A Prospective, Open-Label, Pilot, Multicentric Clinical Investigation to Evaluate the Performance and Safety of Cerviron Ovules® in the Local Treatment of Non-Specific or Endogenous, Symptomatic Vaginitis
Phase: NA
Conditions: Vaginitis and Vulvovaginitis
Sponsor: Perfect Care Distribution

 
CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
 
A PROSPECTIVE, OPEN-LABEL, PILOT, MULTICENTRIC CLINICAL INVESTIGATION TO EVALUATE THE 
PERFORMANCE AND SAFETY OF CERVIRON® OVULES IN THE LOCAL TREATMENT OF NON-SPECIFIC OR 
ENDOGENOUS, SYMPTOMATIC VAGINITIS 
 
Authors of the Report: 
Ramona Petrita, Alexandru-Remus Pința 
Document Type: 
Clinical Study Report 
Version Number: 
1.0 
Medical Device Name: 
Cerviron® 
Medical Device Class: 
IIb 
Medical Device Manufacturer: 
Perfect Care Distribution 
Medical Device Manufacturer 
Contact Details: 
17-19 Scarlatescu Street, 3rd Floor, 011158 Bucharest, Romania 
Country of Study: 
Romania 
Release Date: 
05 Apr 2022 
ClinicalTrials.gov Identifier: 
NCT04735705 
CIP Identification: 
CIP version V1.0 dated 06 Jan 2021 
ISO 
14155:2020 
Compliance 
Statement: 
This investigation was conducted in compliance with legal 
requirements for interventional studies 
 
 
 
 
 
 
 
CONFIDENTIAL 
This document is the property of Perfect Care Distribution and may not - in full or in part - be 
passed on, reproduced or otherwise used without the express permission of Perfect Care 
Distribution. 
 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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TABLE OF CONTENTS 
1 GENERAL ............................................................................................................................................... 4 
1.1 
TITLE OF THE CLINICAL INVESTIGATION .................................................................................. 4 
1.2 
SCIENTIFIC APPROACH IN CLINICAL STUDY DESIGN, PLANNING, CONDUCT, ANALYSIS AND 
REPORTING .......................................................................................................................................... 4 
1.3 
PROTECTION OF THE CLINICAL INVESTIGATION PARTICIPANTS ............................................. 4 
1.4 
OVERALL SYNOPSIS OF THE CLINICAL INVESTIGATION REPORT ............................................. 5 
2. INTRODUCTION ................................................................................................................................. 12 
2.1 
STUDY RATIONALE AND BACKGROUND ................................................................................ 12 
2.2 BENEFIT/RISK ASSESSMENT ......................................................................................................... 14 
3. INVESTIGATIONAL DEVICE AND METHODS ....................................................................................... 15 
3.1 
DESCRIPTION OF THE INVESTIGATIONAL DEVICE...................................................................... 15 
3.1.1 
THE INTENDED USE OF THE INVESTIGATIONAL DEVICE(S) ................................................ 17 
3.1.2  
DESCRIPTION OF MECHANISM OF ACTION OF THE INVESTIGATIONAL DEVICE, ALONG 
WITH SUPPORTING SCIENTIFIC LITERATURE ..................................................................................... 18 
3.1.3 
PREVIOUS INTENDED USES OR INDICATIONS FOR USE, IF RELEVANT .............................. 23 
3.1.4 
ANY CHANGES TO THE INVESTIGATIONAL DEVICE DURING THE CLINICAL INVESTIGATION 
OR ANY CHANGES FROM THE IB ....................................................................................................... 24 
3.2 
CLINICAL INVESTIGATION PLAN (CIP) ........................................................................................ 24 
3.2.1 
THE CLINICAL INVESTIGATION OBJECTIVES ....................................................................... 24 
3.2.2 
THE CLINICAL INVESTIGATION DESIGN .............................................................................. 24 
3.2.3 
THE ETHICAL CONSIDERATIONS ........................................................................................ 25 
3.2.4 
THE DATA QUALITY ASSURANCE ....................................................................................... 26 
3.2.5 
THE PARTICIPANT POPULATION ........................................................................................ 26 
3.2.5.1 
INCLUSION/EXCLUSION CRITERIA .................................................................................. 27 
3.2.6 
THE TREATMENT AND TREATMENT ALLOCATION SCHEDULE ........................................... 27 
3.2.7 
ANY CONCOMITANT MEDICATIONS AND TREATMENTS ................................................... 28 
3.2.8 
DURATION OF FOLLOW-UP ............................................................................................... 28 
3.2.8.1  
THE STATISTICAL ANALYSIS ....................................................................................... 29 
3.2.8.2 
THE CLINICAL INVESTIGATION HYPOTHESIS OR PASS/FAIL CRITERIA ........................... 29 
3.2.8.3 
 SAMPLE SIZE CALCULATION.......................................................................................... 29 
3.2.8.4 
STATISTICAL ANALYSIS METHODS ................................................................................. 30 
4. 
RESULTS ......................................................................................................................................... 30 
4.1 CLINICAL INVESTIGATION INITIATION/CONCLUSION AND SUBJECTS BASELINE CHARACTERISTICS30 
4.2 CLINICAL INVESTIGATION CLOSE-OUT ............................................................................................. 30 
4.3 DISPOSITION OF SUBJECTS .............................................................................................................. 31 

