of an AE or SAE that can be 
reasonably related to study drug, he should promptly notify the sponsor. 
8.3 
Reporting of SAEs, SUSARs and AESIS  
All SAEs must be reported immediately to the pharmacovigilance department of the CRO GCP-
Service International Ltd. & Co. KG as soon as they become known to the investigator and not 
later than within 24 h of their knowledge of the occurrence of an SAE. 


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The SAE Report Form is included in the eCRF system and must be completed and submitted 
according to the instructions provided on the form. In case the CRF cannot be accessed and 
hence the SAE Report Form cannot be filled in within the eCRF system, a paper SAE Report 
Form is filed as back-up in the Investigator Site Folder (ISF) which should be used and sent via 
fax using the contact details below. The information on the form must be transferred to the 
electronic CRF when it is available again. 
CRO: GCP-Service International Ltd. & Co. KG 
Email: pv@gcp-service.com 
Phone +49-(0)421-8967 6636 
Fax +49-(0)421-1669 7547 
Expedited Reporting 
GCP-Service International Ltd. & Co. KG will report all AEs that are serious, unexpected, and 
with a reasonable possible causality to the IMP (Suspected Unexpected Serious Adverse Events, 
SUSARs) as judged by either the investigator or sponsor within the stipulated timelines. 
SAEs will be considered reportable, regardless of whether or not the IMP was used in 
accordance with the provisions in the protocol, Investigator’s Brochure, and labelling. 
In accordance with national regulations and GCP guidelines the sponsor or his representative 
should promptly notify all concerned investigators, institutions and the regulatory authorities 
of SUSARs and all findings that could affect adversely the safety of subjects, impact the 
conduct of the study or alter IEC/authority approval to continue the study. 
All available information relevant for the evaluation of the SAE must be reported by the 
investigator. Adverse events that are serious but expected (related and/or unrelated to the 
IMP) will be reported in accordance with local requirements. 
Timelines: 
Fatal or life-threatening SUSARs must be reported to local competent authorities of countries 
where the trial is conducted as soon as possible, but not later than 7 calendar days after 
becoming aware of the event, with a possible follow-up report within 8 additional calendar 
days. 
All other SUSARs must be submitted as soon as possible, but no later than 15 calendar days 
after becoming aware of the case. 
8.4 
Pregnancy 
To prevent pregnancies during the course of the study, patients are to be informed about 
highly effective contraception methods. Local barrier methods should be excluded. 
Patients will be instructed to notify the investigator in the case of pregnancy during the study. 
If a pregnancy is suspected during the study, the study medication must be immediately 
withheld until the result of a pregnancy test is available. If the pregnancy is confirmed, the use 
of study medication must be stopped by the patient and the patient must be withdrawn from 
the trial. The Pregnancy Form must be completed and the sponsor (representative of sponsor) 
must be informed by fax within 24 h after first knowledge of the pregnancy. 
A newly diagnosed pregnancy itself will not be considered as an AE but reported as such. 
Adverse Events related to pregnancy must be reported like any other AE. The mother and the 
fetus will be followed up at least until the final outcome (e.g. birth, induced or spontaneous 


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abortion etc.). In general, the follow-up will include the course, duration and the outcome of 
the pregnancy and the infant. In case of normal outcome, the infant will be followed up for 4-
6 weeks after the birth. 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (e.g. 
spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be 
documented], stillbirth, neonatal death or congenital abnormally), the investigator will report 
the event by completing a SAE form within 24 hours after becoming aware of the event. 
8.5 
Data Safety Monitoring Board 
NA 
8.6 
Development Safety Update Report 
Once a year or on demand, the sponsor will supply a report on the safety of trial subjects in 
accordance with the guidance ENTR/CT 3 with all relevant information during the reference 
period to the competent federal authority and the responsible ethics committee. 
The reference period for the annual report on the safety of trial subjects begins with the date 
that the trial is approved by the competent federal authority. This date is the reference date 
for the start of the year of the annual Development Safety Update Report (DSUR). The sponsor 
will supply the report once a year within 60 days after the annual reference date (data-lock 
point).  
 


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9 
STATISTICAL METHODS 
This section describes the main statistical and analytical aspects foreseen at the time of study 
planning. The main analysis of the primary endpoint will be performed according to the 
statistical methods described in this study protocol. A Statistical Analysis Plan (SAP) will 
additionally be written by the study statistician, containing more technical and detailed 
explanation of methods used, as well as additional information on the analysis of secondary 
criteria and a list of the output that will be generated. This SAP will be finalized and approved 
before the first analysis of study data for the interim analysis. 
Changes made to the envisaged analysis after the SAP is finalized and prior to the analysis 
as well as their reason(s) should be described in the SAP or, in case of important changes 
(e.g. changes affecting the main analysis of the primary endpoint) in amendments to the 
study protocol. If the actually performed analysis deviates from the SAP, changes, reasons 
and impact will be described in the clinical study report. 
The statistical analysis will be done using   SAS® Version 9.4 or higher. 
 
9.1 
Determination of Sample Size  
The sample size calculation for the trial is based on the proportions of clinical cure rate 
(greater than or equal to 80%, based on the Amsel criteria) 8 to 10 days after start of 
treatment as the primary endpoint.  
This clinical trial is designed to evaluate if Fluomizin is at least as efficacious as 
Metronidazole in terms of the clinical cure rate as a non-inferiority comparison.  
In this study, the alternative hypothesis H1 is that the clinical cure rate of Fluomizin, πF, differs 
from the clinical cure rate of Metronidazole, πM, by less than the clinically significant 
difference, δ (non-inferiority margin: 15%), or Fluomizin has higher cure rate compared to 
Metronidazole. The null hypothesis, H0, therefore is that Fluomizin is equal or worse than 
Metronidazole by the clinically significant difference, δ. 
Thus,  
H0: ȧF – ȧM  ≤ - δ  
H1: πF – ȧM ˃ - δ  
The minimum number n, of evaluable patients necessary for each treatment groups is 
determined by the following equation: 
݊ൌʹ൫ݖଵିఈ൅ݖଵିఉ൯
ଶȧெሺͳ െȧெሻ
ߜଶ
 
Assuming  
x 
ݖଵିఈ: The 1- ߙ quantile of the normal distribution, with α=2.5%, the type 1 error 
x 
ݖଵିఉ: The 1- ߚ  quantile of the normal distribution, with 1-β=80% the power 
x 
an incidence of successful treatment with Fluomizin according to previous studies  
[Weissenbacher et al., 2012]:  
ȧF : 80% (0.80), 


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x
an incidence of successful treatment with Metronidazole according to previous 
studies that found cure rates between 60-90% [Larsson and Forsum, 2005; Bradshaw, 
Morton, et al., 2006]: ȧM: 80% (0.80) 
x 
smallest clinically relevant differences in the responder rate in treatment of Fluomizin 
and Metronidazole (δ) of maximum 15% (0.15) are defined as clinically relevant to 
show non-inferiority of Fluomizin compared to Metronidazole, 
 
the minimum number of evaluable patients per treatment group is 112. Assuming a drop-
out rate of 5 %, a total of 118 patients per treatment group is planned. Since in this case the 
sample size is larger than 50 and the proportion is 0.8, this power calculation gives similar 
results as if binomial enumeration would be used. 
 
Screening failures and patients withdrawing prior to application of treatments will be 
replaced. 
 
The sample size was calculated by using nQuery from Statsols, Version 8.5.2.0. For more 
details regarding efficacy assumptions see sections 2.1.2 for Fluomizin and 2.1.3 for 
Metronidazole. 
 
9.2 
Subject Disposition 
The numbers and percentages of subjects will be summarized separately for the following 
subsets, overall and per site: 
- 
Screened 
- 
Screening failures 
- 
Randomized 
- 
Randomized and treated 
- 
ITT 
- 
PP 
- 
SES  
- 
Nugent score subgroup at baseline (score 0 – 3, score 4 – 6, score 7 - 10) 
- 
Subjects completing the study 
- 
Subjects terminating the study early 
 
Reasons for screening failures and early termination will additionally be tabulated. 
Demographics and baseline characteristics will be summarized by randomized groups for 
the ITT and PP populations and by the actual treatment group for the safety population. 
9.3 
Analysis Populations 
 Intention To Treat (ITT) 
In the intention to treat set all subjects having been randomized and treated will be included. 
This set will be used for the primary analysis 
For the analysis with the ITT population, subjects will be allocated to the treatment group 
they were randomized to, following the intention-to-treat principle. 
 Per protocol population (PP) 


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The Per Protocol set includes all subjects that have not experienced major protocol violations. 
This set of subjects is used for additional and supportive sensitivity analyses. 
Major protocol deviations are events that have direct impact on the primary endpoint. 
Possible examples of major protocol violations are: 
- 
Violations of inclusion or exclusion criteria 
- 
Use of any antimicrobial treatment (local or systemic) during the study  
- 
Use of any vaginal medication or vaginal douching during the study  
- 
Immunosuppressive therapy during the study 
- 
Alcohol consumption during treatment, and 48 hours after the treatment 
- 
Major time window violations 
 Safety Evaluation Set (SES) 
The SES includes all study subjects who have received Fluomizin or Metronidazole. For the 
analysis with the SES population, subjects will be allocated to the treatment group they 
actually received, rather than to that the one they were randomized to. This set will be used 
for the safety analysis. 
 Subgroups 
The Nugent score represents an important factor for the severity of the disease. Therefore, 
subgroups based on the Nugent score at baseline will be defined: 
- 
Normal: subjects with score 0 - 3 at baseline 
- 
Intermediate: subjects with score 4 – 6 at baseline 
- 
BV positive: subjects with score 7 – 10 at baseline 
9.4 
Statistical Analysis  
 Descriptive statistics 
Summary statistics will be provided at least in the following way: 
x 
Quantitative Parameters will be presented in terms of mean, standard deviation, 
median, Q1, Q3, extreme values, number of patients and missing data. 
x 
Qualitative parameters will be presented in terms of number and percentage of each 
modality as well as number of patients and missing data. 
If not specified otherwise, percentages will be based on the number of subjects with data 
available in the group of interest within the analysis set.  Percentages will not include missing 
data. If applicable, the number of missing items for the analysis will be given in a “missing” 
category. 
 Demographics and baseline 
Additionally to the at baseline taken variables for primary, secondary and safety analysis (see 
sections 0, 9.4.4 and 9.4.5), only the parameter age will be assessed. It will be presented in 
terms of mean, standard deviation, median, Q1, Q3, extreme values, number of patients and 
missing data.  
 Medical history 


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Absolute and relative frequency of medical history and concomitant diseases as well as past 
and current medication will be tabulated based on coded terms (MedDRA or WHO-CC, as 
applicable). Data will be analysed by system organ class (SOC) and preferred term (PT). Further 
details will be explained in the SAP. Primary Efficacy Analysis 
 Main analysis 
The main criterion of this trial is to investigate if Fluomizin has an equal or better clinical 
cure rate in treatment of bacterial vaginosis compared to Metronidazole after 8-10 days. The 
clinical cure rate is a binary response-variable, defined by the evaluation of the Amsel criteria. 
Further confirmatory analyses are not foreseen for this trial. 
In addition to the standard summary statistics (as described in section 9.4.1), the differences 
in clinical cure rate between Fluomizin and Metronidazole will be analysed in a confirmatory 
manner using a one-sided Farrington-Manning test [1990] on a 2.5% significance level with 
following hypothesis: 
H0: ȧF – ȧM  ≤ - δ 
H1: ȧF – ȧM > - δ 
where 
H0 = null hypothesis for the non-inferiority test of the primary endpoint 
H1 = alternative hypothesis for the non-inferiority test of the primary endpoint 
πM = clinical cure rate of Metronidazole 
πF = clinical cure rate of Fluomizin 
δ = smallest clinically significant difference between the two groups  
(non-inferiority margin: 15% or 0.15) 
 
With the Farrington and Manning [1990] Likelihood Score test, differences in proportions 
between two groups can be tested as following: 
 
୊୑ୈൌ
݌Ƹிെ݌ƸெെɁ
ට݌෤ெכ ሺͳ െ݌෤ெሻ
݊ெ
൅݌෤ிכ ሺͳ െ݌෤ிሻ
݊ி
 
where 
 
zFMD = the Farrington-Manning test statistic 
δ = smallest clinically significant difference between the two groups  
(non-inferiority margin: 15% or 0.15) 
nM = number of subjects in Metronidazole group 
nF = number of subjects in Fluomizin group 
݌Ƹெ = proportion of success rate in Metronidazole group 
݌Ƹி = proportion of success rate in Fluomizin group  
݌෤ெ =  maximum likelihood estimation of the probability of success in Metronidazole group 
݌෤ி = e maximum likelihood estimation of the probability of success in Fluomizin group
 
 
 
 
It is evaluated whether the observed difference is greater than the non-inferiority margin -δ. 
The test statistic is based on the asymptotic normality of the score statistic. 
Efficacy will be analysed based on the ITT population and repeated as sensitivity analysis for 
PP population. The ITT is selected as primary analysis set to conduct the analysis in a most 
realistic scenario. The treatment effect could be interpreted as the mean difference in the 
clinical cure rate of patients diagnosed by using the Amsel criteria. This reflects the practice 
most realistically, where the treatment decision is also based on the Amsel criteria. The 


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Farrington-Manning test will provide a p-value for the outcome variable, on which the 
decision will be based. Furthermore, the analysis will be made by Nugent score subgroups 
(see section 9.3.4). 
If non-inferiority can be shown, data can furthermore be tested for superiority of Fluomizin 
over the leading therapy option Metronidazole. The Farrington-Manning test is also providing 
a confidence interval for this purpose, which will be specified with 0.95 (95%). The 
hypotheses tested for the evaluation of possible superiority are the following: 
H0: ȧF – ȧM  ≤ δ 
H1: ȧF – ȧM ˃ δ 
where denotations are the same as explained for the non-inferiority hypothesis above. 
If the cure rate of Fluomizin exceeds Metronidazole by more than 15% (δ), and the null 
hypothesis can be rejected, then Fluomizin is considered superior to Metronidazole with 
respect to efficacy. 
There is no multiplicity problem to be considered since this analysis corresponds to a closed 
hierarchical test procedure.  
9.4.3.1 Additional sensitivity analysis 
1. Logistic regression model to consider the parameter time: 
Apart from the above-mentioned sensitivity analysis, additionally a logistic regression will 
be calculated for the ITT set to consider the large variance in time given by broader 
frames of visit schedules. The factor time will be included in the model by a time variable 
that includes the day on which the visit was performed (8-10). It will be furthermore 
evaluated, which other considerable variables have an influence on the observed events. 
Candidates for explanatory parameters included could be age, weight, treatment, and 
the continuous Variable of the Nugent score:  
Logit (Amsel criteria=1 | Xi=xi) = Intercept + xi1*Time + xi2*Age + xi3*Weight + xi4*Treatment + 
xi5*Nugent Score 
Odds ratios for the specified variables will be given, and a p-value provided. 
2. Logistic regression to measure effect of Nugent Score: 
To furthermore evaluate the effect of the Nugent score criteria on the outcome variable, 
a logistic regression will be calculated including the explaining parameters ‘Nugent 
score’ and ‘treatment’ only. Odds ratios for the specified variables will be given, and a p-
value provided. 
3. Tipping point analysis: 
Another sensitivity analysis addressing the missing values will be a tipping point analysis, 
which allows to evaluate the effect of missing data on the outcome. It can determine, for 
which success probability for the missing subjects in the Fluomizin group the conclusions 
regarding the primary variable remain stable. For this analysis it is assumed that missing 
values are missing not at random, and that there is a tipping point that reverses the study 
outcome. 
This analysis is conducted by the following steps: 
1. Missing values are multiply imputed into the dataset a defined number of times.  