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4.4 DEMOGRAPHY AND OTHER BASELINE CHARACTERISTICS .............................................................. 31 
4.5 CLINICAL INVESTIGATION PLAN COMPLIANCE ................................................................................ 33 
4.6. DATA QUALITY ASSURANCE ........................................................................................................... 33 
4.7 PRIMARY OUTCOMES ...................................................................................................................... 33 
4.8 AE, SAEs ........................................................................................................................................... 35 
4.8.1 DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT ADVERSE EVENTS .... 36 
4.8.1.1 DEATHS .............................................................................................................................. 36 
4.8.1.2 OTHER SERIOUS ADVERSE EVENTS .................................................................................... 36 
4.8.1.3 OTHER SIGNIFICANT ADVERSE EVENTS ............................................................................. 36 
4.8.1.4 NARRATIVES OF DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT 
ADVERSE EVENTS ........................................................................................................................... 36 
4.8.1.5 ANALYSIS AND DISCUSSION OF DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER 
SIGNIFICANT ADVERSE EVENTS ..................................................................................................... 36 
4.8.1.6 CLINICAL LABORATORY EVALUATION................................................................................ 36 
4.8.1.7 VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATION RELATED TO SAFETY ....... 36 
4.8.1.8 ANALYSIS OF LOCAL AND SYSTEMIC REACTIONS .............................................................. 36 
4.8.1.9 SAFETY CONCLUSION ......................................................................................................... 36 
4.9 SECONDARY OUTCOMES ................................................................................................................. 37 
4.9.1 CHANGE IN VAGINAL DISCHARGE ASPECT ............................................................................... 37 
4.9.2 CHANGE IN VAGINAL PH VALUES ............................................................................................. 38 
4.9.3 CHANGE IN VAGINAL MICROFLORA AND LACTOBACILLI COUNT ............................................. 38 
4.9.4 CHANGE IN VAGINAL INFLAMMATION .................................................................................... 39 
4.9.5 PARTICIPANT SATISFACTION .................................................................................................... 39 
4.9.6 EXPLORATORY ANALYSIS .......................................................................................................... 40 
4.9.6.1. PERFORMANCE IN POSTMENOPAUSAL WOMEN ............................................................. 40 
4.9.6.2 PERFORMANCE IN BALANCING VAGINAL PH IN SEXUALLY ACTIVE PATIENTS .................. 43 
5.  DISCUSSIONS AND OVERALL CONCLUSIONS ................................................................................. 43 
6.  ABBREVIATED TERMS AND DEFINITIONS ...................................................................................... 46 
7.  ETHICS ............................................................................................................................................ 46 
8.  INVESTIGATORS AND ADMINISTRATIVE STRUCTURE OF CLINICAL INVESTIGATION .................... 47 
INSTITUTUL NATIONAL PENTRU SANATATEA MAMEI SI COPILULUI " ALESSANDRESCU-RUSESCU" 47 
8.1 SITE PERFORMANCE .................................................................................................................... 47 
9 REFERENCES ........................................................................................................................................ 49 
ANNEX 1. STUDY-RELATED ESSENTIAL DOCUMENTATION ................................................................... 52 
ANNEX 2. THE EC FAVOURABLE OPINION AND ESSENTIAL CORRESPONDENCE ................................... 52 
AUTHORS AND SPONSOR SIGNATURE PAGE ......................................................................................... 53 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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1 GENERAL 
1.1 TITLE OF THE CLINICAL INVESTIGATION 
A Prospective, Open-Label, Pilot, Multicentric Clinical Investigation to Evaluate the Performance and 
Safety of Cerviron® ovules in the Local Treatment of Non-Specific or Endogenous, Symptomatic 
Vaginitis. 
1.2 SCIENTIFIC APPROACH IN CLINICAL STUDY DESIGN, PLANNING, CONDUCT, ANALYSIS AND 
REPORTING 
Cerviron® is a class IIb medical device indicated as an adjuvant treatment in atrophic, irritant, and 
inflammatory vaginitis caused by the imbalance of the vaginal pH and changes of the vaginal 
microflora. It favors the healing and re-epithelialization processes of the vaginal mucosa and reduces 
the proliferation of endogenous pathogens. 
The present clinical investigation was design as a national, open-label, pilot, multicentric clinical 
investigation following the provisions of good clinical practice stated in the international standard ISO 
14155:2020 (1) and the applicable national legislation. 
All risks associated with the investigational device were estimated in accordance with ISO 14971:2019 
(2) prior to initiating the clinical investigation. The justification for the design of the clinical 
investigation was based on the description and specification of the medical device and the evaluation 
of pre-clinical data included in the General Description. Emerging non-clinical and pharmaceutical 
quality data were reviewed and evaluated by qualified experts to assess the potential implications for 
the safety of study participants. 
Following the principles of ICH E8 (R1), Guideline on general considerations for clinical studies, the 
clinical investigation design was informed by input from a broad range of stakeholders, including 
participants and healthcare providers. Several discussion sessions were opened from the side of the 
sponsor organization with the clinical investigators and other site staff, with the scope of not only 
building quality into the clinical investigation, but also to select the best eligibility criteria and clinically 
meaningful endpoints for the participants.  
The Clinical Investigation Plan version 1.0 dated 06 January 2021 was followed during the execution of 
the clinical investigation. The Ethics Committee favourable opinion is listed in ANNEX 2.  
No major protocol deviations were reported.  
No amendments to the Clinical Investigation Plan were performed during the study conduct. 
All investigators involved in study conduct received training commensurate with their role in the study 
prior to their becoming involved in the study. Adherence to the CIP and other relevant documents was 
monitored throughout the study performance and documented. 
1.3 PROTECTION OF THE CLINICAL INVESTIGATION PARTICIPANTS 
The clinical investigation was carried out following the principles stated in the Declaration of Helsinki. 
(3) The National Ethics Committee (CNBMDM) evaluated all participant-related documentation and 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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released its favorable opinion prior to the site initiation. All clinical investigators and all parties involved 
in the conduct of the clinical investigation shared the responsibility for its ethical conduct. 
1.4 OVERALL SYNOPSIS OF THE CLINICAL INVESTIGATION REPORT 
Name of Sponsor 
PERFECT CARE DISTRIBUTION (ROMANIA) 
Title 
A Prospective, Open-Label, Pilot, Multicentric Clinical Investigation to 
Evaluate the Performance and Safety of Cerviron Ovules® in the Local 
Treatment of Non-Specific or Endogenous, Symptomatic Vaginitis 
Protocol Code 
CYRON/01/2021 
Indication 
Non-Infectious, Symptomatic Vaginitis 
Hypothesis 
The primary hypothesis is that the medical device can be effectively and 
safely administered in human participants for the treatment of non-
specific or endogenous, symptomatic vaginitis. 
Clinical 
Investigation 
Objectives 
Primary Objectives 
The primary objective is to assess the therapeutic performance and 
tolerability of Cerviron® Ovules in participants with symptomatic, non-
specific, non-infectious vaginitis, and endogenous symptomatic infections. 
Secondary Objectives 
The secondary objective of this clinical investigation is the assessment of 
performance of the medical device by several additionally clinical 
outcomes (vaginal discharge, vaginal pH, microscopic characteristics of 
inflammatory cells and characteristics of vaginal microflora). 
Participants will also evaluate the degree of satisfaction related to the use 
of the medical device. 
Clinical 
Investigation 
Method 
This investigation used as a clinical research method a pilot, intervention 
study with the primary purpose of treating an existing condition and an 
additional goal of optimizing intervention delivery, with specific attention 
to adherence and fidelity. 
Trial Design Overview 
The clinical investigation was conducted in Romania, in two 
geographically different research institutions (Bucharest and Timisoara), 
in a hospital-based setting.  
Voluntary participants were recruited onsite and included women aged 18 
years and older, presenting vaginal symptoms and a diagnosis of 
endogenous vaginitis. 
The clinical data was collected using the electronic platform OpenClinica. 
OpenClinica is compliant with FDA and EMA regulations, including 21 CFR 
Part 11, HIPAA, GDPR, ICH-GCP, as well as with data practices and security 
standards (ISO, SOC). 