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2. The imputed values for missing observations in the Fluomizin group are then 
adjusted by a shift parameter (success probability), to consider that the distribution 
of missing responses have a lower expected value than those of the observed ones. 
3. After a logistic regression will be performed for each imputed dataset, the proportion 
of tests that would reject the null hypothesis will be calculated. 
4. Step 1 to 3 will be repeated until tipping point, meaning the according shift 
parameter, is found, where the p-value changes to be > 0.05. 
This approach is like a stress-test, to assess how severe deviations of success rates within 
the missing values have to be, to overturn the conclusions from the primary analysis. 
 Secondary Efficacy Analysis 
The following described analyses are of exploratory nature and are used as supportive 
analyses for the primary endpoint. When possible p-values will be provided to evaluate 
differences between treatment arms. The analysis will be based at least on the ITT and 
repeated for the subgroups in section 9.3.4.Further details will be provided in the statistical 
analysis plan. 
9.4.4.1 Clinical cure rate at C2 
The clinical cure rate at C2 (after 24 to 30 days) will be analysed as a secondary parameter 
to test the long-term efficacy based on the Amsel-criteria. Analysis will be conducted as 
described for the primary endpoint (see section 9.4.3) in an exploratory manner based on 
the ITT.  
A logistic regression model including the factor time will be conducted as a sensitivity 
analysis according to section 9.4.3.1, point 1. 
9.4.4.2 Bacteriological and therapeutic cure rate 
The bacteriological cure rate (Nugent score ≤ 3) will be summarized and presented 
descriptively and in an exploratory nature for Visits C1 (after 8 to 10 days) and C2 (after 24 
to 30 days).  
The therapeutic cure rate (clinical and bacteriological cures) will be evaluated descriptively 
for Visits C1 (after 8 to 10 days) and C2 (after 24 to 30 days). If both aspects, the Nugent-
score, and the Amsel-criteria have improved as defined (Nugent-score ≤ 3, Amsel criteria all 
negative except pH), the patient is assumed to be cured on a clinical and bacteriological level.  
 
In both cases groups will be compared with a z-test for two proportions and an exploratory 
evaluation made, based on the given p-value.  
9.4.4.3 Evaluation of Nugent Score 
The development of the 3 Nugent Score categories (1) Normal (score 0 - 3), (2) intermediate 
(score 4 - 6), and BV positive (score 7 - 10) will be analysed over time in an exploratory 
manner; p-values will be provided comparing the two treatment arms. 
9.4.4.4 Evaluation of individual Amsel criteria 
The number of clue cells, the KOH test, the vaginal pH and the absence/presence of abnormal 
vaginal discharge will be analyzed descriptively, and an exploratory evaluation made, based 
on the given p-value. 


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9.4.4.5 Subjective assessment of efficacy  
A subjective assessment of efficacy of the two treatments will be made by evaluating the 
patients’ and investigators’ assessments on an ordinal scale. The number and percentage of 
patients as well as the number and percentage of investigators reporting each category of 
the subjective assessment of efficacy (very good, good, moderate, poor) will be reported for 
each control visit.  
The interrater reliability (in this case patients and investigator) will be evaluated by the 
Cohen`s Kappa statistic. 
 Safety Analysis  
Details regarding the below envisaged descriptive statistics of the safety criteria will be 
provided in the SAP. At least summary statistics by visit and treatment arm will be provided 
based on the SES.  
9.4.5.1 Adverse Events and Adverse Drug Reactions 
The safety profile of Fluomizin will be assessed by descriptive analysis of adverse events, 
treatment emergent adverse events and adverse drug reactions. 
Adverse events, treatment emergent adverse events and adverse drug reactions will be coded 
prior to the database lock using the MedDRA dictionary in affect at the time of database 
closure. They will be classified by System Organ Class and Preferred Term. 
An adverse event will be considered as treatment-emergent adverse event (TEAE) if: 
x 
It was not present prior to the first treatment with either Fluomizin or Metronidazole  
x 
It was present prior to the first treatment with either Fluomizin or Metronidazole and 
worsened after start of treatment (increase of intensity/ change to SAE) 
TEAEs will be summarised by System Organ Class and Preferred Term. At least the following 
tables will be provided: 
x 
Number and percentages of patients with TEAE 
x 
Number and percentages of patients with serious TEAE 
x 
Number and percentages of patients with TEAE according to the most severe intensity 
x 
Number and percentages of patients with TEAE according to the relationship to the 
study drug 
The number and percent of subjects that experienced TEAEs will be provided overall and on 
the System Organ Class/Preferred Term level. Additionally, the number of events will be 
provided for the first two tables. 
A summary table of other serious adverse events, adverse events leading to death, and 
adverse events leading to discontinuation will be provided. In case of low incidence, only a 
listing will be provided instead. 
9.4.5.2 Subjective assessment of tolerability 
The subjective assessment of tolerability is analyzed descriptively. The number and 
percentage of patients as well as the number and percentage of investigators reporting each 


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category of the subjective assessment of tolerability (very good, good, moderate, poor) will 
be reported for each control visit. 
The interrater reliability (in this case patients and investigator) will be evaluated by the 
Cohen`s Kappa statistic. 
9.4.5.3 Vital signs 
Vital signs, namely: weight, heart rate, systolic and diastolic blood pressure, will be reported 
descriptively according to section 9.4.1 for both visits and per treatment arms. 
 
Further details for the analysis of the above-mentioned exploratory analysis will be provided 
in the SAP.  
 Additional Analysis  
9.4.1.1 Treatment compliance 
Treatment compliance will be assessed by ‘number of medications taken divided by number 
of medications provided’. Number and percentages of treatment compliance will be provided 
for both groups at C1 per treatment arm. 
9.4.1.2 Clinical symptoms 
Clinical symptoms and changes of the physiological status of the  
- 
vaginal epithelium and microflora (including the vaginal pH),  
- 
laboratory values. 
These parameters will be summarized and presented descriptively for Visits C1 (after 8 to 10 
days) and C2 (after 24 to 30 days) per treatment arm. 
9.5 
Statistical and Analytical Issues 
 Adjustment for Covariates 
 Handling of dropouts and missing data  
9.5.2.1 Dropout rate 
Considering possible deviations from the assumptions a dropout rate of 5% is assumed. 
In case of dropouts or withdrawals of patients they will be documented and described by 
means of descriptive statistics and frequency tables for each study site and in total. 
9.5.2.2 Missing data 
Data is used as given. No imputation is foreseen. The impact of missing data will be evaluated 
in sensitivity analysis (see 9.4.3.1). 
 Interim Analysis  


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An interim analysis is planned after 50% of subjects have completed the study. The interim 
analysis will be performed pseudo-blinded, without revealing the treatment allocation. The 
following aspects will be reported: 
- 
descriptive summary statistics of baseline values, 
- 
evaluation of drop-out rate, 
- 
assessment of safety parameters,  
- 
percental evaluation of compliance, 
- 
evaluation of responder rates,  
- 
Decision on sample size increase (if applicable to the new sample size) 
Within the frame of the interim analysis no confirmatory analysis regarding the primary 
endpoint will be conducted. Therefore, no control of the alpha error has to be considered.  
The conditional power, the probability of correctly rejecting the null hypothesis at the end of 
the trial, will be calculated based on the unblinded data, given at the time of interim analysis. 
This opens the possibility to reassess the sample size. The following formula will be used to 
calculate the conditional power: 
ܲሺߠሻൌȰ ቆܼ௞ඥܫ௞െݖଵିఈඥܫ௄൅ߠሺܫ௄െܫ௞ሻ
ඥܫ௄െܫ௞
ቇ 
with 
 ߠ: the expected difference under the alternative hypothesis: P2-P1 with P1 and P2 being the 
population proportions in groups 1 and 2, 
ܫ௞: the information level at interim stage: ܫ௞ൌ
ଵ
ఙమቀ
ଵ
௡భೖ൅
ଵ
௡మೖቁ
ିଵ
, 
ܫ௄: the information level at final stage: ܫ௄ൌ
ଵ
ఙమቀ
ଵ
௡భ൅
ଵ
௡మቁ
ିଵ
, 
ܼ௞: the test statistic calculated from the observed data up to interim analysis, 
ݖଵିఈ: standard normal value for the test with α as type one error. 
According to Chen et al. [2004] a conditional power of more than 50% allows an increase in 
sample size without an inflation of the type one error. 
The interim analysis regarding the sample size will be conducted by an independent external 
statistician. Details for the implementation of the interim analysis will be described in the 
SAP. 
 Multicenter Studies 
Approximately fifteen study sites are included in this trial. Since patients were randomized 
with site considered as a stratification factor into the treatment groups, and due to the features 
of the randomization scheme (see Randomization Plan), the possibility of ending up with 
unbalanced groups within one site was minimized. 
 


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10 
DATA MANAGEMENT AND QUALITY CONTROL  
10.1 
Data Collection and Storage 
Subject data recorded on CRFs during the study will be documented in a coded fashion. The 
subject will only be identified by the subject number, and by their year of birth if also required. 
Confidentiality of subject records must be maintained to ensure adherence to applicable local 
privacy regulations. 
The Investigator must retain essential documents according to the applicable local regulatory 
requirements after the completion of the study, unless otherwise notified by the Sponsor. 
Essential documents include but are not limited to the following: 
x 
study protocol/amendments 
x 
Protocol Signature Page signed and dated by the Principal Investigator 
x 
EC approved blank as well as copies of all signed subject ICFs 
x 
all EC approvals, correspondence, and reports (e.g., SAE reports, protocol deviations, 
and safety updates) 
x 
curriculum vitae and medical licenses for the PI and all sub-investigators (if applicable) 
x 
regulatory documents (e.g., financial disclosure and DOA forms) 
x 
source documents 
x 
archive of CRFs 
x 
Device Investigator Agreement 
x 
investigational product accountability records 
x 
relevant correspondence from and to the Sponsor 
x 
any other documents relevant to the conduct of the study 
In the event that the Investigator withdraws from the study (e.g., retirement, relocation), study 
records will be transferred to a mutually agreed upon designee (e.g., another Investigator, site 
EC). The Investigator will provide notice of such transfer in writing to Sponsor. 
10.2 
Data Management 
All data management procedures will be detailed in a separate document known as the Data 
Management Plan (DMP). The DMP will also describe the Clinical Data Management System 
(CDMS) that will be used to collect data with an eCRF in detail. The CDMS will be validated prior 
to data entry based on standard operating procedures (SOP). In compliance with FDA guidance 
21 CFR part 11 each user of the CDMS will be assigned a unique user name and will be allocated 
to a special user role. This special user role controls the user’s permissions in the CDMS 
depending on the function within the study. All staff involved in the study in each site has to 
be instructed how to maintain the eCRF and therefore be able to edit eCRF entries according 
to their role permissions. The investigator must sign a declaration on the eCRF attesting to 
his/her responsibility for the quality of all data entered and that the data represents a complete 
and accurate record of each subject's participation in the study.  


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The CDMS is integrated into a general IT infrastructure and safety concept with a firewall and 
backup system. A regularly backup of all trial data will be ensured.  
Trial sites will enter data online via Internet. For each enrolled study participant an eCRF will 
be maintained. CRFs must be kept current to reflect subject status at each phase during the 
course of study. Data on subjects collected on eCRFs during the study will be documented in 
an anonymous fashion and contains an electronic audit trail. Plausibility checks are run during 
data entry, thereby detecting discrepancies immediately. These computerized edit checks will 
be performed according to a Data Validation Plan (DVP). In addition, the data management will 
conduct further checks for completeness and plausibility. Inconsistencies in the data will be 
queried to the investigators via the electronic data capture system. Manual queries can also 
be raised during medical or safety review. Answers to queries or changes to the data will be 
documented in this electronic data capture system directly by an authorized member of the 
trial site without unreasonable delay. The audit trail in the eCRF documents all changes. These 
processes will be performed on an ongoing basis as outlined in the DMP until all queries are 
resolved.  
After all data are entered, all queries are solved and quality control procedures have been 
completed respectively each subject’s evaluability is determined, the database will be 
authorized for lock. In case of any changes to the data after database close, these changes 
will be documented according to respective SOP. Electronic case report form data per site will 
be provided to the responsible investigator at the end of the study and will need to be retained 
by the investigator. The complete data will be provided to the sponsor at the close of the study 
for archiving. 
10.3 
Data Quality Assurance  
 Documentation 
Source data are all the information in original records and certified copies of original records 
of clinical findings, observations, or other activities in the study, which are necessary for the 
reconstruction and evaluation of the study. The investigator will permit trial-related 
monitoring, audit(s), IEC review(s) and regulatory inspection(s), providing direct access to 
source data/records. 
For each subject enrolled, the investigator will indicate in the source record(s) that the subject 
participates in this study. The investigator will maintain adequate case histories for each 
subject enrolled. Source records should be preserved for the maximum period of time 
permitted by local regulations. 
The investigator will record the following data in the source records in this study:  
- 
Results from diagnostic procedures for BV 
- 
AE and AR 
- 
Concomitant medication 
- 
Subjective assessment of efficacy and tolerability 
- 
Summaries from patient diaries 
 Monitoring 
The monitoring of this study will be done in accordance with the principles of Good Clinical 
Practice (GCP) as laid out in the International Conference of Harmonization (ICH) guideline.  


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 Audit/Inspection 
The investigator will make all trial-related source data and records available to a medically 
qualified quality assurance auditor mandated by the sponsor, or to regulatory inspectors, after 
reasonable notice. The main purposes of an audit or inspection are to confirm that the rights 
and welfare of the subjects have been adequately protected, and that all data relevant for the 
assessment of safety and effectiveness of the investigational medicinal product have been 
reported to the sponsor. A quality assurance audit/inspection of this study may be conducted 
by 
the 
sponsor/regulatory 
authorities/IEC, 
respectively. 
The 
quality 
assurance 
auditor/inspector will have access to all medical records, the investigator's study related files 
and correspondence, and the Informed Consent documentation that is relevant to this clinical 
study. 
 Investigator Responsibilities 
The Investigator shall ensure that all work and services described herein, or incidental to those 
described herein, shall be conducted in accordance with the highest standards of medical and 
clinical research practice. The Investigator will provide current copies of the study protocol to 
all Sub-Investigators or other site personnel responsible for study conduct.  
The Investigator will provide Medinova AG or designee with copies of all EC actions regarding 
the study. 
 
 


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11 
ETHICAL PRINCIPALS  
11.1 
Basic Principals and Ethical Considerations  
The study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) 
guidelines, including International Conference of Harmonization (ICH) guidelines, and in 
accordance with the ethical principles in the last version of the Declaration of Helsinki. In 
addition, all applicable national laws, and regulatory requirements relevant to the use of 
medicinal products will be adhered to. 
11.2 
Ethical Review Committee and Regulatory Authority 
The final study protocol and the final version of the Written Informed Consent have to be 
approved by the responsible Independent Ethics Committee (IEC) / Institutional Review Board 
(IRB) and the national competent authority (if required by national regulations) as appropriate. 
If national regulations require the investigator to obtain the ethics committee’s opinion, the 
investigator must submit the written IEC/IRB approval to Medinova before he/she may enrol 
any patient into the study. If national regulations require that the sponsor obtains the 
consideration from the ethics committee and the authorization by the competent authority, 
the investigator may enrol patients into the study only after Medinova has provided the 
approval documents to him/her. 
The clinical trial start will only commence after an IEC/IRB approval and the authorization from 
the competent authority have been obtained. 
Approval for any amendment to the protocol must be obtained by the IEC/IRB and the 
competent authority in accordance with national requirements. In addition, the IEC/IRB must 
approve all advertising if used to recruit patients for the study.  
Progress reports and notifications of serious adverse events (SAEs) will be provided to the 
IEC/IRB and competent authorities according to national regulations and guidelines.  
Under no circumstances will the investigation be extended beyond the limitations defined in 
this protocol or any subsequent amendments. 
11.3 
Protocol Modifications 
All amendments must be documented, dated and signed by the investigator and sponsor. 
Before implementation, the amendment must be notified to or approved by the relevant IEC 
and competent authority, if required, National requirements must be followed. 
11.4 
Subject Information and Informed Consent 
The investigator must explain to each patient in a comprehensive way the nature of the study, 
its purpose, the procedures involved, the expected duration and the potential risks and 
benefits of the study. Each patient must be informed that participation in the study is voluntary 
and that she may withdraw from the study at any time without giving any reasons and that 
withdrawal of consent will not affect her subsequent medical treatment. The patient must be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The patients will be informed that their participation in the study as well as their identity will 
be treated confidentially. The patients will also be informed that authorised representatives of 
local / foreign drug regulatory authorities, IEC/IRB and the study sponsor need direct access 
to their medical records at the investigational site to compare data available there to data 
reported in the study, and that this may be done after approval from the investigator 
responsible for their medical records and provided secrecy is maintained. The subject should 
read and consider the statement before signing and dating it and should be given a copy of 


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the signed document. By signing the Written Informed Consent Form, the patient agrees to 
her participation in the study. 
The signed and dated Written Informed Consent must be obtained from each patient before 
conducting any procedures related to the study. The principal investigator must store the 
original, signed Written Informed Consent Form. A copy of the Written Informed Consent Form 
must be given to the patient. The consent form must also be signed and dated by the 
investigator (or his designee) and it will be retained as part of the study records. 
11.5 
Participant Confidentiality 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Subject confidentiality will be further 
ensured by utilising subject identification code numbers, corresponding to treatment data in 
the computer files and eCRFs. 
All personal patient data collected and processed for the purposes of this study should be 
managed by the investigator and his/her staff with adequate precaution to ensure the 
confidentiality of this data in accordance with applicable national laws and regulations on 
personal data protection. 
Monitors, auditors, regulatory authorities and in some countries the ethics committees 
approving this trial will be granted to direct access to the study patients’ original medical 
records for verification of clinical study procedures and/or data, without violating the 
confidentiality of the patients, to the extent permitted by the law and regulations. Within all 
presentations of the results of this study at meetings or in publications, the patient’s identity 
will remain confidential. 
11.6 
Investigator Qualification 
The investigator will be informed of the methods for rating relevant study outcomes and for 
completing CRFs to reduce discrepancies between participating investigators and study 
centers. The investigator will be kept informed of important data which relate to the safe use 
of the investigational medicinal product as the study proceeds. 
12 
DATA HANDLING AND RECORD KEEPING 
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, 
archived, retrieved, or transmitted electronically via computerized systems (and/or any other 
kind of electronic devices) as part of regulated clinical trial activities, such systems must be 
compliant with all applicable laws and regulations governing use of electronic records and/or 
electronic signatures. When paper records from such systems are used in place to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of 
a copy of original information that has been verified, as indicated by a dated signature, as an 
exact copy having all of the same attributes and information as the original.  
All medical information obtained at each study visit must be recorded in the subject’s record 
(source documentation) in real time as it is collected and then transcribed onto the eCRF by 
site personnel. Source documentation consists of original subject documents, data and 
records with all information relevant to the subject and his/her participation in the clinical 
trial.  
Examples of acceptable source documents include for example: hospital records, laboratory 
notes, evaluation checklists. Source data also includes information initially recorded in an 
electronic format.  


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Source documentation worksheets may be provided by the Sponsor to record pertinent 
information. The completed worksheets can then be incorporated into the subject’s medical 
chart. If it is preferred to not use the worksheets in the subject’s permanent record, then the 
worksheets should be used as a reference to determine the type of study data to record in the 
subject’s permanent record. 
12.1 
Study Monitoring and Source Data Verification 
The monitor will contact and visit the investigator periodically to review all trial-related source 
data/records, verify the adherence to the protocol and the completeness, correctness and 
accuracy of all CRF entries compared to source data. The investigator will cooperate with the 
monitor to ensure that any discrepancies identified are resolved. 
Additionally, this clinical trial may be reviewed by representatives of sponsor's or CRO's Quality 
Assurance department and/or regulatory authorities. This implies that auditors/inspectors 
have the right to inspect the sponsor, CRO and the trial sites at any time during or after 
completion of the clinical trial and will have access to source documents, including subject's 
medical records. By participating in this clinical trial, investigators agree to this requirement. 
Detailed information about monitoring arrangements including access to source data and the 
extent of source data verification will be described in the Monitoring Plan, separately from the 
Clinical Trial Protocol. 
 Used Subject and Medication Logs 
It is the responsibility of the investigators to ensure that a current disposition record of 
investigational product (inventoried and dispensed) and application of radiotherapy is 
maintained at the trial site. Records or logs must comply with applicable regulations and 
guidelines and should include: 
x 
amount received and placed in storage area 
x 
amount currently in storage area 
x 
label identification number or batch number 
x 
amount dispensed to and returned by each subject, including unique subject 
identifiers 
x 
amount transferred to another area/site for dispensing or storage 
x 
non-study disposition (e.g. lost, wasted) 
x 
amount destroyed at study site, if applicable 
x 
amount returned to sponsor 
x 
dates and initials of person responsible for Investigational Product 
dispensing/accountability, as per the Delegation of Authority Form. 
The sponsor will provide forms to facilitate inventory control if the trial site does not have an 
established system that meets these requirements. 
 Protocol Compliance 
The clinical trial shall be conducted as described in this approved protocol. All revisions to the 
protocol must be discussed with and be prepared by the sponsor. The investigator should not 
implement any deviation or change to the protocol without prior review and documented 
approval/favorable opinion from the IRB/IEC of an amendment, except where necessary to 
eliminate an immediate hazard(s) to trial subjects.  
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:  
 


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x
IRB/IEC for review and approval/favorable opinion 
x 
The sponsor 
x 
Regulatory Authority  
 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must 
be sent to the sponsor.  
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the informed consent form must be revised and submitted to the IRB(s)/IEC(s) for 
review and approval/favorable opinion; (2) the revised form must be used to obtain consent 
from subjects currently enrolled in the study if they are affected by the amendment; and (3) 
the new form must be used to obtain consent from new subjects prior to enrollment. If the 
revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s). 
12.2 
Data Management 
 Case Report Form  
Subject data required by this protocol are to be recorded on a CRF. The investigators and their 
staff will be responsible for completing the CRF. Data that are derived from source documents 
and reported on the CRF must be consistent with the source documents or the discrepancies 
must be explained. Additional clinical information may be collected and analyzed in an effort 
to enhance understanding of product safety. CRFs will be requested for AEs and/or laboratory 
abnormalities that are reported or identified during the course of the clinical trial.  
For each enrolled trial participant, a CRF will be maintained. CRFs must be kept current to 
reflect subject status at each phase during the course of the clinical trial. Data on subjects 
collected on CRFs during the clinical trial will be documented in an anonymous fashion and 
contains an audit trail.  
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). 
The encoded subject ID does not identify the patient directly without the use of a confidential 
encoder or lookup list.  
The investigators will maintain a signature sheet to document signatures and initials of all 
persons authorized to make entries and/or corrections on CRFs.  
The completed CRF must be promptly reviewed, signed, and dated by the investigator or 
qualified physician who is a sub-investigator and who is delegated this task on the Delegation 
of Authority Form. For electronic CRFs, review and approval/signature are completed 
electronically through the sponsor's electronic data capture tool.  
Each individual electronically signing electronic CRFs must meet the sponsors training 
requirements and must only access the sponsors electronic data capture tool using the unique 
user account provided by the sponsor. User accounts are not to be shared or reassigned to 
other individuals.  
The monitor will be responsible for reviewing and verifying the data recorded on the CRF, 
utilizing the original source documentation and will query discrepant findings. In addition, 
computerized edit checks will be performed according to a Data Management Plan (DMP). 
Inconsistencies in the data will be queried to the investigators. Answers to queries or changes 
to the data will also be documented directly by an authorized member of the investigator’s 
staff. The audit trail in the CRF documents all changes. Edit checks fire automatic queries 
during data entry when a field is not populated to specifications defined in the DMP. Queries 
can be raised during medical or safety review and data management review. The investigator 
and staff will be responsible for answering all queries.  


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The CRFs will be retained by the CRO, who must ensure that it is stored in a secure place. All 
CRFs will be reviewed for completeness, and evidence recording errors will be rectified by 
contact with the clinical site. 
12.3 
Record Keeping 
The investigator must retain essential documents indefinitely after the completion of the 
clinical trial, unless otherwise notified by the sponsor. The investigator agrees to adhere to 
the document retention procedures when signing the protocol signature page.  
The documents should be stored for at least 15 years. The investigator must contact the 
sponsor prior to destroying any records associated with the clinical trial. The sponsor will 
notify the investigator when the study records are no longer needed.  
Essential documents include but are not limited to the following:  
x 
IRB/IEC approvals for the clinical trial protocol, all amendments, informed consent 
form(s), and advertisements  
x 
IRB/IEC correspondence and reports  
x 
Regulatory documents (e.g. financial disclosure and delegation of authority forms)  
x 
All source documents  
x 
CRFs  
x 
Subject's signed ICFs  
x 
Any other documents relevant to the conduct of the clinical trial  
13 
FINANCE AND INSURANCE 
The trial is financially supported by Medinova AG. 
13.1 
Compensation to Subjects 
No remuneration and reimbursement are intended for subjects participating in the trial as trial 
visits schedule is in compliance with local standard practice. 
13.2 
Insurance and Indemnity 
Medinova AG confirms that it carries liability insurance, in compliance with national laws 
governing the clinical study insurance. 
The sponsor will be responsible for any damage caused to third parties by the study 
medication used during this clinical study.  
The sponsor confirms that he carries a liability insurance covering the participants in this study 
and that the present study has been notified to its insurance company.  
The sponsor warrants that the insurance policy is valid during the complete period of this 
clinical study. 
13.3 
Investigators’ Fee 
The investigators will be remunerated for the clinical trial performance and maintenance of 
proper documentation. 
 


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14 
PUBLICATION POLICY 
14.1 
Reporting and Publication 
 Reporting 
A draft study report will be prepared by the sponsor after the completion of the study. The 
coordinating principal investigator will sign the final study report intended to be submitted to 
regulatory authorities. 
 Publication 
Medinova shall retain ownership of the data collected during the study and of the reports, 
which result from this study. 
All information obtained as a result of the study will be regarded as confidential, until 
appropriate analysis and review by the investigators and Medinova are completed. The results 
of the study shall be published or presented by the investigators after the study has been 
completed.  
Authorship will be determined by mutual agreement. The coordinating investigator will be first 
name author of the resulting publication. 
Medinova must receive copies of any intended communication in advance of publication (at 
least 15 working days for an abstract or oral presentation and 30 working days for a journal 
submission) for review of proprietary information and to allow the company an opportunity to 
comment. If additional time is required in order for Medinova to ensure protection of its 
intellectual property Medinova will notify the publication panel who will delay submission of 
the abstract or manuscript. 
 


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15 
REFERENCES 
 
Amsel, R, Totten, PA, Spiegel, CA, Chen, KCS, Eschenbach, DA, and Holmes, KK. (1983). Nonspecific 
vaginitis. Diagnostic criteria and microbial and epidemiological associations. Am J Med, 74: 14-
22. 
 
Arredondo, JL, Higuera, F, Hidalgo, H, Narcio, L, Casanova, G, Beltran, M, and Sanchez, CJ. (1992). 
Clindamycin vaginal cream vs oral metronidazole in the treatment of bacterial vaginosis. Arch. 
AIDS Res, 6: 183-95. 
 
Austin, MN, Beigi, RH, Meyn, LA, and Hillier, SL. (2005). Microbiologic response to treatment of bacterial 
vaginosis with topical clindamycin or metronidazole. J. Clin. Microbiol, 43: 4492-97. 
 
Bohbot, JM, Vicaut, E, Fagnen, D, and Brauman, M. (2010). Treatment of bacterial vaginosis: a 
multicenter, double-blind, double-dummy, randomised phase III study comparing secnidazole 
and metronidazole. Infect Dis Obstet Gynecol, 2010. 
 
Bradshaw, CS, Morton, AN, Hocking, J, Garland, SM, Morris, MB, Moss, LM, Horvath, LB, Kuzevska, I, 
and Fairley, CK. (2006). High recurrence rates of bacterial vaginosis over the course of 12 
months after oral metronidazole therapy and factors associated with recurrence. J Infect Dis, 
193: 1478-86. 
 
Bradshaw, CS, Tabrizi, SN, Fairley, CK, Morton, AN, Rudland, E, and Garland, SM. (2006). The 
association of Atopobium vaginae and Gardnerella vaginalis with bacterial vaginosis and 
recurrence after oral metronidazole therapy. J Infect Dis, 194: 828-36. 
 
D'Auria, FD, Simonetti, G, and Strippoli, V. (1989). Caratteristiche antimicrobiche di una tintura al 
dequalinio cloruro. Ann Ig, 1: 1227-41. 
 