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The safety evaluable individuals included Intention-to-Treat (ITT) cohort 
consisting of all the participants who received the investigational medical 
device. 
The efficacy analysis was done in Per-Protocol (PP) population, which 
included only participants who have attended the 3rd follow-up visit (at 
3 months) and did not record any major protocol deviations.  
The Medical Device 
The medical device is Cerviron® Vaginal Ovules. 
Perfect Care Distribution has developed a formulation of vaginal ovules 
containing a combination of active compounds and plant extracts, with an 
adjuvant role in the treatment of vaginitis of mechanical etiology, caused 
by imbalances in vaginal pH or disturbances of the vaginal microflora. 
Cerviron® Vaginal Ovules as per its Instructions for Use is indicated also for 
re-epithelization and repair of the cervical mucosa after cervical lesions, 
ulcerations and wounds of mechanical etiology. The composition of the 
ovules is as follows: Bismuth subgalate 100 mg, Hydrolyzed collagen 15 mg, 
Thyme extract (Thymus vulgaris) 10 mg, Hydrastis canadensis extract 10 
mg, Marigold extract (Calendula officinalis) 10 mg, Turmenic extract 
(Curcuma longa ) 10 mg and Hexylresorcinol 2 mg.  
Cerviron® Vaginal Ovules has obtained the European Conformity marking 
during the assessment performed in March 2020 under the requirements 
of the Medical Device Directive (MDD 93/42/EEC), that was replaced by the 
new MDR (Medical Device Regulation) 2017/745.  
The recommended use of Cerviron® is one ovule per day, inserted on the 
first day after the menstruation and during 15 consecutive days. Its 
adjuvant role is consolidated during the administration for a period of 3 
consecutive months. 
Participant population 
Inclusion criteria 
 
1 
Adult females, aged 18 years to 65 years; 
2 
Participants presenting two or more vaginal symptoms such as 
leucorrhoea, pruritus, burning sensation, erythema, pain, odour, 
dysuria, or dyspareunia; 
3 
Participants with a diagnosis of either non-infectious vaginitis, or 
endogenous, symptomatic infection; 
4 
Negative for Gardnerella vaginalis, Candida albicans, Trichomonas 
vaginalis; 
5 
Participants willing to provide signed informed consent to clinical 
investigation participation. 
 
Exclusion criteria 
 
1 
Participants in menstrual period or suffering from menorrhagia; 
2 
Colpectomy; 
3 
Participants with undiagnosed abnormal genital bleeding; 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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4 
Participants with vulvar, vaginal or cervical cancer; 
5 
Known, active sexually transmitted infection (STI) in partner, as per 
anamnesis; 
6 
Participants with HIV or other immunodeficiency; 
7 
Participants with any pathology of the female reproductive organs; 
8 
Known allergy or hypersensitivity to the medical device 
ingredients; 
9 
Use of spermicides; 
10 Use of diaphragm; 
11 Concomitant topical or systemic anti-infective treatment; 
12 Unable to comply with visit procedures; 
13 Participants included in other clinical investigations; 
A total number of 50 subjects were screened and 47 participants were 
considered eligible for the completion of this study. The 47 participants 
fully met the inclusion and exclusion criteria, signed the Inform Consent, 
and performed the Baseline visit. Out of 50 subjects enrolled in the clinical 
study, three subjects did not meet the inclusion and exclusion criteria, as a 
result they were not included in the clinical trial. The safety population 
included the 47 subjects that took the treatment; more precisely 39 
subjects had a 100% compliance, 6 subjects had a 75% compliance, and 2 
participants had a 50% compliance. The ITT population included 47 
subjects that received the treatment of the study medical device. The Per 
Protocol Set population, subjects who completed all the visits without 
major protocol deviations, was 47 subjects. 
Clinical investigation endpoints 
The primary endpoints are: 
• 
Clinical Performance assessed by the investigator by gynecological examination and participant's 
interview at 90 days, or after 3 consecutive months of treatment. 
Success was defined by resolution (return to participant's usual gynecological conditions, i.e., 
before the episode which warranted inclusion in the study) OR substantial improvement of 
clinical signs of infectious vaginitis (i.e., abnormal vaginal discharge), and/or vaginal symptoms 
(vaginal burning and/or vaginal pain, and/or vaginal irritation and/or pruritus and/or odour). 
Failure is defined by persistence or worsening of symptoms and clinical signs or requirement of 
an alternative or specific treatment. 
• 
The number of treatment-related Adverse Events in volunteers participating in the clinical 
investigation collected during 90 days. 
The secondary endpoints are: 
• 
Change in vaginal discharge aspect during clinical exam, assessed by the investigator at 1, 2 and 
3 months by using a score between 0 = absent and 4=purulent. 
• 
Change in vaginal pH values at 1, 2 and 3 months, compared to its normal values (3.8 - 4.5). 
• 
Change in vaginal microflora and Lactobacilli count by microscopy performed at 3 months. 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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• 
Change in vaginal inflammation by microscopy performed at 3 months. 
• 
Participant Satisfaction performed at 3 months by using a five-point Likert Scale. 
 
Statistical analysis 
All statistical analyses were be performed using the R statistical software (version 4.1.1) with a few 
extra statistical packages added, all of which have been revised and updated to the latest version. 
The final analysis was completed after all subjects have finalized the study, all queries have been 
resolved, and the database has been locked. 
The overall type I error was preserved at 5%.  
Statistical analyses were conducted on all subjects who have successfully completed the study 
without a CIP deviation that is regarded as impacting the assessment of the key variables (as per CIP). 
Quantitative variables (i.e., demographic) if normally distributed were described through mean ± 
Standard Deviation (SD), otherwise median, minimum, maximum, and interquartile range were 
showed. Qualitative variables were evaluated using frequencies and percentages. 
To evaluate changes of proportions over time before and after the treatment, for categorical 
variables two-proportions z test were performed. 
The quality and completeness of the collected data were evaluated preliminary compared to data 
analysis.  
No study participant has been involved in any violation of inclusion/exclusion criteria. 
Primary endpoint 
As defined in the CIP, the primary efficacy outcomes to evaluate the tested Cerviron® were: Clinical 
Performance assessed by the investigator by gynecological examination and tolerability related to 
the therapy at 90 days, or after 3 consecutive months of treatment. The primary hypothesis is that, 
after 3 months after using the medical device, the clinical symptoms will be improved by 100.00% of 
the treated participants. 
Secondary endpoints 
As secondary hypotheses we assume that several additionally clinical outcomes will be improved with 
100.00% of the participants using the medical device. The secondary objective of this clinical 
investigation included the assessment of performance of the medical device by several additionally 
clinical outcomes, such as change in vaginal discharge aspect, change in vaginal pH values, change in 
vaginal microflora and Lactobacilli count, change in vaginal inflammation, and Participant Satisfaction 
at the end of 3 months of treatment. 
Safety endpoints 