Della Casa, V, Noll, H, Gonser, S, Grob, P, Graf, F, and Pohlig, G. (2002). Antimicrobial activity of 
dequalinium chloride against leading germs of vaginal infections. Arzneimittelforschung, 52: 
699-705. 
 
Donders, G. (2010). Diagnosis and management of bacterial vaginosis and other types of abnormal 
vaginal bacterial flora: a review. Obstet. Gynecol. Surv, 65: 462-73. 
 
Donders, GG, Zodzika, J, and Rezeberga, D. (2014). Treatment of bacterial vaginosis: what we have 
and what we miss. Expert. Opin. Pharmacother, 15: 645-57. 
 
EJ, G, DM, C, CE, C, and SL, H. (1993). Comparative susceptibility of the Bacteroides fragilis group 
species and other anaerobic bacteria to meropenem, imipenem, piperacillin, cefoxitin, 
ampicillin/sulbactam, clindamycin and metronidazole. J Antimicrob Chemother, 31: 363-72. 
 
Eschenbach, DA, Hillier, S, Critchlow, C, Stevens, C, DeRouen, T, and Holmes, KK. (1988). Diagnosis 
and clinical manifestations of bacterial vaginosis. Am. J. Obstet. Gynecol, 158: 819-28. 
 
Farrington, CP, Manning G. (1990). Test statistics and sample size formulae for comparative binomial 
trials wit null-hypothesis of non-zero risk difference or non-unity relative risk. Statistics in 
Medicine, 9(12): 1447-1454. 
 


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Ferris, DG, Litaker, MS, Woodward, L, Mathis, D, and Hendrich, J. (1995). Treatment of bacterial 
vaginosis: a comparison of oral metronidazole, metronidazole vaginal gel, and clindamycin 
vaginal cream. J. Fam. Pract, 41: 443-49. 
 
Ferris, DG, Nyirjesy, P, Sobel, JD, Soper, D, Pavletic, A, and Litaker, MS. (2002). Over-the-counter 
antifungal drug misuse associated with patient-diagnosed vulvovaginal candidiasis. Obstet. 
Gynecol, 99: 419-25. 
 
Fischbach, F, Petersen, EE, Weissenbacher, ER, Martius, J, Hosmann, J, and Mayer, H. (1993). 
Efficacy of clindamycin vaginal cream versus oral metronidazole in the treatment of bacterial 
vaginosis. Obstet Gynecol, 82: 405-10. 
 
Freeman, CD, Klutman, NE, and Lamp, KC. (1997). Metronidazole. A therapeutic review and update. 
Drugs, 54: 679-708. 
 
Goldstein, EJ, Citron, DM, Merriam, CV, Warren, YA, Tyrrell, KL, and Fernandez, HT. (2002). In 
vitro activities of Garenoxacin (BMS 284756) against 108 clinical isolates of Gardnerella 
vaginalis. Antimicrob. Agents Chemother, 46: 3995-96. 
 
Hugo, WB, and Frier, M. (1969). Mode of action of the antibacterial compound dequalinium acetate. 
Appl Microbiol, 17: 118-27. 
 
Joesoef, MR, Schmid, GP, and Hillier, SL. (1999). Bacterial vaginosis: review of treatment options and 
potential clinical indications for therapy. Clin Infect Dis, 28 Suppl 1: S57-65. 
 
Kenyon, C, Colebunders, R, and Crucitti, T. (2013). The global epidemiology of bacterial vaginosis: a 
systematic review. Am. J. Obstet. Gynecol. 
 
Koumans, EH, and Kendrick, JS. (2001). Preventing adverse sequelae of bacterial vaginosis: a public 
health program and research agenda. Sex Transm. Dis, 28: 292-97. 
 
Larsson, PG, and Forsum, U. (2005). Bacterial vaginosis--a disturbed bacterial flora and treatment 
enigma. APMIS, 113: 305-16. 
 
Livengood, CH. (2009). Bacterial vaginosis: an overview for 2009. Rev Obstet Gynecol, 2: 28-37. 
 
Lopes dos Santos Santiago, G, Grob, P, Verstraelen, H, Waser, F, and Vaneechoutte, M. (2012). 
Susceptibility testing of Atopobium vaginae for dequalinium chloride. BMC Res Notes, 5: 151. 
 
Marrazzo, JM. (2006). A persistent(ly) enigmatic ecological mystery: bacterial vaginosis. J Infect Dis, 
193: 1475-77. 
 
Mehta, SD. (2012). Systematic review of randomized trials of treatment of male sexual partners for 
improved bacteria vaginosis outcomes in women. Sex Transm. Dis, 39: 822-30. 
 
Mendling, W, Weissenbacher, ER, Gerber, S, Prasauskas, V, and Grob, P. (2016). Use of locally 
delivered dequalinium chloride in the treatment of vaginal infections: a review. Arch. Gynecol. 
Obstet, 293: 469-84. 
 
Nagaraja, P. (2008). Antibiotic resistance of Gardnerella vaginalis in recurrent bacterial vaginosis. Indian 
J. Med. Microbiol, 26: 155-57. 


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Nasioudis, D, Linhares, IM, Ledger, WJ, and Witkin, SS. (2017). Bacterial vaginosis: a critical analysis 
of current knowledge. BJOG, 124: 61-69. 
 
Oleen-Burkey, MA, and Hillier, SL. (1995). Pregnancy complications associated with bacterial vaginosis 
and their estimated costs. Infect Dis Obstet Gynecol, 3: 149-57. 
 
Petersen, EE, Weissenbacher, ER, Hengst, P, Spitzbart, H, Weise, W, Wolff, F, Dreher, E, Ernst, U, 
Della, C, V, Pohlig, G, Graf, F, and Kaiser, RR. (2002). Local treatment of vaginal infections of 
varying etiology with dequalinium chloride or povidone iodine. A randomised, double-blind, 
active-controlled, multicentric clinical study. Arzneimittelforschung, 52: 706-15. 
 
Ravel, J, Gajer, P, Abdo, Z, Schneider, GM, Koenig, SS, McCulle, SL, Karlebach, S, Gorle, R, Russell, 
J, Tacket, CO, Brotman, RM, Davis, CC, Ault, K, Peralta, L, and Forney, LJ. (2011). Vaginal 
microbiome of reproductive-age women. Proc. Natl. Acad. Sci. U. S. A, 108 Suppl 1: 4680-87. 
 
Snapinn, SM. (2000) Noninferiority trials. Curr Control Trials Cardiovasc Med, 2000, 1:19–21. 
 
Sobel, JD. (1997). Vaginitis. N Engl J Med, 337: 1896-903. 
 
Sobel, JD. (2000). Bacterial vaginosis. Annu. Rev. Med, 51: 349-56. 
 
Sobel, JD. (2001). Antimicrobial Resistance in Vulvovaginitis. Curr Infect Dis Rep, 3: 546-49. 
 
Srinivasan, S, and Fredricks, DN. (2008). The human vaginal bacterial biota and bacterial vaginosis. 
Interdiscip. Perspect. Infect. Dis, 2008: 750479. 
 
Srinivasan, S, Hoffman, NG, Morgan, MT, Matsen, FA, Fiedler, TL, Hall, RW, Ross, FJ, McCoy, CO, 
Bumgarner, R, Marrazzo, JM, and Fredricks, DN. (2012). Bacterial communities in women with 
bacterial vaginosis: high resolution phylogenetic analyses reveal relationships of microbiota to 
clinical criteria. PLoS. ONE, 7: e37818. 
 
Strecker, M, Kokemohr, H, Teucher, T, and Schmitz, H. (1993). Antiseptika gegen Vulvovaginitiden. TW 
Gynäkologie, 6: 409-12. 
 
Sweet, RL. (2000). Gynecologic conditions and bacterial vaginosis: implications for the non-pregnant 
patient. Infect Dis Obstet Gynecol, 8: 184-90. 
 
Turner, RJ, Taylor, DE, and Weiner, JH. (1997). Expression of Escherichia coli TehA gives resistance 
to antiseptics and disinfectants similar to that conferred by multidrug resistance efflux pumps. 
Antimicrob. Agents Chemother, 41: 440-44. 
 
Weissenbacher, ER, Donders, G, Unzeitig, V, Martinez de, TB, Gerber, S, Halaska, M, and Spacek, J. 
(2012). A comparison of dequalinium chloride vaginal tablets (Fluomizin(R)) and clindamycin 
vaginal cream in the treatment of bacterial vaginosis: a single-blind, randomized clinical trial of 
efficacy and safety. Gynecol. Obstet. Invest, 73: 8-15. 
 
 
 
 


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1Swab for Nugent Score will be taken; result will be available 2-3 days later 
²By both the patient and the investigator 
16 
APPENDICES 
16.1 
Study schedule 
Activities and assessments 
Screening 
Visit 
Control Examinations 
 
 
 
 
 
E 
C1 
C2 
Early drop-
out 
Day 1 
Day 8-10 
Day 24-30 
 
 
 
 
 
Inclusion criteria 
 
 
 
 
x Reproductive age ≥18 years 
x 
 
 
 
x Diagnosis of BV 
 
 
 
 
1) Amsel criteria all positive (4+) 
x 
 
 
 
 
 
 
 
 
x Written Informed Consent 
x 
 
 
 
Exclusion criteria  
x 
 
 
 
Pregnancy test 
x 
 
x 
 
Medical history  
 
 
 
 
x Demographic characteristics 
x 
 
 
 
x Anamnesis & concomitant diseases 
x 
 
 
 
x Concomitant medication 
x 
x 
x 
x 
Assessment of efficacy parameters 
 
 
 
 
x Sampling / Cure rates 
 
 
 
 
1) Clinical cure (Amsel criteria) 
x 
x 
x 
x 
2) Bacteriological cure (Nugent score) 
x 
x 
x 
x 
3) Therapeutic cure (Clin. & Bact. cure) 
 
x 
x 
x 
x Subjective assessment of efficacy2 
 
x 
x 
x 
x Reason for discontinuation 
 
x 
x 
x 
Assessment of safety parameters 
 
 
 
 
x Treatment compliance (from diary) 
 
x 
x 
x 
x Adverse events and adverse reactions  
 
x 
x 
x 
x Subjective assessment of tolerability² 
 
x 
x 
x 
x Vital signs 
x 
x 
x 
x 
Study management 
 
 
 
 
x Randomization & schedule next visit 
x 
x 
 
 
x Dispense / collect study medication 
x 
 
x 
 
x Hand out of online link to patient’s diary 
& questionnaire  
x 
 
 
 
x Check patient questionnaire compliance  
 
x 
x 
x 
 


 
 
 
 
GCPS_STF_011.3 
Effective Date: 08/OCT/2020 
Page 1 of 33 
 
STATISTICAL ANALYSIS PLAN 
 
MNFM380119 
 
 
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 
 
 
 
 
The information provided in this document is strictly confidential. No part of this document may be reproduced, transmitted or 
copied in any form nor its contents disclosed to the third parties without prior written consent of Medinova or a nominated 
representative. 
 
 
 
Sponsor: 
Medinova AG 
Eggbühlstrasse 28 
CH-8052 Zurich / Switzerland 
 
Author:  
 
Simona Botta 
GCP-Service International Ltd. & Co. KG 
Anne-Conway-Str. 2 
28359 Bremen, Germany 
Tel   +49 (0)421 20 80 98 74 
 
 
Date of document: 
 
     Document version: 
15-JUN-2022 
 
Final v2.0 


 
 
Medinova 
 
                      Statistical Analysis Plan – Final 2.0 
Study Protocol MNFM380119 
 
15-JUN-2022 
 
GCPS_STF_011.3 
Effective Date: 08/OCT/2020 
Page 2 of 33 
Document History 
Version 
Date 
Author(s) 
Description 
0.1 
08-MAR-2021 
Carolin Herbon 
First draft version 
0.2 
06-APR-2021 
Carolin Herbon 
Incorporated changing requests from 
sponsor review 
1.0 
14-JUL-2021 
Carolin Herbon 
Final Version 
1.1 
11-MAY-2022 
Simona Botta 
Update after the CIP amendment 
2.0 
15-JUN-2022 
Simona Botta 
Finalization after Sponsor review 
 
 
 


 
 
Medinova 
 
                      Statistical Analysis Plan – Final 2.0 
Study Protocol MNFM380119 
 
15-JUN-2022 
 
GCPS_STF_011.3 
Effective Date: 08/OCT/2020 
Page 3 of 33 
Signatures 
I confirm that this Statistical Analysis Plan accurately describes the planned statistical analyses to the best of 
my knowledge and was finalized before breaking the blind/database close. 
 
Author: 
Simona Botta 
Statistician 
GCP-Service Int. -Ltd. & Co. KG 
Anne-Conway-Straße 2 
28359 Bremen, Germany 
 
 
 
 
 
Date                                Signature 
Review: 
Matthes Metz 
Senior Statistician 
GCP-Service Int. Ltd & Co. KG 
Anne-Conway-Straße 2 
28359 Bremen, Germany 
 
 
 
 
 
Date                                Signature 
Approved: 
Anahí Hurtado-Chong 
Senior International Medical Research Manager 
Medinova AG 
Eggbühlstrasse 28 
CH-8052 Zurich / Switzerland 
 
 
 
Date                                Signature 
 
Dr. Philipp Grob 
Global Scientific & Technical Affairs Director 
Medinova AG 
Eggbühlstrasse 28 
CH-8052 Zurich / Switzerland 
 
 
 
Date                                      Signature 
Signature

Signature


	
            Signature

 
	
Signature




 
 
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                      Statistical Analysis Plan – Final 2.0 
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15-JUN-2022 
 
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Effective Date: 08/OCT/2020 
Page 4 of 33 
Table of Contents  
 
Document History .............................................................................................................. 2 
Signatures ........................................................................................................................ 3 
Table of Contents .............................................................................................................. 4 
List of Abbreviations and Key Terms .................................................................................... 7 
1. 
Introduction ................................................................................................................ 8 
2. 
Study Design and Objectives ........................................................................................ 8 
2.1 
Study Design ........................................................................................................ 8 
2.2 
Treatments .......................................................................................................... 8 
2.3 
Trial Schedule ...................................................................................................... 8 
2.4 
Study Objectives ................................................................................................. 10 
2.4.1 
Primary Objective ......................................................................................... 10 
2.4.2 
Secondary Objectives ................................................................................... 10 
2.5 
Study Hypothesis ................................................................................................ 10 
2.6 
Handling of Screening Failures and Drop-outs ........................................................ 10 
2.7 
Randomization and Stratification ........................................................................... 11 
2.8 
Blinding ............................................................................................................. 11 
2.9 
Sample Size Calculation ...................................................................................... 11 
2.10 Planned Interim or Sequential Analysis .................................................................. 12 
2.11 Handling of Changes to Study Protocol .................................................................. 12 
3. 
Technical Aspects and Coding Conventions ................................................................. 12 
3.1 
Date Coding and Day Numbering .......................................................................... 13 
3.2 
Coding Systems and Conventions ......................................................................... 13 
3.2.1 
Coding of Adverse Events, Medical History, Concomitant Pathology and Prior and 
Concomitant Procedures ........................................................................................... 13 
3.2.2 
Separation of Medical History from Concomitant Pathology ................................ 13 
3.2.3 
Separation of Prior from Concomitant Procedures ............................................. 14 
3.2.4 
Coding of Medications ................................................................................... 14 
3.2.5 
Separation of Prior from Concomitant Medication .............................................. 14 