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The safety of Cerviron® was measured by the rate of treatment-related adverse events, including 
serious adverse events (SAEs). 
Safety analysis  
There were a total number of 3 adverse events unrelated to the medical device usage reported for 
participants 0203, 0213 and 0224. 
At the end of study, no treatment-related AE were reported. 
Results 
Primary outcome 
For 34 (72.34%) study participant using Cerviron® the medical device had a beneficial effect on the 
score of Vaginal Symptoms, while for only 13 participants (27.66%) the score remained the same (p 
< 0.001). 
Secondary outcomes. 
Change in Vaginal Discharge Aspect. The difference in change for Vaginal Discharge Aspect between 
baseline visit and final visit was statistically significant at 5% significance level (p < 0.05). 
Change in Vaginal pH values. Determination of pH values compared to its normal values (3.8 – 4.5). 
The difference in change of Vaginal pH values between the baseline and final visit, at 5% significance 
level was statistically significant (p < 0.05). 
Change in vaginal microflora and Lactobacilli count. The change in Lactobacilli species throughout the 
study was not statistically significant (p > 0.05). 
Change in vaginal inflammation. The difference in change in vaginal inflammation between baseline 
and final visit, at 5% significance level was statistically significant (p < 0.001). 
Participant satisfaction. The degree of satisfaction when using the medical device was assessed using 
a five-point Likert Scale. A total number of 32 out of 47 participants (82.98%) were very satisfied, 6 
participants (12.77%) were satisfied, and 2 participants were neutral. No participants were reported 
as unsatisfied or very unsatisfied. 
Trial Duration: 
The regulatory submission of the clinical investigation dossier was performed on 24 February 2021. 
The NEC favorable opinion for the clinical investigation performance was received on 01 April 2021. 
The total study duration was between 27 April 2021 and 28 February 2022. 
Each participant was followed for 3 months or approximately 90 days. 
The Visit Flow Chart is detailed in Table 1. 

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Table 1. Visit Flow Chart 
PROCEDURE \ EVENT 
Screening 
Visit 1 
(Day -3 to Day 0) 
Clinic 
Visit 1 
(Day 0) 
Clinic 
Visit 2 
(Day 30) 
Clinic 
Visit 3 
(Day 60) 
Clinic 
Visit 4 
(Day 90) 
VISIT CODE 
SV1 
CV1 
CV2 
CV3 
CV4 
Informed consent 
X 
 
 
 
 
Demography data 
X 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Physical examination 
X 
 
X 
X 
X 
Participant’s Interview (collection of vaginal 
symptoms) 
X 
 
X 
X 
X 
Collection of vaginal swab 
X 
 
X 
X 
X 
Vaginal smear (collection of vaginal discharge) 
X 
 
X 
X 
X 
Vaginal pH 
 
X 
X 
X 
X 
Inflammatory and parabasal cells (microscopy) 
 
X 
 
 
X 
Participant satisfaction (Likert Scale) 
 
 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
Medical device prescription and instructions for 
use 
 
X 
 
 
 
Medical device accountability 
 
 
 
 
X 

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End of Clinical investigation Definition: 
The end of clinical investigation was considered as the last visit for the last participant in the study 
(participant no. 0235) that perform the onsite visit in 28 Feb 2022. 
Conclusions 
The purpose of the present clinical investigation was to evaluate the therapeutic performance and 
tolerability of Cerviron® Ovules in participants with symptomatic, non-specific, non-infectious 
vaginitis, and endogenous symptomatic infections. The beneficial effects were assessed as changes 
between the final visit, visit 3, visit 2, and visit 1 (Baseline) in the following performance outcomes: 
Clinical Performance after thorough gynecological examination and participant’s interview at end of 
treatment visit over 90 days. The results obtained show very clearly that during the 3 months of 
treatment with Cerviron®, out of the 47 participants who initially showed vaginal symptoms, a 
proportion of 72.24% unequivocally showed an improvement in symptoms. Significant improvements 
were also found in Vaginal discharge aspect score, pH values and vaginal inflammation score. Some 
improvements were found in vaginal microflora and Lactobacilli count, but they were not statistically 
significant. 
In terms of adverse events, 3 study participants reported Grade 1 - vaginal infection, that were 
resolved under treatment with Cerviron®. At the end of study, no treatment - related AE were 
reported. 
In conclusion, administration of Cerviron® vaginal ovules for a period of 3 months significantly 
alleviates the symptoms of symptomatic, non-specific, non-infectious vaginitis, and endogenous 
symptomatic infections and its administration is considered safe. 
 
 

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2. INTRODUCTION 
2.1 
STUDY RATIONALE AND BACKGROUND 
Vaginitis is the general term characterizing a spectrum of disorders of the vagina caused by infection, 
inflammation, or changes in the normal vaginal flora. Symptoms include abnormal vaginal discharge, 
odor, pruritus, pain, dysuria, discomfort and dyspareunia. (4,5) Moreover, vaginitis is responsible for 
the most common problems in clinical medicine, and it is the reason cited most often for visits to 
obstetricians and gynecologists. In the past years, the problem of vaginitis has all too often been 
ignored by the medical community or regarded merely as a minor annoyance to women. According to 
Gardner, “Vaginitis must cause more unhappiness on earth than any other gynecologic disease”. In 
addition to the many physical and emotional problems associated with vaginitis, the economic loss 
involved is of astronomic proportions.”(6) 
The most common causes of vaginitis are bacterial vaginosis, vulvovaginal candidiasis, and 
trichomoniasis. (7) Bacterial vaginosis is the cause in 40% to 50% of cases in which a cause is identified, 
with vulvovaginal candidiasis accounting for 20% to 25% and trichomoniasis for 15% to 20% of cases.  
There is no cause of vaginitis identified in up to 30% of women. These women may have a range of 
conditions, including irritant or allergic vaginitis, atrophic vaginitis, or physiologic discharge. (8) 
Notable infective cause include Group A streptococci, Haemophilus, Staphylococci and rarely Shigella. 
(5) The presence of objective signs of vulvar inflammation in the absence of vaginal pathogens after 
laboratory testing suggests the possibility of mechanical, chemical, allergic, or other non-infectious 
causes of vulvovaginal signs or symptoms. It is believed that the oxidative stress has a major role in 
vaginal epithelial cells apoptosis leading to non-specific vaginitis. Normally, a healthy vaginal 
environment maintains a balance between the protective organisms (Lactobacillus) and other 
anaerobic and aerobic flora, with Lactobacillus as the majority organism. The adversely altered balance 
between protective organisms and potential pathogens in the microenvironment of genital tract 
results in gynecological disease, such as non-specific vaginitis. In healthy women, H2O2 is produced by 
lactobacilli and maintained a typical concentration in the vaginal fluid. This typical concentration of 
H2O2 is toxic to many microorganisms and thus provides an intrinsic protective mechanism in the 
vaginal compartment.  
Non-specific vaginitis (also called vaginal dysbiosis) is the disruption of the vaginal microbiome. Recent 
studies show that the vaginal dysbiosis affects human papilloma virus acquisition, persistence, and 
progression to related cervical premalignancy. (9) 
Several other types of non-infectious vaginitis are encountered in clinical practice: inflammatory 
vaginitis, desquamative inflammatory vaginitis, irritant vaginitis, atrophic vaginitis, cytolytic vaginitis 
and aerobic vaginitis.  
Inflammatory vaginitis is an uncommon condition characterized by purulent vaginal discharge, 
burning, and dyspareunia, and should be considered in participants with these symptoms if no 
infectious cause is found. Inflammatory vaginitis is associated with low estrogen levels, such as in 
menopausal or perimenopausal women.  

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Desquamative inflammatory vaginitis is a chronic inflammatory process involving both vagina and 
vestibule, occurring almost exclusively in white women, that responds well to topical anti-
inflammatory therapy. Long-term maintenance therapy is frequently required. (10,11) 
Irritant/allergic vaginitis is characterized by symptoms such as burning and soreness and signs such as 
vulvar erythema. 
Atrophic vaginitis is an uncommon condition that occurs as a consequence of estrogen deficiency and 
is characterized by symptoms such as thin, clear discharge, vaginal dryness, dyspareunia, itching. An 
examination of the vulva can indicate inflammation and thin and friable vaginal mucosa. Risk factors 
contributing to atrophic vaginitis are menopause, lactation, oophorectomy, radiation therapy, 
chemotherapy, immunologic disorders, premature ovarian failure, endocrine disorders, and 
antiestrogen medications. (7) 
Aerobic vaginitis is a distinct vaginal condition, requiring different clinical management and with 
distinct clinical risks. (12) Aerobic vaginitis is defined by disruption in Lactobacillus dominance but is 
accompanied by more extreme inflammatory changes than bacterial vaginosis and the presence of 
mainly 
aerobic 
enteric 
commensals 
or 
pathogens, 
including 
Group 
B Streptococcus (S. 
agalactiae), Enterococcus faecalis, Escherichia coli, and Staphylcoccus aureus. Streptococcus 
agalactiae vaginal pathogenicity is not uniformly acknowledged throughout the literature. Group 
B Streptococcus virulence for vagina was recognized in the past, as the organism has been observed to 
potentially cause local inflammation and discharge, as well as Lactobacilli rarefaction. (13) 
Cytolytic vaginosis is another condition which has been recently described as an entity distinct from 
either normal flora or bacterial vaginosis. This condition, also called Döderlein’s vaginitis, has 
numerous, active lactobacilli damaging epithelial cells because of extreme acidity and low pH. The bare 
nuclei and cellular debris that are seen during microscopy, should not be mistaken for leucocytes and 
cocci. (14) 
Cerviron ovules® is a class IIb medical device developed as adjuvant in the treatment of the following 
conditions: 
1. acute and chronic vulvovaginitis of mechanical etiology, caused by changes of vaginal pH and 
changes of the vaginal flora.  
2. cervical lesions of mechanical origin as it favors the healing and re-epithelialization processes 
of the cervical mucosa and reduces the proliferation of endogenous pathogens. 
Cerviron ovules® is indicated as a maintenance treatment to prevent relapse of non-specific vaginitis, 
as this occurs very often. 
The Cerviron® medical device is intended to be used with antibiotics as a treatment for non-specific 
vaginitis. Cerviron® vaginal ovules prevents relapses and helps restore vaginal pH while preserving 
Lactobacilli species. They are indicated as long-term supportive therapy, either as a stand-alone 
treatment or in combination with other oral therapies with antibiotics, antifungals or antivirals. The 
plant alkaloids in its composition (Marigold, Thyme and Turmenic) and in addition, alkylresorcinols 
exert an excellent support in its antibacterial action. Cerviron® supportive therapy may be prescribed 
for 10 or 15 consecutive days. 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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When used as a stand-alone treatment, the medical device Cerviron® performed well in reducing 
unpleasant symptoms in atrophic vaginitis. Topical agents such as Cerviron ® ovules are preferred in 
treating these cases versus hormonal treatments that increase the risk of estrogen exposure, 
Treatment with Cerviron® vaginal ovules showed a beneficial effect in atrophic vaginitis, offering a 
good local control of the disease without containing any estrogen derivate. (15) 
NCT04735705 was the first planned clinical investigation on human volunteers, in which 50 
participants were screened and 47 participants were enrolled, design to investigate the performance 
and safety of Cerviron® ovules when administered in participants with symptomatic, non-specific, non-
infectious vaginitis. The primary objective was to assess the therapeutic performance and tolerability 
of Cerviron® ovules in participants with symptomatic, non-specific, non-infectious vaginitis, and 
endogenous symptomatic infections. The secondary objective of the clinical investigation was the 
assessment of performance of the medical device by several additionally clinical outcomes, including 
vaginal discharge, vaginal pH, microscopic characteristics of inflammatory cells and characteristics of 
vaginal microflora.  
A second clinical investigation, NCT04735718 is currently conducted to evaluate the performance and 
safety of Cerviron® ovules in cervix lesions postoperative care. 
2.2 BENEFIT/RISK ASSESSMENT 
Cerviron® ovules contains ingredients that provide therapeutic performance as an adjunct in the 
treatment of acute and chronic vulvovaginitis of mechanical etiology, caused by changes in vaginal pH 
and changes in vaginal flora. The main mechanism of action of the medical device is the dispersion of 
ingredients in the vagina, thus forming a protective barrier that promotes and accelerates the healing 
process of damaged epithelium, restoring the original vaginal ecosystem.  
The solutions drafted to design and create the medical device Cerviron® ovules ensures, according to 
the Medical Device Regulation 2017/745, the elimination of any kind of internal and external risks 
associated to the use of the product, respectively the medical device was designed and performed not 
to compromise the participants’ health or safety. The risks related to biocompatibility and toxicity are 
eliminated using materials that fall within the stipulated norms, the microbiological and physio-
chemical verification of the raw materials, of the intermediate product and of the finished product. 
The risk of toxicity is eliminated from the design of the medical device by setting the doses of active 
substances below the limit provided by the literature for the occurrence of toxic effects. The active 
ingredients used have a local therapeutic effect, their systemic absorption being very low, which leads 
to the elimination of systemic side effects. 
The risk associated to the use of the medical device Cerviron® ovules is in the acceptable limits in 
relation to the participant’s benefit, being compatible with a high level of safety and health protection 
- according to the certificates of analysis and to the physical, chemical and microbiological test reports. 
Moreover, the medical device was designed, manufactured, and packed so that its features and 
performances were not affected as a result of the transport and storage according to its instructions 
for use. 
While the performance and safety profile of the Cerviron® ovules are subject to investigation when 
used in postoperative care, the only contraindication to Cerviron® ovules has been determined as 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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hypersensitivity to the active substance or to any of the excipients within the medical device. 
Therefore, participants volunteering for this trial are not considered to be at additional risk related to 
the administration of the medical device. Collection of other samples, like vaginal swabs, and vaginal 
smears are considered not to cause any significant harm.  
Considering its short-term duration of action as well as the medical device’s instructions for use, a 
small sample size of 50 participants was defined for this clinical investigation. 
3. INVESTIGATIONAL DEVICE AND METHODS 
3.1 
DESCRIPTION OF THE INVESTIGATIONAL DEVICE 
The generic name of the device: Vaginal mucosa protection suppository  
The commercial name of the device: Cerviron® 
Medical device class: IIb 
The medical device comes in contact with the vaginal mucosa for a prolonged exposure time - the 
cumulative amount of single, multiple or repeated contact time is likely to exceed 24 hours but will not 
exceed 30 days. 
Cerviron® vaginal ovules is a class IIb medical device intended to be used as adjuvant in the treatment 
of acute and chronic vulvovaginitis of mechanical etiology, caused by changes of vaginal pH and/or 
changes of the vaginal flora, and in cervical lesions of mechanical origin. It favors the healing and re-
epithelialization processes and reduces the proliferation of endogenous pathogens. 
Composition per ovule 
Cerviron® is composed of: Bismuth subgallate 100 mg, hydrolyzed Collagen 15 mg, Thyme extract 
(Thymus vulgaris) 10 mg, Goldenseal extract (Hydrastis canadensis) 10 mg, Marigold extract (Calendula 
officinalis) 10 mg, Turmeric extract (Curcuma longa) 10 mg, Hexylresorcinol 2 mg. 
The structural formula 
Semisolid, ovoid ovules, with yellow to intense yellow colour, weighing 2 g per each ovule, with no 
color spots or areas with agglomerated powder. In longitudinal section, the ovule has a homogenous 
aspect, no powder agglomerations or air bubbles. 
The medical device is essentially a dispersion of active substances in a molten mass (50°C), in a 
stainless-steel melting device. After homogenization, the melted mass is distributed in PVC/PE shapes 
and cooled down. This product’s formula was prepared using selected excipients, frequently used in 
the pharmaceutical industry for manufacturing similar products.  
The specifications of the most important compounds are defined in the European Pharmacopeia.  For 
the others, the features are specified in the internal monographs. 
The base is mainly composed by fat, an excipient frequently used to manufacture vaginal ovules and 
medicinal suppositories. The base contains a modified content of monoglycerides, which offer 
hydrophilic properties. 
Melting characteristic: the fat bases must liquefy only at body temperature.  