 
 
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4. 
Analysis Populations and Subgroups ........................................................................... 15 
4.1 
Analysis Populations ........................................................................................... 15 
4.1.1 
Intention To Treat (ITT) ................................................................................. 15 
 
A subject is considered treated if at least one medication is taken. This will be checked 
using the drug accountability done by the site at C2 (i.e., the number of medications given to 
the subject and the number of medications returned). .................................................... 15 
4.1.2 
Per protocol population (PP) ....................................................................... 15 
4.1.3 
Safety Evaluation Set (SES) .......................................................................... 15 
4.2 
Subgroups ......................................................................................................... 15 
4.3 
Stratification ....................................................................................................... 15 
5. 
Data Handling .......................................................................................................... 16 
5.1 
Handling of Missing Data and Outliers ................................................................... 16 
5.2 
Handling of Withdrawals and Drop-outs ................................................................. 16 
5.3 
Handling of Multiple Comparisons and Multiple Primary Variables ............................. 16 
5.4 
Data Review ....................................................................................................... 16 
6. 
Variables for Analysis ................................................................................................ 17 
6.1 
Disposition of Subjects......................................................................................... 17 
6.2 
Demographics and Baseline Characteristics ........................................................... 17 
6.3 
Primary Variable ................................................................................................. 17 
6.4 
Secondary Variables ........................................................................................... 18 
6.5 
Safety Variables ................................................................................................. 18 
6.6 
Other Variables................................................................................................... 18 
7. 
Statistical Analysis Methods ....................................................................................... 19 
7.1 
Descriptive Statistics ........................................................................................... 19 
7.2 
Rounding Rules ................................................................................................. 19 
7.2.1 
Estimates of the Mean and Standard Deviation ............................................ 19 
7.2.2 
Other data .................................................................................................. 19 
7.3 
Data derivation ................................................................................................... 19 
7.3.1 
Categorization of subjects .............................................................................. 19 
7.3.2 
Change from baseline ................................................................................... 20 


 
 
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7.3.3 
Time to onset and duration of adverse events ................................................... 20 
7.3.4 
Time to resolution of clinical symptoms ............................................................ 20 
7.4 
Evaluation of Demographics and Baseline Characteristics ........................................ 20 
7.4.1 
Disposition of Patients ................................................................................... 20 
7.4.2 
Demographics and Baseline Characteristics ..................................................... 20 
7.4.3 
Medical History, Concomitant Diseases, Previous and Concomitant Medication .... 21 
7.5 
Evaluation of Primary Variable .............................................................................. 21 
7.5.1 
Main analysis ............................................................................................... 21 
7.5.2 
Additional sensitivity analysis ..................................................................... 22 
7.6 
Evaluation of Secondary Variables ........................................................................ 24 
7.6.1 
Clinical cure rate at C2 ............................................................................... 24 
7.6.2 
Bacteriological cure rate ............................................................................. 24 
7.6.3 
Therapeutic cure rate ................................................................................. 24 
7.6.4 
Nugent score development over time and in categories .............................. 25 
7.6.5 
Individual Amsel criteria ............................................................................. 25 
7.6.6 
Subjective assessment of treatment efficacy ............................................... 25 
7.7 
Evaluation of Safety Variables .............................................................................. 25 
7.7.1 
Adverse Events  .......................................................................................... 25 
7.7.2 
Subjective assessment of tolerability .......................................................... 26 
7.7.3 
Vital signs .................................................................................................. 27 
7.8 
Evaluation of Other Variables ............................................................................... 27 
7.8.1 
Treatment compliance from medication returned ............................................... 27 
7.8.2 
Time to resolution of clinical symptoms ............................................................ 27 
7.8.3 
Patients’ satisfaction with treatment ................................................................. 27 
7.8.4 
Incidence of bacterial vaginosis reoccurrences ................................................. 27 
7.8.5 
Clinical improvement rate............................................................................... 28 
7.9 
Special Analytical Issues ...................................................................................... 28 
7.9.1 
Unscheduled visits ........................................................................................ 28 
7.9.2 
Adjustment for Covariates .......................................................................... 28 
7.9.3 
Interim Analysis ............................................................................................ 28 
8. 
Changes in the Planned Analysis ................................................................................ 30 
9. 
APPENDIX 1 ............................................................................................................ 31 


 
 
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10. Literature ................................................................................................................. 33 
 
List of Abbreviations and Key Terms 
AE 
 
 
Adverse Event 
ADR 
 
 
Adverse Drug Reaction 
ATC 
 
 
Anatomical Therapeutic Classification System 
BL 
 
 
Baseline 
C1 
 
 
Control Examination 1 
C2 
 
 
Control Examination 2 
DRM 
 
 
Data Review Meeting 
E 
 
 
Examination at Screening Visit 
ITT 
 
 
Intention To Treat 
KOH Test 
 
Potassium hydroxide Test 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
PP 
 
 
Per Protocol 
PT 
 
 
Preferred Term 
SAE 
 
 
Serious Adverse Event 
SAP 
 
 
Statistical Analysis Plan 
SES 
 
 
Safety Evaluation Set 
SOC 
 
 
System Organ Class 
TEAE  
 
Treatment Emergent Adverse Event 
WHO-CC 
 
WHO Collaborating Centre for Drug Statistics Methodology  
 
 
 
 


 
 
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1.  Introduction 
This statistical analysis plan (SAP) contains a more technical and detailed elaboration of the principal features 
of the statistical analyses as described in the Study Protocol MNFM380119 v2.0, dated 13th April 2022. The 
purpose of the SAP is to serve as a guideline for the statistical analysis and the creation of the analysis tables, 
figures, and listings for the clinical study report. The SAP is finalised and signed prior to hard lock of the 
database. 
2. Study Design and Objectives 
2.1 
Study Design  
This is an international, multi-centre, active-controlled, randomized, double-dummy, phase IV study with 
parallel group design. It will be assessed whether vaginal tablets containing 10 mg dequalinium chloride 
(Fluomizin) for 6 days are comparable in clinical efficacy to orally 2x500mg/day for 7 days metronidazole in 
patients suffering from bacterial vaginosis. The clinical cure rate 8-10 days after start of treatment will be 
assessed. Patients will be followed up to 30 days after start of treatment. For this trial 236 patients will be 
recruited in 15 sites within Europe.  
2.2 
Treatments 
Patients will be randomized into one of the two following treatment groups: 
x 
Treatment 1: Fluomizin vaginal tablets (10 mg Dequalinium chloride) administrated intravaginally daily, 
before going to sleep, for 6 days and comparator (Metronidazole) matching placebo administrated 
orally twice daily for 7 days 
x 
Treatment 2: Fluomizin matching placebo administrated intravaginally daily, before going to sleep, for 
6 days and Metronidazole 500mg tablets administrated orally twice daily for 7 days  
2.3 
Trial Schedule  
Outpatients suffering from bacterial vaginosis will be informed about the study at initial visit. After signing the 
informed consent, baseline characteristics will be recorded, and randomization applied. Patients will start 
treatment on screening day. They will have two more control examinations after start of treatment, until latest 
90 days after the initial visit. A more detailed overview of the visit schedule and the assessed parameters can 
be taken from Table 1. 
 


 
 
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Table 1: Visit schedule 
Activities and assessments 
Screening 
Visit 
Control Examinations 
 
E 
C1 
C2 
Early drop-out 
Day 1 
Day 8-10 Day 24-30 
 
Inclusion criteria 
 
 
 
 
x Reproductive age ≥18 years 
x 
 
 
 
x Diagnosis of BV 
 
 
 
 
1) Amsel criteria all positive 4+ 
x 
 
 
 
x Written Informed Consent 
x 
 
 
 
Exclusion criteria (incl. Pregnancy test) 
x 
 
 
 
Pregnancy test 
x 
 
x 
 
Medical history  
 
 
 
 
x Demographic characteristics 
x 
 
 
 
x Anamnesis & concomitant diseases 
x 
 
 
 
x Concomitant medication 
x 
x 
x 
x 
Assessment of efficacy parameters 
 
 
 
 
x Sampling / Cure rates 
 
 
 
 
1) Clinical cure (Amsel criteria) 
x 
x 
x 
x 
2) Bacteriological cure (Nugent score1) 
x 
x 
x 
x 
3) Therapeutic cure (Clin. & Bact. cure) 
 
x 
x 
x 
x Subjective assessment of efficacy
2 
 
x 
x 
x 
x Reason for discontinuation 
 
x 
x 
x 
Assessment of safety parameters 
 
 
 
 
x Treatment compliance (from diary) 
x Treatment compliance (from returned 
medications) 
 
 
x 
 
 
x 
x 
 
x 
x 
 
x Adverse events and adverse reactions  
 
x 
x 
x 
x Subjective assessment of tolerability
2 
 
x 
x 
x 
x Vital signs 
x 
x 
x 
x 
Study management 
 
 
 
 
x Randomization & schedule next visit 
x 
x 
 
 
x Dispense / collect study medication 
x 
 
x 
 
x Hand out of online link to patient´s diary 
and questionnaire  
x 
 
 
 
x Check patient questionnaire compliance 
 
x 
x 
x 
1: Swab for Nugent Score will be taken; result will be available 2-3 days later 
2: by both, patient and investigator 


 
 
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2.4 
Study Objectives 
2.4.1 
Primary Objective 
The main objective is to evaluate whether vaginal tablets containing 10 mg dequalinium chloride (Fluomizin) 
for 6 days are comparable in clinical efficacy to metronidazole orally 2x500mg/day for 7 days oral tablets in 
women suffering from bacterial vaginosis. 
2.4.2 
Secondary Objectives 
As secondary objectives the following aspects will be evaluated: 
 
the clinical, bacteriological, and therapeutic cure rate on short-term and/or long-term follow-up 
 
the physiological status of the vaginal ecosystem during the respective treatments 
 
the subjective assessment of efficacy and tolerability  
 
the safety profile of Fluomizin in this patient population 
2.5 
Study Hypothesis 
The main hypothesis of this study is that Fluomizin is not inferior to Metronidazole in the clinical cure rate of 
patients with acute bacterial vaginosis. The null hypothesis to reject therefore is that Fluomizin (πF)  is equal 
or worse than Metronidazole (πM) by the clinically relevant difference (δ=15%). The alternative hypothesis is 
that the clinical cure rate of Fluomizin differs from the clinical cure rate of Metronidazole by less than the 
clinically significant difference, or Fluomizin has higher cure rate compared to Metronidazole. 
H0: πF – πM  ≤ - δ 
H1: πF – πM > - δ 
In case the null hypothesis can be rejected, the primary endpoint will hierarchically be tested for superiority 
of Fluomizin over the leading therapy option Metronidazole. The hypotheses tested for the evaluation of 
possible superiority are the following: 
H0: πF – πM  ≤ δ 
H1: πF – πM ˃ δ 
where denotations are the same as explained for the non-inferiority hypothesis above. 
If the cure rate of Fluomizin exceeds Metronidazole by more than 15% (δ), and the null hypothesis can be 
rejected, then Fluomizin is considered superior to Metronidazole with respect to efficacy. 
 
2.6 
Handling of Screening Failures and Drop-outs 
Patients dropping out after inclusion into the clinical study will be replaced, but the subjects will not be allowed 
to re-enter the study. 


 
 
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2.7 
Randomization and Stratification 
For the allocation of subjects to treatment arms, a centre-stratified block randomization with variable block size 
will be used. The randomisation ratio between treatments will be 1:1. The randomization list will be prepared 
by a statistician and an interactive randomization tool will be used. 
2.8 
Blinding 
As this is a double-blind double dummy study each subject will receive an identical medication kit containing 
both vaginal and peroral medication from which one will be placebo and the second active substance. There 
are no laboratory or clinical assessments or specific AEs that could unblind the subject. 
2.9 
Sample Size Calculation 
The sample size calculation for the trial is based on the proportions of clinical cure rate (greater than or equal 
to 80%, based on the Amsel criteria) 8 to 10 days after start of treatment as the primary endpoint.  
This clinical trial is designed to evaluate if Fluomizin is at least as efficacious as Metronidazole in terms of the 
clinical cure rate as a non-inferiority comparison.  
In this study, the alternative hypothesis H1 is that the clinical cure rate of Fluomizin, πF, differs from the clinical 
cure rate of Metronidazole, πM, by less than the clinically significant difference, δ (non-inferiority margin: 15%), 
or Fluomizin has higher cure rate compared to Metronidazole. The null hypothesis, H0, therefore is that 
Fluomizin is equal or worse than Metronidazole by the clinically significant difference, δ. 
Thus,  
H0: πF – πM  ≤ - δ 
H1: πF – πM > - δ 
The minimum number n, of evaluable patients necessary for each treatment groups is determined by the 
following equation: 
݊ൌʹ൫ݖଵିఈ൅ݖଵିఉ൯
ଶɎெሺͳ െɎெሻ
ߜଶ
 
Assuming  
x 
ݖଵିఈ: The 1- ߙ quantile of the normal distribution, with α=2.5%, the type 1 error 
x 
ݖଵିఉ: The 1- ߚ  quantile of the normal distribution, with 1-β=80%, the power 
x 
an incidence of successful treatment with Fluomizin according to previous studies [Weissenbacher et  
al., 2012]: πF : 80% (0.80), 
x 
an incidence of successful treatment with Metronidazole according to previous studies that found cure  
rates between 60-90% [Larsson and Forsum, 2005; Bradshaw, Morton, et al., 2006]: πM : 80% (0.80), 


 
 
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Page 12 of 33 
x 
smallest clinically relevant differences in the responder rate in treatment of Fluomizin and  
Metronidazole (δ) of maximum 15% (0.15) are defined as clinically relevant to show non-inferiority of  
Fluomizin compared to Metronidazole. 
 
the minimum number of evaluable patients per treatment group is 112. Assuming a drop-out rate of 5%, a total 
of 118 patients per treatment group is planned. Since in this case the sample size is larger than 50 and the 
proportion is 0.8, this power calculation gives similar results as if binomial enumeration would be used. 
Screening failures and patients withdrawing prior to application of treatments will be replaced. 
The sample size was calculated by using nQuery from Statsols, Version 8.5.2.0. 
2.10 
Planned Interim or Sequential Analysis 
An interim analysis is planned after approximately 50% of subjects have completed the study. The exploratory 
interim analysis is performed pseudo-blinded, without revealing the treatment allocation. Sample size will be 
recalculated by an independent statistician, such that blinding is preserved. Details are given in section 7.9.3. 
2.11 
Handling of Changes to Study Protocol 
Any change which is not only editorial but indicates a change in the statistical analyses planned in the CIP will 
be justified and documented at least in the SAP text part if it was decided before database close. Any change 
made to the statistical analysis after database close might be described in a new version of the SAP but has 
to be justified and documented at least in the final study report. It has to be specified that these changes 
occurred after database close and whether they were data-driven or not. 
3. Technical Aspects and Coding Conventions 
All programs will be written using SAS® version 9.4 or higher. There will be an individual SAS® program written 
for each table, figure, and listing. Each analysis program will be validated by a second qualified SAS® 
programmer to ensure a correct output and a correct presentation of the data. The validation process is 
documented in the validation sheet (GCPS_DMF_033 A-C), which also prespecifies criteria for risk 
categorization of programs and the corresponding validation actions. 
All relevant outputs of the SAS® programs will be transferred into RTF documents with DIN A4 format and 
saved as write-protected PDF documents with a table of content preceding the content of the file. There will 
be one RTF/PDF document for tables, one for figures and one for listings. Courier New is used as font. The 
font size should be consistent within each document and reasonable, i.e. there should be as much required 
information as possible on one page, but the text should be still easy to read.  