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In order to formulate this product, a hard fat produced by Gattefosse - France, called Suppocire Nas 
50, was chosen. The melting point for this base is between 33,5°C and 35°C. The melting point for the 
finished product is between 35°C and 37°C. This melting interval is adequate for vaginal ovules.  
Cerviron® ovules are packaged in cardboard boxes imprinted according to the legislation in force. Each 
box contains 2 PVC/PVC blisters with 5 ovules each, with instructions of use. 
The quality and quantity structure of the medical device is detailed in the Table 2 below. 
Table 2: Active ingredients and excipients 
No. 
Ingredients  
Quantity/ 
100g 
Quantity/ 
ovule 
(mg) 
Function 
Reference 
standard 
1. 
Bismuth subgallate 
5 
100,0 
Astringent, 
healing 
Eu.Ph.10.0 
2. 
Hexylresorcinol 
0,1 
2,0 
Antimicrobial 
Eu.Ph.10.0 
3. 
Hydrolyzed collagen 
0.75 
15.0 
Healing 
ST 
producer 
4. 
Thyme extract (Thymus vulgaris) 
0.5 
10.0 
Antifungal 
ST 
producer 
5. 
 Goldenseal 
extract 
(Hydrastis 
canadensis) 
0.5 
10.0 
Hemostatic 
ST 
producer 
6. 
Marigold 
extract 
(Calendula 
officinalis) 
0.5 
10.0 
Healing 
ST 
producer 
7. 
Turmeric extract (Curcuma longa) 
0.5 
10.0 
Anti-
inflammatory 
ST 
producer 
8. 
Semi-synthetic 
glycerides/ 
SUPPOCIRE NAS 50 PELLETS 
84.5 
1690.0 
Base 
Eu.Ph.10.0 
9. 
Anhydrous lanolin 
6.15 
123.0 
Base 
Eu.Ph.10.0 
10. 
Colloidal silicon dioxide 
1.5 
30.0 
Stabilizing 
agent 
Eu.Ph.10.0 
TOTAL 
2000 mg 
 
 

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The technical features of the medical device are shown in Figure 1.
 
Figure 1. Technical Drawing 
 
Contraindications  
Hypersensitivity to any of the ingredients of the medical device.  
Warnings and Special Cautions for Use  
Considering its composition, in general, no cautions are necessary when using the medical device. Due 
to insufficient data regarding the use of the medical device during pregnancy, caution and a referral to 
the specialist physician are recommended in case of pregnancy.  
Pregnancy and Breastfeeding  
Due to insufficient clinical data, it is recommended to consult a specialist before administration to 
pregnant women. No caution is necessary in case of use during breastfeeding. The active compounds 
are not excreted in breast milk following the use of Cerviron®. 
Effects on the Ability to Drive and Use Machines  
Cerviron® do not influence the ability to drive vehicles or use machines. 
Side Effects  
Rarely local, light, transient irritations can appear. Hypersensitivity reactions can appear. 
Overdose  
No overdose cases are known. 
3.1.1 
THE INTENDED USE OF THE INVESTIGATIONAL DEVICE(S) 
The existing scientific data from the literature regarding the active compounds as well as the structural 
formula constitute a scientific support for the intended use of the medical device.   