 
 
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In headings, titles, and listings only the first word will be capitalised. Whenever data are derived, and the 
derivation method is not obvious from the information given in the header, a footnote should be added to clarify 
the derivation method. A footnote should also be considered if additional information facilitates the 
interpretation of the data.  
Patient listings will be sorted by site and subject number unless specified otherwise. Furthermore, derived data 
will be marked by “#” in patient listings, while missing data will be represented as blank field. If data from a 
subject are presented by visit, only attended visits will be listed.  
3.1 
Date Coding and Day Numbering 
The format for presentation of date variables will be DDMMMYYYY. The format for presentation of time 
variables will be hh.mm. 
Missing or incomplete dates will not be completed. For additional considerations towards the time allocation of 
diseases and medication, refer to sections 3.2.2 and 3.2.5, respectively. 
3.2 
Coding Systems and Conventions 
3.2.1 
Coding of Adverse Events, Medical History, Concomitant Pathology and Prior and 
Concomitant Procedures 
All medical terms reported as adverse events (AE), as medical history/concomitant pathology or as 
concomitant procedures are coded according to the Medical Dictionary for Regulatory Activities (MedDRA) 
version in effect at the time the database is closed for the final analysis. At least the primary System Organ 
class (SOC) as well as the Preferred Term (PT) should be available for the statistical analysis. 
3.2.2 
Separation of Medical History from Concomitant Pathology  
Separation of past and current medical conditions will be done by comparison of the stop date of the medical 
condition with the date of start of the treatment. Each medical condition will be allocated unambiguously either 
to medical history or concomitant pathology.  
x 
Medical history: If the stop date is before start of the treatment, the medical condition will be allocated 
to medical history. If the stop date is partially given and unambiguously before starting with the 
treatment, the medical condition will also be allocated to medical history.  
x 
Concomitant diseases: If the stop date is at or after the start of the treatment or the medical condition 
is active at start of study participation, the medical condition will be allocated to concomitant diseases.  


 
 
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3.2.3 
Separation of Prior from Concomitant Procedures 
Separation of past and concomitant procedures will be done by comparison of the stop date of the medical 
procedure with the date of treatment start. Each medical procedure will be allocated unambiguously either to 
past or concomitant procedures.  
x 
Prior procedures: If the stop date is before the start of the treatment, the medical procedure will be 
allocated to past procedures. If the stop date is partially given and unambiguously before start of the 
treatment, the medical procedure will also be allocated to past procedures. Furthermore, if the stop 
date is missing and the medical procedure is not known to be active at start of study participation, 
findings will also be allocated to past procedures. 
x 
Concomitant procedures: If the stop date is at or after start of the treatment or the medical procedure 
is concomitantly performed at start of study participation, the medical condition will be allocated to 
concomitant procedures. 
3.2.4 
Coding of Medications 
Concomitant medications will be coded using the Anatomical Therapeutic Chemical classification system 
provided by the WHO Collaborating Centre for Drug Statistics Methodology (WHO-CC). At least the ATC level 
2 and 3 should be available for the statistical analysis. 
3.2.5 
Separation of Prior from Concomitant Medication  
Separation of prior and concomitant medication will be done by comparison of the stop date of the medication 
with the date of treatment start. Each medication will be allocated unambiguously either to previous or 
concomitant medication.  
x 
Prior medication: If the stop date is before the start of the treatment, the medication will be allocated 
to prior medication. If the stop date is partially given and unambiguously before treatment start, the 
medication will also be allocated to prior medication. 
x 
Concomitant medication: If the medication is ongoing or the stop date is at or after treatment start, 
the medication will be allocated to concomitant medication. Furthermore, if the stop date is partially 
missing and ambiguous or completely missing, and the medication is not known to be active at the 
start of study participation, it will also be allocated to concomitant medication. 
4. Analysis Populations and Subgroups 
4.1 
Analysis Populations 
In the following the analysis sets for the statistical analysis of this clinical study will be defined. 


 
 
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4.1.1 
Intention To Treat (ITT) 
In the intention to treat set all subjects having been randomized and treated will be included. This set will be 
used for the primary analysis. For the analysis with the ITT population, subjects will be allocated to the 
treatment group they were randomized to, following the intention-to-treat principle.  
A subject is considered treated if at least one medication is taken. This will be checked using the drug 
accountability done by the site at C2 (i.e., the number of medications given to the subject and the number of 
medications returned). 
4.1.2 
Per protocol population (PP) 
The Per Protocol set includes all subjects that have not experienced major protocol violations. Patients whose 
menstruation starts within the 7 days of treatment will also be excluded from this analysis set, since they will 
have to pause the vaginally applied treatment during menstruation. For additional details on protocol deviations 
and examples of them see section 5.4. All patients will be evaluated based on the treatment they actually 
received. This set of subjects is used for primary supportive analysis, as well as for sensitivity analyses.
4.1.3 
Safety Evaluation Set (SES) 
The SES includes all study subjects who have received Fluomizin or Metronidazole. For the analysis with the 
SES population, subjects will be allocated to the treatment group they actually received, rather than to the one 
they were randomized to. This set will be used for the safety analysis. 
4.2 
Subgroups 
To evaluate the effect of the Nugent score, the patients will be divided into three subgroups based on the 
Nugent score at baseline:  
- 
Normal: subjects with score 0 – 3 at baseline 
- 
Intermediate: subjects with score 4 – 6 at baseline 
- 
BV positive: subjects with score 7 – 10 at baseline 
4.3 
Analyses of the subgroups are described in respective sections 7.4 - 7.9Stratification 
Since for the randomization ‘study sites’ have been considered as a stratification factor, it will furthermore be 
used for stratified analysis. See section 5.4 to find more details. 


 
 
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5. Data Handling  
5.1 
Handling of Missing Data and Outliers 
Missing data will only be considered in a sensitivity analysis (see section 7.5.2). No imputation is foreseen for 
the main analysis, in which data is used as given. 
5.2 
Handling of Withdrawals and Drop-outs 
A dropout rate of 5% is assumed in this study. In case of dropouts or withdrawals of patients they will be 
documented and described in the disposition (see section 7.4.1). 
5.3 
Handling of Multiple Comparisons and Multiple Primary Variables 
Since the analysis of non-inferiority and superiority hypotheses follows a closed hierarchical testing procedure 
in this trial, the problem of multiplicity does not apply here, therefore no adjustment of the type I error has to 
be considered. Secondary endpoints and subgroup analysis will be done in an exploratory manner. 
5.4 
Data Review  
A data review meeting (DRM) will take place after database (soft)lock prior to the - final analysis, in order to 
discuss remaining issues (outstanding queries, unresolved errors) and to confirm and approve relevant 
protocol deviations on an individual base. The DRM is also responsible for the exclusion of outliers and 
exclusion of subjects from the analysis populations. It will be also investigated the study sites effect on the 
primary endpoint variable, and if a clinically significant sites effect is found the site variable will be considered 
in the analysis being included in the sensitivity analysis. 
After the final DRM has taken place and the database is considered cleaned, the database will be hard locked 
for the final statistical analysis. 
Protocol deviations will be identified in a joined effort by the Sponsor, project management, data management, 
clinical monitors, and statisticians prior to the DRM. A complete list of all identified protocol deviations will be 
prepared by the Statistician and provided to the DRM members for classification. It is important to note that 
protocol deviations may be rated as major for the clinical data monitoring during the conduct of the trial although 
they do not affect data integrity (e.g., delayed SAE reporting, incorrect informed consent process) and should 
not be rated as major for the determination of analysis sets for the statistical analysis.  
Possible examples of major protocol violations are: 
- 
Violations of inclusion or exclusion criteria 
- 
Use of any antimicrobial treatment (local or systemic) during the study  
- 
Use of any vaginal medication or vaginal douching during the study  
- 
Immunosuppressive therapy during the study 
- 
Alcohol consumption during treatment, and 48 hours after the treatment  
- 
Major time window violations of C1 


 
 
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6. Variables for Analysis 
6.1 
Disposition of Subjects 
Disposition of subjects will be presented by means of: 
x 
Screened subjects defined as subjects with a date for the screening visit 
x 
Eligible subjects defined as all screened subjects fulfilling the eligibility criteria of this study 
x 
Subjects eligible and randomized 
x 
Subjects treated - - 
x 
Subjects completing the study 
x 
Subjects in the different analysis sets (ITT, PP and SES) as assigned in the data review meeting 
x 
Subjects in the different subgroups (see section 4.2, normal, intermediate and BV positive) 
x 
Screening failure (incl. reason for screening failure) 
x 
Discontinuation (completion status, reason for discontinuation) 
6.2 
Demographics and Baseline Characteristics 
 The following demographics and baseline variables are planned to be evaluated: 
x 
Age (in years) 
x 
Gender (male/female) 
x 
Ethnicity (Hispanic or Latino/ not Hispanic or Latino) 
x 
Race (American Indian or Alaska native/ Asian/ Black or African American/ Native Hawaiian or other 
Pacific islander/ White/ Other) 
x 
Height (in cm) 
x 
Childbearing potential by subject (yes/no) 
x 
Use of highly effective contraceptive method by subject (yes/no) 
x 
Number of pregnancies by subject 
x 
Number of births by subject 
x 
Number of vaginal infections during the last 12 months by subject 
x 
Number of bacterial vaginosis during the last 2 years by subject 
x 
Subjects with at least one finding in relevant medical history and concomitant diseases (see section 
3.2.1) as well as SOC and PT 
x 
Subjects with at least one finding in prior and concomitant medications (see section 3.2.4) as well as 
ATC level 2 and 3 
6.3 
Primary Variable 
The primary efficacy variable is the clinical cure rate at C1 (8 to 10 days after start of treatment), defined as 
having the following three Amsel criteria negative:  
- 
greyish white thin discharge 


 
 
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- 
KOH test or ‘fishy’ smell 
- 
presence of > 20% clue cells 
6.4 
Secondary Variables 
The variables for the secondary endpoints are: 
1. Clinical cure rate at follow-up (at C2 = at 24 to 30 study days, derivation in section 6.3) 
2. Bacteriological cure rate at C1 and C2 (for derivation see section 7.6.2) 
3. Therapeutic cure rate at C1 and C2 (derivation see section 7.6.3) 
4. Nugent Score  
a. as continuous variable at C1 and C2 
b. within 3 categories, i.e. (1) normal, (2) intermediate, and (3) BV positive at C1 and C2 
5. Individual Amsel criteria at E, C1 and C2 
6. Subjective assessment of efficacy (very good, good, moderate, poor) 
a. By the investigator at C1 and C2 
b. By the patients at day 8-10 and 10 – 30 
6.5 
Safety Variables 
Variables for evaluating safety rate: 
1. Number of adverse events 
a. Occurrences of treatment-emergent adverse events by SOC and PT (see section 7.7.1) 
b. Occurrence of treatment-emergent adverse events by severity 
c. Occurrence of treatment-emergent adverse events by relatedness to study drug 
d. Occurrences of adverse events by SOC and PT (see section 3.2.1) 
2. Subjective assessment of tolerability (very good, good, moderate, poor) 
a. By the investigator at C1 and C2 
b. By the patients at day 8 – 10 and 10 – 30 
3. Vital signs: Weight (in kg), heart rate (in bpm), systolic and diastolic blood pressure (in mmHg) at 
visits E, C1, C2 
6.6 
Other Variables 
Additional aspects will be assessed, based on the following variables: 
1. Treatment compliance based on number of medications distributed/returned (derivation defined in 
section 7.8.1) 
2. Time to resolution of symptoms based on patient diary (derivation defined in section Error! 
Reference source not found.) 
3. Patients’ satisfaction with treatment  
4. Incidence of bacterial vaginosis reoccurrences rate by the patients at day 10 - 30 
5. Clinical improvement rate (see section 7.8.5) 


 
 
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7. Statistical Analysis Methods 
7.1 
Descriptive Statistics 
The default summary statistics for quantitative variables will be the number of non-missing observations (n) 
and the number of missing observations (miss) as well as arithmetic mean, standard deviation (SD), lower 
quartile (Q1), upper quartile (Q3), minimum (min), median, and maximum (max). 
For categorical variables, the number (n) and percentage (%) of subjects per category will be the default 
summary presentation, and, if applicable, the number of missing values is provided in a “miss” category. For 
the number of missing values, all subjects in the respective study population will be counted. Percentages will 
be calculated using a denominator of all subjects in a specified population with non-missing data. If necessary, 
the denominator will be specified in a footnote to the tables for clarification. 
7.2 
Rounding Rules 
7.2.1 
Estimates of the Mean and Standard Deviation 
When using actual data, the mean and standard deviation will both be calculated to at least 2 extra places 
than the actual data and the result will be rounded to one more decimal place than the original data. 
When using derived means/standard deviations, i.e. means/standard deviations already derived from actual 
data, results are calculated to at least one more decimal place than these derived means/standard deviations 
and subsequently rounded to the same number of decimal places as the used values. 
7.2.2 
Other data 
Quartiles, confidence intervals (CIs) and median will be presented with the same number of decimal places as 
the mean. Minimum and maximum will be presented with the same number of decimal places as the data 
used. For estimates of proportions, the result will be rounded to 3 decimal places. If proportions are displayed 
as percentage, 1 decimal place will be displayed. For example, a proportion of 0.655 will be presented in 
percentage as 65.5%.  
7.3 
Data derivation 
7.3.1 
Categorization of subjects 
Subjects will be categorized for frequency calculations associated with several variables defined in section 6.4 
into responder and non-responder (for details, see section 7.6). The definition for categorization will be 
highlighted in a footnote to each of the respective tables.  


 
 
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7.3.2 
Change from baseline 
Whenever the change from baseline is analysed, the value at baseline is subtracted from the post-baseline 
value: 
Change from baseline = Post-baseline value – Baseline value 
7.3.3 
Time to onset and duration of adverse events 
Time to onset and duration of adverse events will be calculated as follows: 
x 
Time to onset = start date of AE - date of start of treatment  
x 
Duration of adverse event = stop date – onset/worsening date + 1  
7.3.4 
Time to resolution of clinical symptoms 
Time to resolution of symptoms will be based on the information provided in the patient diary, being calculated 
using the date of resolution reported by the patients at day 8 – 10, and it is defined as follow for the subjects 
that experienced the event: 
x 
Time to symptom’s resolution = date reported of symptoms disappeared – randomization date 
If at day 8 – 10 symptoms are declared to be still present, the data will be presented as censored in the analysis 
with the date of entry of the data. If the patient does not enter the ePRO or has no entry for the resolution of 
clinical symptoms, data will be excluded from the analysis.   
7.4 
Evaluation of Demographics and Baseline Characteristics 
7.4.1 
Disposition of Patients 
The disposition of subjects will be presented according to section 6.1. 
Primary reasons for early termination will additionally be tabulated (withdrawn consent, inability to continue, 
death, discontinued by investigator, lost to follow up). Early termination will include frequency and percentage, 
where percentage is based on the number of subjects with early discontinuation. A table detailing the number 
of patients per visit will further be provided.  
A flow-chart detailing the number of subjects at the different stages will be prepared. 
7.4.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics (see section 6.2) will be summarized by randomized groups for 
the ITT, PP and SES according to the analysis described in section 7.1. 


 
 
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7.4.3 
Medical History, Concomitant Diseases, Previous and Concomitant Medication 
Absolute and relative frequencies (n, %) of medical history, concomitant pathology as well as past and 
concomitant procedures will be described based on MedDRA system organ class (SOC) and preferred term 
(PT) levels for the -ITT on subject level by treatment arm. 
Absolute and relative frequencies (n, %) of past and concomitant medication will be provided based on 
Anatomical Therapeutic Chemical (ATC) Classification code levels 2 and 3 for the ITT on subject level by 
treatment arm. 
7.5 
Evaluation of Primary Variable 
7.5.1 
Main analysis 
The main criterion of this trial is to investigate whether Fluomizin has a non-inferior clinical cure rate in 
treatment of bacterial vaginosis (with regard to the 15% non-inferiority margin) compared to Metronidazole 
after 8-10 days. The clinical cure rate is a binary response-variable, defined by the evaluation of three individual 
Amsel criteria (see section 6.3 for more details). Further confirmatory analyses are not foreseen for this trial. 
In addition to the standard summary statistics (as described in section 7.1Error! Reference source not 
found.), the differences in clinical cure rate between Fluomizin and Metronidazole will be analysed in a 
confirmatory manner using a one-sided Farrington-Manning test on a 2.5% significance level with following 
hypothesis: 
H0: πF – πM ≤ -δ 
H1: πF – πM > -δ  
 
 
where 
H0 = null hypothesis for the non-inferiority test of the primary endpoint 
H1 = alternative hypothesis for the non-inferiority test of the primary endpoint 
πM = clinical cure rate of Metronidazole 
πF = clinical cure rate of Fluomizin 
δ = smallest clinically significant difference between the two groups  
(non-inferiority margin: 15% or 0.15) 
 
With the Farrington and Manning [1990] Likelihood Score test, differences in proportions between two groups 
can be tested using the following procedure in SAS version 9.4:  
 
PROC freq data=<data> order=data;  
tables group*response/ riskdiff(noninf margin=.15 method=fm);  
format response response.;  
RUN; 
 


 
 
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Efficacy will be analysed based on the ITT set. The Farrington-Manning test will provide a p-value for the 
outcome variable, on which the decision will be based. If the test produces a p-value lower than 0.025, non-
inferiority with regard to the non-inferiority margin can be declared. The same analysis will be repeated as a 
sensitivity analysis on the PP set.  
If non-inferiority can be shown, data can furthermore be tested for superiority of Fluomizin over the leading 
therapy option Metronidazole. The Farrington-Manning test is also providing a confidence interval for this 
purpose, which will be specified with a significant level of 5% (i.e., 95% confidence interval). The hypotheses 
tested for the evaluation of possible superiority are the following: 
1. H0a: πF – πM  ≤ 0 
H1a: πF – πM ˃ 0 
where denotations are the same as explained for the non-inferiority hypothesis above. 
If the clinical cure rate of Fluomizin is superior to Metronidazole, the null hypothesis can be rejected.  
If statistical significance on the above-described superiority test is given, it can furthermore be tested, if it is 
also clinically relevant using the smallest clinically significant difference between the two groups (15%):   
2. H0b: πF – πM  ≤ δ 
H1b: πF – πM > δ 
where denotations again are the same as explained for the non-inferiority hypothesis above. 
If the null hypothesis can be rejected to the clinically relevant margin of 15% (δ), Fluomizin is considered 
superior to Metronidazole with respect to clinical efficacy. 
There is no multiplicity problem to be considered since this analysis corresponds to a closed hierarchical test 
procedure.  
7.5.2 
Additional sensitivity analysis 
1. Logistic regression model to consider the parameter time: 
A logistic regression will be calculated using the ITT, as well as the PP set to consider the variance in 
time given by broader frames of visit schedules. The factor time will be included in the model by a time 
variable that includes the day on which the visit was performed (8-10). The effect of the Nugent score 
criteria on the outcome variable  will be considered as a continuous variable in the model. Further 
considerable variables will be included as explanatory parameters into the model, such as treatment as 
well as age or weight. Which variables are included, is finally decided based on a statistical criterion for 
model selection.  


 
 
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Logit (Amsel criteria=1 | Xi=xi) = 
 Intercept + β1*Time[i] + β2*Age[i] + β3*Weight[i] + β4*Treatment[i] + β5*Nugent Score[i] 
Odds ratios with its 95%CI for the specified variables as well as corresponding p-values will be given. 
2. Logistic regression to measure the effect of Nugent Score: 
To furthermore evaluate the effect of the Nugent score criteria at baseline on the outcome variable, a 
logistic regression will be calculated including the explaining parameters ‘Nugent score’ and ‘treatment’ 
only. Odds ratios with its 95%CI for the specified variables will be given, and a p-value provided. If 
meaningful, an interaction between treatment and the Nugent score at baseline will be added to the 
model and investigated.  
3. Subgroup analysis 
To investigate the impact of the Nugent score, the primary analysis (as described in section 7.5.1) will 
be repeated for the subgroups listed in section 4.2. 
4. Stratified analysis  
In case it’s found a clinically significant effect site on the primary endpoint (see section 5.4), the primary 
analysis as described in section 7.5.1 will be repeated for each site. 
5. Tipping point analysis 
Another sensitivity analysis addressing the missing values will be a tipping point analysis, which allows 
to evaluate the effect of missing data on the outcome. It can determine, for which success probability for 
the missing subjects in the Fluomizin group the conclusions regarding the primary variable remain stable. 
For this analysis it is assumed that missing values are missing not at random, and that there is a tipping 
point that reverses the study outcome. It will be conducted on the ITT set and only if the non-inferiority 
null hypothesis can be rejected and if the missing values rate is at least of 10%. 
This analysis is conducted by the following steps: 
1. Missing values are imputed into the dataset one thousand times-.  
2. The imputed values for missing observations in the Fluomizin group are then adjusted by a shift 
parameter (success probability), to consider that the distribution of missing responses have a lower 
expected value than those of the observed ones. 
3. After a logistic regression will be performed for each imputed dataset, the proportion of tests that 
would reject the null hypothesis will be calculated. 
4. Step 1 to 3 will be repeated until tipping point, meaning the according shift parameter, is found, where 
the p-value changes to be > 0.05. 
This approach is like a stress-test, to assess how severe deviations of success rates within the missing 
values have to be, to overturn the conclusions from the primary analysis. 


 
 
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7.6 
Evaluation of Secondary Variables 
The following described analyses are of exploratory nature and are used as supportive analyses for the 
primary endpoint. Descriptive statistics will be conducted as explained in section 7.1. When possible, p-
values will be provided to evaluate differences between treatment arms. Furthermore, if converge, it will be 
conducted a logistic regression including, in addition to the treatment group, the factor time and the 
subgroups will be included as covariates. If necessary and due to the exploratory character of the analysis, 
the model will be extended or reduced to improve the model fit by the study. For the evaluation of the 
secondary endpoints the ITT set is used. In case the ITT and the PP sets differ at least by 10% of subjects 
in both arms, the analysis will be repeated also in the PP set. 
7.6.1 
Clinical cure rate at C2 
The clinical cure rate at C2 (after 24 to 30 days) will be analysed as a secondary parameter to test the long-
term efficacy based on the Amsel-criteria. Analysis will be conducted as described for the primary endpoint 
(see section 7.5.1) by subgroups (defined in section 4.2), in an exploratory manner, based on the ITT, and 
eventually in the PP set, as described above in section 7.6. A logistic regression model including the factor 
time will be conducted additionally as a sensitivity analysis, as described in section 7.6. An exploratory 
evaluation will be made, based on the given p-value.  
7.6.2 
Bacteriological cure rate 
The bacteriological cure rate is defined as a Nugent score ≤ 3. It will be presented and summarized 
descriptively in an exploratory manner for Visits C1 (after 8 to 10 days) and C2 (after 24 to 30 days). 
Treatment groups will be compared as described for the primary endpoint (see section 7.5.1) in an 
exploratory manner based on the -ITT, and eventually on the PP set. A logistic regression model including 
the factor time will be conducted additionally as a sensitivity analysis according to section 7.6.  An exploratory 
evaluation will be made, based on the given p-value.  
7.6.3 
Therapeutic cure rate 
If both aspects, the Nugent-score, and the Amsel-criteria have improved as defined (Nugent-score ≤ 3, Amsel 
criteria all negative except pH), the patient is assumed to be cured on a clinical and bacteriological level. 
Therefore, a new binary variable will be created, that rates the patient as cured if both criteria are fulfilled: 
clinical cure (see section 6.3) and bacteriological cure (see section 7.6.2), and as not cured if at least one of 
the criteria are rated as not cured. The therapeutic cure rate (clinical and bacteriological cures) will be 
evaluated descriptively by subgroups (defined in section 4.2) for Visits C1 (after 7 to 14 days) and C2 (after 
24 to 30 days).  
Treatment groups will be compared as described for the primary endpoint (see section 7.5.1) in an 
exploratory manner based on the ITT. A logistic regression model including the factor time will be conducted 


 
 
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additionally as a sensitivity analysis according to section  7.6. An exploratory evaluation will be made, based 
on the given p-value.  
7.6.4 
Nugent score development over time and in categories 
The Nugent score will be reported in two approaches. Firstly, mean and standard deviation of the raw numeric 
values will be presented in descriptive statistics and graphically over time and per treatment arm for the ITT. 
Secondly the development of the single categories of the Nugent score ((1) normal, (2) intermediate, and (3) 
BV positive) will be presented in descriptive statistics, providing the frequencies per category and 
distinguishing between the two treatment groups. An exploratory Wilcoxon-Mann-Whitney-test will provide p-
values comparing the two treatment arms at each visit. To illustrate the development, the mean Nugent score 
with its 95% CIs will be plotted for each visit and separately by treatment group. In addition, a shift table will 
be provided to see the development of the Nugent score categories during the study visits, including a figure 
that will show graphically the development by categories. 
7.6.5 
Individual Amsel criteria 
The presence of clue cells, the KOH test, the vaginal pH, and the absence/presence of abnormal vaginal 
discharge will be evaluated descriptively according to section 7.1 for each visit. 
-. An exploratory Chi square test will provide p-values comparing the two treatment arms for each criterion.  
7.6.6 
Subjective assessment of treatment efficacy  
An assessment of the efficacy of the two treatments will be made by evaluating the patients’ and investigators’ 
subjective evaluation on an ordinal scale. The number and percentage of patients as well as the number and 
percentage of investigators evaluating each category of the global assessment of tolerability (very good, 
good, moderate, poor), will be reported for each control visit and separately by treatment group. An 
exploratory evaluation will be made, based on the - p-value given by the Wilcoxon-Mann-Whitney-test. 
The interrater reliability (in this case patients and investigator) will be evaluated by the weighted Cohen`s 
Kappa statistic by treatment group. 
7.7 
Evaluation of Safety Variables 
Safety variables will be envisaged descriptively. At least summary statistics by visit and treatment arm will 
be provided based on the SES, according to the description in section 7.1.  
7.7.1 
Adverse Events  
The safety profile of Fluomizin will be assessed by descriptive analysis of adverse events, treatment 
emergent adverse events and adverse drug reactions. 


 
 
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Adverse events will be coded prior to the database lock using the MedDRA dictionary in affect at the time of 
database closure. They will be classified by System Organ Class (SOC) and Preferred Term (PT). 
An adverse event will be considered as treatment-emergent adverse event (TEAE) if: 
x 
It was not present prior to the first treatment with either Fluomizin or Metronidazole and has emerged 
prior to study day 24 (17 days after start of treatment) 
x 
It was present prior to the first treatment with either Fluomizin or Metronidazole and worsened after 
start of treatment (increase of intensity/ change to SAE) 
For the classification in TEAES and non-TEAES the date of onset / worsening will be compared with the date 
of the screening visit. 
TEAEs will be summarised by System Organ Class and Preferred Term. At least the following tables will be 
provided: 
x 
Number and percentages of patients with TEAE 
x 
Number and percentages of patients with serious TEAE (if more than 10 serious TEAEs are observed, 
otherwise they will be only listed) 
x 
Number and percentages of patients with TEAE according to the most severe intensity 
x 
Number and percentages of patients with TEAE according to the relationship to the study drug 
Incidences (number and percentage) of treatment-emergent adverse events (TEAEs) will be calculated on 
the system organ class (SOC) level and on the preferred term (PT) level, on the subject level for the SES. 
Percentages will only be calculated for the number of subjects and not the number of events. The 
denominator used will be the number of subjects in the SES.  
Incidences of TEAEs will further be summarized by intensity and relationship to the study drug, where each 
subject will be counted only once towards the worst intensity or highest relationship to the study drug within 
a SOC/PT. For the analysis by relationship to the study drug, all TEAEs will be categorized into either related 
(all TEAEs at least possibly related to the study device) or unrelated. 
If meaningful (more than 10 drug related TEAEs), Kaplan-Meier plots will be presented for the time to first 
drug-related TEAE, where subjects discontinuing the study for any reason will be included as censored 
observations unless they previously experienced a drug-related TEAE. 
Listings and, if applicable, tables displaying incidences for TEAEs leading to discontinuation, serious AEs, 
drug-related serious AEs and deaths will also be provided. In case at least 10 serious AEs were observed, 
summary statistics will be provided on the SOC and PT level. 
7.7.2 
Subjective assessment of tolerability 
The subjective assessment of tolerability will be analyzed descriptively. The number and percentage of 
patients as well as the number and percentage of investigators evaluating each category of the global 
assessment of tolerability (very good, good, moderate, poor) will be reported for each control visit. An 
exploratory evaluation will be made, based on the p-value given by the Wilcoxon-Mann-Whitney-test. 