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Cerviron vaginal ovules is a medical device with local therapeutic effect recommended for adult 
women suffering from atrophic, aerobic and traumatic vaginitis, cervicitis, cervix erosions and 
leucorrhea of unspecified cause. 
3.1.2  DESCRIPTION OF MECHANISM OF ACTION OF THE INVESTIGATIONAL DEVICE, ALONG WITH 
SUPPORTING SCIENTIFIC LITERATURE 
Cerviron® vaginal ovules is a class IIb medical device, intended to be used as an adjuvant in the 
treatment of acute and chronic vulvovaginitis of traumatic etiology, vulvovaginitis caused by changes 
of vaginal pH and changes of the vaginal flora, atrophic vulvovaginitis and also of cervical lesions of 
traumatic origin. It favors the healing and re-epithelialization processes and reduces the proliferation 
of endogenous pathogens. 
During the development of the medical device, the manufacturer aimed to obtain a product with 
astringent, re-epithelializing and protective properties intended to be used as an adjuvant in the 
treatment of gynecological diseases without microbial component and to promote the restoration of 
normal vaginal flora. 
Cerviron® vaginal ovules has a content of substances that grants beneficial properties in the treatment 
of non-infectious vulvovaginitis and cervical erosions. The ovule melts in the vaginal mucosa forming 
a cream that ensures uniform dispersion of substances contained and acts as a protective barrier with 
astringent effect, favoring re-epithelialization of damaged tissue and restoration of the initial colpo-
ecosystem without affecting the vaginal Döderlein bacilli and thus it creates favorable conditions for 
their multiplication while preserving the healthy vaginal microenvironment. 
Bismuth subgallate  
Bismuth subgallate is a yellow, odorless powder that fades when exposed to sunlight. Bismuth 
subgallate is a potent astringent agent, an action which can promote precipitation of some proteins 
and the formation of a protective film which lines the biopsied area in the time period immediate to 
the surgery or local trauma. Although the exact mechanism(s) of action by which bismuth compounds 
are able to cause such antimicrobial effects is not very well defined, a number of experimental 
observations suggest that bismuth forms a protective barrier that decreases the adhesion of bacteria 
to epithelial cells. his film can represent a physical protection, reducing the bacteria colonization and 
preventing the excessive formation of granulation tissue. (16,17) Its astringent, local hemostatic and 
healing properties recommend Cerviron® as a potential candidate for the treatment of gynecological 
conditions with an inflammatory component. Its strong astringent ability can facilitate both its 
deodorizing and hemostatic effects that support its use in a number of over-the -counter products 
such as hemorrhoidal suppositories or other topical applications.   
Studies have shown that bismuth compounds such as bismuth subgallate are able to demonstrate 
antimicrobial effects against various pathogens such as E. coli, Salmonella, Shigella, Vibrio cholera, 
Campylobacter jejuni, H. pylori and some enteric viruses such as Rotaviruses. (18) Another advantage 
is its capacity to block the colonization of bacteria, preventing the reinfection and vaginitis recurrence, 
which occur very often. Bismuth subgallate promotes a high-quality scar formation, very important in 
women of childbearing age. Studies have shown that bismuth compounds such as bismuth subgallate 
are able to demonstrate antimicrobial effects against various pathogens such as E. coli, Salmonella, 
Shigella, Vibrio cholera, Campylobacter jejuni, H. pylori and some enteric viruses such as Rotaviruses.  