 
 
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The interrater reliability (in this case patients and investigator) will be evaluated by the weighted Cohen`s 
Kappa statistic by treatment group. 
7.7.3 
Vital signs 
Vital signs, namely weight, heart rate, systolic and diastolic blood pressure, will be reported descriptively 
according to section 7.1 for both visits (C1, C2) and per treatment arm. 
7.8 
Evaluation of Other Variables 
The in the following described analyses are of exploratory nature. Descriptive statistics will be conducted in 
the ITT set as explained in section 7.1. When possible, p-values will be provided to evaluate differences 
between treatment arms. 
7.8.1 
Treatment compliance from medication returned 
Treatment compliance will be assessed by ‘number of medications taken divided by number of medications 
provided’. The number of medications taken will be calculated from the difference between the number of 
medications provided (visit E) and the number of the medications returned (visit C2 or study termination). 
Number and percentages of treatment compliance will be provided for both groups at C2 per treatment arm. 
7.8.2 
Time to resolution of clinical symptoms 
Descriptive statistics of the time to resolution will be provided according to section 7.1 for both treatments. 
If meaningful, time to resolution of clinical symptoms will additionally be prepared as Kaplan-Meier plot, where 
patients discontinuing the study will be included as censored observations unless they previously experience 
clinical cure based on the patient diary. 
7.8.3 
Patients’ satisfaction with treatment 
The satisfaction of the patient with the treatment will be assessed descriptively. The number and percentage 
of patients evaluating each category of the satisfaction with the treatment (very satisfied, satisfied, moderate, 
not satisfied), will be reported for each control visit. An exploratory evaluation will be made, based on the p-
value given by the Wilcoxon-Mann-Whitney-test. 
7.8.4 
Incidence of bacterial vaginosis reoccurrences 
Confirmed healed cases at visit C1, that are diagnosed with bacterial vaginosis again at visit C2, will be 
flagged as recurrent disease subjects. The number and percentage of these subjects will be reported for both 
treatment arms. 


 
 
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7.8.5 
Clinical improvement rate 
The clinical improvement rate will be presented as numbers and percentages of subjects that have at least 
two Amsel criteria negative at both visits, C1 and C2, per treatment arm. 
7.9 
Special Analytical Issues 
7.9.1 
Unscheduled visits 
Unscheduled visits may be performed, as necessary, to ensure the safety and well-being of subjects. Data 
from these visits will only be included in the patient listings but not in the statistical analysis, tables, and figures, 
with the following exceptions: 
x 
AEs  
x 
Concomitant diseases  
x 
Concomitant medications  
7.9.2 
Adjustment for Covariates 
Since with a range of 8 to 10 days a higher variance is assumed for the primary endpoint, data will be adjusted 
for the factor time in the sensitivity analysis, where the number of days after randomization will be considered 
by including them into the model. Therewith possible influences of the factor time can be evaluated exploratory. 
Further considerable variables will be included in the model, as specified in section 7.5.2.  
7.9.3 
Interim Analysis 
An interim analysis is planned after approximately 50% of subjects have completed the study. The interim 
analysis will be performed pseudo-blinded, without revealing the treatment allocation. The aim of the interim 
analysis is to check the assumptions made for the sample size calculation by using a conditional power 
approach. The idea behind is to consider the possibility that the assumption made in the planning phase of the 
study can differ from the real situation due to lack of knowledge in the planning phase. Therefore, it is checked 
the possibility of having the necessity to increase the sample size. Further details can be obtained in Chen et 
al. 2004. 
 The data export for the interim analysis will be placed direct after approval of the amendment of the CIP 
version 2.0. In any case, only the subjects that attended visit C1 by that time will be included in the analysis. 
The following aspects will be reported descriptively at interim time point: 
- 
summary statistics of baseline values, considering the variables described in section 6.2 and the 
methodology of section 7.1; 
- 
evaluation of drop-out rate; 
- 
assessment of safety parameters 
o 
List of adverse events overall, without considering the treatment allocation,  
o 
Table of the incidence of the adverse events overall, 


 
 
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o 
Table of vital signs listed in section Error! Reference source not found., following always 
the rules of section 7.1;   
- 
percental evaluation of compliance, calculated as described in section 7.8.1, only for the patients 
who completed C2 already; 
- 
evaluation of responder rates by pseudo-blinded treatment group (A vs. B) calculated following the 
derivation’s rules described in section Error! Reference source not found.; decision on how to 
continue the study (with or without sample size recalculation). 
 
Since the number of medications returned is recorded at visit C2, only for the interim analysis patients will be 
considered treated, and thus will be in the ITT set, if the patient received at least one medication according to 
the patient diary report. 
Within the frame of the interim analysis no confirmatory analysis regarding the primary endpoint will be 
conducted. Therefore, no control of the alpha error has to be considered.  
The conditional power, the probability of correctly rejecting the null hypothesis at the end of the trial, will be 
calculated based on the unblinded data, given at the time of interim analysis by an external statistician. This 
opens the possibility to reassess the sample size. The following formula will be used to calculate the conditional 
power: 
ܲሺߠሻൌȰ ቆܼ௞ඥܫ௞െݖଵିఈඥܫ௄൅ߠሺܫ௄െܫ௞ሻ
ඥܫ௄െܫ௞
ቇ 
with 
 ߠ: the expected difference under the alternative hypothesis: P2-P1 with P1 and P2 being the population 
proportions in groups 1 and 2, 
ܫ௞: the information level at interim stage: ܫ௞ൌ
ଵ
ఙమቀ
ଵ
௡భೖ൅
ଵ
௡మೖቁ
ିଵ
, 
ܫ௄: the information level at final stage: ܫ௄ൌ
ଵ
ఙమቀ
ଵ
௡భ൅
ଵ
௡మቁ
ିଵ
, 
ܼ௞: the test statistic calculated from the observed data up to interim analysis, 
ݖଵିఈ: standard normal value for the test with α as type one error. 
According to Chen et al. [2004] a conditional power of more than 50% would allow an increase in sample size 
without an inflation of the type one error. Sample size would then be recalculated, based on the process given 
in section 2.9, by an external statistician to preserve blinding for the statistician conducting the final analysis, 
and if the result is in the promising region, meaning a conditional power between 50% and 80%, otherwise no 
action will be made. 
A meeting will take place to discuss the interim analysis results, providing in advance a Power Point 
presentation with the contents that will be discussed, joined to the previous list of the tables with the results. 


 
 
Medinova 
 
                      Statistical Analysis Plan – Final 2.0 
Study Protocol MNFM380119 
 
15-JUN-2022 
 
GCPS_STF_011.3 
Effective Date: 08/OCT/2020 
Page 30 of 33 
8. Changes in the Planned Analysis  
This SAP include all the changes encompassed in the new protocol after the amendment, with some additional 
changes to clarify definitions and analysis descriptions. They are summarized in the following 
1. Primary analysis set has changed from mITT (exclusion of Nugent score ≤ 7) to ITT (all randomized 
and treated patients), as described in section 4.1 
2. Addition of subgroups regarding the Nugent score at baseline, as described in section 4.2 
3. Adjustment of sample size because of a drop out decreasing as a consequence of 1.  
4. Change of the compliance definition to make possible a check from the sites (section 7.8.1) 
5.  Specifications on the site effects analysis (sections 5.4 and 7.5.2) 
6. Extension of the PDs description (section 5.4) 
7. Rewording of variables definitions to make them clearer and more specific (section 6) 
8. Clarifications of the analysis with more details in the descriptions (sections 7.3 - 7.9) 
The aim of the main change, the new definition of the analysis sets, is to be more in line with the population 
that effectively take the study drug, the one diagnosed ill based on the Amsel criteria, and investigate further 
the relationship with the Nugent score value additionally.  
 


 
 
Medinova 
 
                      Statistical Analysis Plan – Final 2.0 
Study Protocol MNFM380119 
 
15-JUN-2022 
 
GCPS_STF_011.3 
Effective Date: 08/OCT/2020 
Page 31 of 33 
 
 
9. APPENDIX 1   
Tables  
14.1 Study subjects 
 
14.1.1 Disposition of subjects 
 
14.1.1.1 Subject disposition, by site and total 
 
14.1.1.2 Subjects per visit, by site and total 
 
14.1.2 Demographics and Baseline Characteristics 
 
14.1.2.1 Demographics 
 
14.1.2.2 Other baseline characteristics (continuous) 
             14.1.2.3 Other baseline characteristics (categorical) 
 
14.1.3 Medical history and concomitant diseases 
 
14.1.3.1 Medical history by SOC and PT 
 
14.1.3.2 Concomitant diseases by SOC and PT 
 
14.1.4 Prior and concomitant medication 
 
14.1.4.1 Prior medication by ATC level 
 
14.1.4.2 Concomitant medication by ATC level 
 
14.1.5 Prior and concomitant procedures 
 
14.1.5.1 Prior procedures by SOC and PT 
 
14.1.5.2 Concomitant procedures by SOC and PT 
 
14.2 Performance data 
 
 
14.2.1 Primary endpoints 
                         14.2.1.1  Results of the confirmatory analysis 
14.2.1.2 Sensitivity analyses, Logistic regression 
14.2.1.3 Tipping point analysis  
 
 
 
14.2.2 Secondary endpoints 
14.2.2.1 Clinical cure rate at C2 
14.2.2.1.1 Descriptive results 
14.2.2.1.2 Results of the logistic regression model 
 
14.2.2.2 Bacteriological cure rate at C1 and C2 
14.2.2.2.1 Descriptive results 
14.2.2.2.2 Results of the logistic regression model 
 
14.2.2.3 Therapeutic cure rate at C1 and C2 
14.2.2.3.1 Descriptive results 
14.2.2.3.2 Results of the logistic regression model 
 
 
 
14.2.2.4 Nugent Score 
                                       14.2.2.4.1 Continuous results 
 
 
 
14.2.2.4.2 Descriptive results by category 
 
 
 
14.2.2.4.3 Shift table 
  


 
 
Medinova 
 
                      Statistical Analysis Plan – Final 2.0 
Study Protocol MNFM380119 
 
15-JUN-2022 
 
GCPS_STF_011.3 
Effective Date: 08/OCT/2020 
Page 32 of 33 
 
 
 
14.2.2.5 Amsel Criteria 
 
 
 
14.2.2.6 Subjective assessment of treatment efficacy 
                                       14.2.2.6.1 By patients and investigator 
 
 
 
14.2.2.6.2 Interrater reliability 
 
 
 
14.3 Safety data 
 
14.3.1 Adverse Events 
 
14.3.1.1 Overall Summary of treatment emergent adverse events 
14.3.1.2 Treatment emergent adverse events by Worst Causal Relationship 
14.3.1.3 Treatment emergent adverse events by Worst Severity 
14.3.1.4 Serious adverse events (SAEs), listing of subjects 
4.3.1.5 Overall Summary of adverse events 
 
 
14.3.2 Subjective assessment of tolerability 
14.3.2.1 By patients and investigator 
 
 
14.3.2.2 Interrater reliability 
 
 
 
14.3.3 Vital signs 
 
14.4 Other Variables 
 
 
14.4.1 Treatment compliance at C1 
 
14.4.2 Time to resolution of clinical symptoms 
 
14.4.3 Patient’s satisfaction with the outcome of the treatment 
 
14.4.4 Incidence of bacterial vaginosis reoccurrences 
 
14.4.5 Clinical improvement rate 
 
 
 
Figures 
14.1 Flowchart: disposition of subjects 
14.2.2.4.1 Development of Nugent score 
14.2.2.4.2 Shift in Nugent score over time 
14.3.1.2 Kaplan Meier plot time to first related TEAE 
14.4.2 Kaplan Meier plots for Time to resolution of clinical symptoms 
 
Listings 
16.1 Study subjects  
 
16.1.1 Disposition of subjects 
 
 
16.1.1.1 Screening failures 
 
 
16.1.1.2 Visit dates and discontinuation 
 
 
16.1.1.3 Site numbers and principal investigators 
 
 
 
 
 
16.1.2 Eligibility and protocol deviations 
 
 
16.1.2.1 Subjects with violation of inclusion / exclusion criteria 
 
 
16.1.2.2 Protocol deviations and other reason for exclusion from analysis sets,  
 assignment to analysis sets 
 
 
16.1.3 Demographic data and other baseline characteristics 
  
 
16.1.3.1 Demographics 


 
 
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                      Statistical Analysis Plan – Final 2.0 
Study Protocol MNFM380119 
 
15-JUN-2022 
 
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Effective Date: 08/OCT/2020 
Page 33 of 33 
 
 
16.1.3.2 Other baseline characteristics 
 
 
16.1.3.3 Findings in medical history 
 
 
16.1.3.4 Findings in concomitant diseases 
 
 
16.1.3.5 Findings in prior procedures 
 
 
16.1.3.6 Findings in concomitant procedures 
 
 
16.1.3.7 Findings in prior medication 
 
 
16.1.3.8 Findings in concomitant medication 
 
16.2   Efficacy parameters 
 
 
 
16.2.1 Clinical, bacteriological and therapeutic cure 
16.2.1.1 Amsel criteria and clinical cure 
 
16.2.2 Subjective assessment of efficacy and tolerability of the investigator 
 
16.2.3 Patient reported outcome 
 
 
16.2.3.1 Patient reported outcome: treatment and after treatment 
 
 
16.2.3.2 Patient reported outcome: treatment compliance 
 
16.2.4 Treatment compliance 
 
 
16.3 Safety data 
 
 
16.3.1 Adverse events listing 
 
 
16.3.1.1 Adverse events 
 
                          16.3.1.2 Serious adverse events 
                          16.3.1.3 Serious adverse events related to the study drug 
                          16.3.1.4 Adverse events leading to discontinuation 
                          16.3.1.5 Patient deaths 
 
 
 
16.3.2 Vital signs 
 
16.4 Other data 
 
 
16.4.1 Unscheduled visits 
10. 
Literature 
Chen, Y.H.J, DeMets, D.L., Lan, K.K.G., 2004. Increasing the sample size when the unblinded interim result 
is promising. Statistics in Medicine, 23:1023-1038 (DOI: 10.1002/sim.1688). 
 
Farrington, C.P., Manning, G., 1990. Test statistics and sample size formulae for comparative binomial trials 
with null hypothesis of non-zero risk difference or non-unity relative risk. Statistics in Medicine 9(12):1447-
1454 (DOI: 10.1002/sim.4780091208).  
 


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