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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Histometric measurements in studies of bismuth subgallate-treated wounds showed a larger area of 
ulceration of bismuth subgallate-treated wounds on the first day, which could be explained by the 
presence of bismuth subgallate that fills the wound to the tip and acts as a barrier to the initial 
contraction. This filling could be a factor that helps protect the wounds from trauma and bacteria. An 
interesting finding is that, as the test wounds healed, the bismuth subgallate was located deep in the 
tissues in a small amount. This did not significantly impede the normal healing of this tissue (connective 
tissue and epithelium). (19) 
In the composition of Cerviron® vaginal ovules medical device, the Bismuth Subgallate powder is in the 
amount of 5% and it is used, due to its astringent properties, to create a physical barrier over the 
affected area of the vaginal mucosa and therefore to clock oxygen and pathogens to come in contact 
with it. In this way, the substance creates the premises that allow the damaged tissue to heal naturally 
and prevents the development of pathogenic bacteria by favoring the restoration of normal vaginal 
flora. 
Hexylresorcinol  
Hexylresorcinol has local anesthetic, antiseptic and anthelmintic properties. 
On July 22, 1991, the US Food and Drug Administration (FDA) has published the Final monograph for 
first aid antimicrobial- antiseptic products where Hexylresorcinol was identified as 1st category 
antimicrobial ingredient. The antimicrobial resistance continues to be a universal concern with a huge 
impact on the therapeutic arsenal. Extended efforts were made to validate new agents for 
antimicrobial effect. For example, recent studies made by Chaudhuri et al. showed that Hexylresorcinol 
has DNA topoisomerase inhibition activity (IC50 30 pM), which is well comparable with m-Amsacrine 
(30 pM) and Purpurin (40 pM). (10) Chaudhuri concluded that Hexylresorcinol has an excellent 
antimicrobial activity. Specifically, Chaudhuri has performed an assessment to assess the value of the 
minimum HR inhibiting concentration (MIC in µg / ml) against various relevant organisms, according 
to the US Pharmacopeia Products Compendia for the 2nd category. (20) 
Hexylresorcinol is used in the composition of the medical device Cerviron® vaginal ovules with a 
consistent role, to prevent the development of endogenous bacteria and possibly those that can reach 
inside the vagina when administering the medical device. The 0.1% concentration of hexylresorcinol in 
the medical device inhibits the development of endogenous and exogenous bacteria in the ovule 
during handling and administration. (21) 
Nikolaev and colleagues also demonstrated that alkylresorcinols such as 4- Hexylresorcinol can be used 
as an adjuvant to increase the efficiency of several known antibiotics. The therapeutic approach where 
hexylresorcinol is associated with an antibiotic could minimize the risk for development of genetically 
determined antibiotic resistance and could be assumed that it reduces the episodes of recurrence due 
to antibiotic treatment failure. (22)  
Vegetable Collagen 
Collagen is the main construction element of living tissues, being a complex of amino acids with 
nutritive, hydrating, healing, trophic effect. As hydrolysate is easily soluble and absorbable, helping to 
revitalize the damaged areas and restoring the trophicity of the vaginal mucosa. 
Collagen is structurally and functionally a key protein of the extracellular matrix which is also involved 
in forming the scars during the healing of conjunctive tissues. Many collagen bandages were developed 
to improve the repair of the wound, especially of non-infected, chronic, idle cutaneous ulcerations. 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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Collagen fibers form the extracellular framework of all tissues. In the early healing of wounds, type III 
collagen is established first, the type I proportion growing while the formation of the scar advances 
and is remodeled. The deposit and remodeling of collagen contributes to increasing the wound’s 
traction resistance, which is approximately 20% at an interval between one to three weeks after the 
trauma and gradually reaching 70% of the regular skin. (23) Although the epithelial structures can heal 
through regeneration, the conjunctive tissues cannot depend also on the repair process, especially 
through the formation of collagenous scar tissue, mainly type I, which serves to restore the continuity, 
resistance and function of the tissues. (24) Collagen is a fragile substitute of the unwanted tissue, and 
the scar tissue rarely exceeds 70% of the power of the unwanted tissue.  
In vitro, natural collagen can be formed into highly organized, three-dimensional scaffolds that are 
intrinsically biocompatible, biodegradable, nontoxic upon exogenous application, and endowed with 
high tensile strength. These attributes make collagen the material of choice for wound healing and 
tissue engineering applications. (25) 
Plant collagen supports a moist environment, conducive to wound healing, encourages the deposition 
of new collagen fibers, supports the growth of new tissues and the formation of granulation tissue in 
the wound bed. A key component of chronic wounds is an increased level of matrix metalloproteinases 
(MMPs). At high levels, MMP not only degrades non-viable collagen, but also viable collagen. In 
addition, fibroblasts in a chronic wound cannot secrete tissue MMP inhibitors at an appropriate level 
to control MMP activity. These events prevent the formation of scaffolds necessary for cell migration 
and ultimately prevent the formation of extracellular matrix (ECM) and tissue granulation. Exogenous 
collagen action acts as a "sacrificial substrate" in the wound. Also, collagen degradation products have 
been shown to be chemotactic for a variety of cell types required for granulation tissue formation. (26) 
Taking into account the data from the specialized literature, collagen, applied topically in the case of 
wounds, maintains the level of humidity at the level of the wound, favoring its healing. At the same 
time, the exogenous intake of collagen favors the degradation of excess MMP and elastase, which, in 
its absence, would degrade natural collagen, delaying the healing of the wound. 
In the medical device Cerviron®, the hydrolysed vegetable collagen is in the amount of 0.75%. 
The thyme extract (Thymus vulgaris)  
The thyme extract (Thymus vulgaris) has a strong antifungal activity on the Gram-positive and Gram-
negative bacteria. The activity is mainly attributed to thymol and carvacrol. (27) The extracts with a 
higher percentage of phenolic compounds show a higher inhibiting activity. The connections between 
the thymol concentration and the minimum concentration of bactericides suggest that the formation 
of the membrane forming perforations is the main manner of action of thymol against oral bacteria. 
(28,29) 
Thymus vulgaris extract is used in the medical device Cerviron® ovules to prevent the development of 
bacteria and fungi that may come in contact with the vaginal mucosa during handling of the medical 
device. This substance acts as a preservative for the ovule. 
Numerous scientific citations support the antimicrobial properties of thyme oil and rank it among the 
most powerful essential oils in this regard. (30) Its effectiveness has been attributed mainly to thymol 
and carvacrol, two phenolic compounds present in the essential oil of T. vulgaris, as well as other 
species of Lamiaceae mentioned under the common names of thyme and oregano. (31) Thymol 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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comprises the main component of herbal essential oil belonging to the so-called thymol chemotype of 
T. vulgaris, while a high thymol content is generally found in commercial thyme oil. 
Thyme essential oil has shown a strong antibacterial action against Staphylococcus aureus, 
Pseudomonas aeruginosa and E. coli in formulary O/W as well as W/O. Data from the literature 
demonstrate an antifungal activity against the mycelia and spores of Aspergillus flavus, Aspergillus 
niger and Aspergillus ochraceus, at a minimum inhibitory concentration of 0.25 - 1 mg / ml. (32) The 
thyme oil presented high invitro activity, with values below 0.50mg/mL for almost all the 
microorganisms tested. (33) 
The LC50 of thyme oil against mice was recorded as 7142.85 μl kg− 1 body weight indicating its non-
mammalian toxicity and strengthening its safe exploitation as preservative. For industrial relevance, 
the thyme essential oil may be recommended for large scale application as a plant-based preservative 
because of its strong antifungal as well as antiaflatoxigenic efficacy. Because of its broad antimicrobial 
spectrum, more efficacy over prevalent synthetic preservatives as well as non-mammalian toxicity, the 
thyme essential oil may be formulated as a safe and economical plant-based preservative against 
fungal infestation and aflatoxin contamination. (34) 
In the composition of Cerviron® vaginal ovules, Thymus vulgaris extract is found in the concentration 
of 0.5% and has a preservative role, in particular, to prevent attacks by exogenous germs during the 
administration of the medical device. 
The Goldenseal extract (Hydrastis Canadensis)  
The main constituents of the goldenseal root are isoquinoline alkaloids, such as hydrastine (1.5-4%), 
berberine (2.5%), canine (0.5%) and other alkaloids. Berberine is usually found in goldenseal roots as 
a sulphate at a concentration of 5000–60,000 ppm (35) Hydrastine is also found in goldenseal in 
concentrations of 15,000-40,000 ppm. Secondary metabolites include also sideroxylin, 8-desmethyl-
sideroxillin and 6-desmethyl-sideroxylin. (36) 
Hydrastis Canadensis powder has an astringent effect on the mucous membranes of the upper 
respiratory tract, the gastrointestinal tract, the bladder, the rectum, and the skin. Astringent herbs are 
used to reduce blood loss from the reproductive tract as well as the gastrointestinal tract, respiratory 
tract, and skin. The astringents most effective in uterine blood loss are often those that are high in 
tannins, although the tannins are most likely not the only constituent responsible. 
The mechanism of such activities is complex and involves various cellular kinases and signaling 
pathways. Berberine has activity against various parasites such as tapeworm, viruses and candida 
(yeast) infection.  Berberine is also known to stimulate the immune system. Rehman et al. have 
reported that, like Echinacea, Goldenseal has also immunomodulator effects, as shown by the growth 
of the primary immunoglobulin answer (IgM) against antigen in rats. The authors have reached the 
conclusion that Goldenseal extract improves the immune answer by increasing the production of 
immunoglobulin specific for the foreign object (antigen). (37) 
In the composition of Cerviron® ovules medical device, the Goldenseal powder is found in the amount 
of 0.5%, used to promote the natural healing of damaged tissues and to reduce the irritative symptoms 
that manifest in non-infectious vulvovaginitis. It promotes the natural re-epithelialization processes. 
 
 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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The Marigold extract (Calendula officinalis)  
The Marigold extract contains as active principles carotenoid substances, triterpenic compounds and 
volatile oil. These give a healing, antitricomonazic, reducing the excessive abnormal vaginal secretion 
(leucorrhea). 
In the composition of Cerviron® ovules medical device, the Calendula officinalis extract is found in the 
amount of 0.5%, used to promote the natural healing of damaged tissues and to reduce the irritative 
symptoms that manifest in non-infectious vulvovaginitis. It promotes the natural re-epithelialization 
processes. 
Calendula officinalis extract is traditionally used for the symptomatic treatment of minor 
inflammations of the skin and as an adjuvant in the healing of minor wounds. (38) 
Calendula officinalis, belonging to the family of Asteraceae, commonly known as English Marigold or 
Pot Marigold is an aromatic herb which is traditionally used for treating wounds, ulcers, herpes, scars, 
skin damage, frostbite and blood purification. It is also used for gastrointestinal diseases, gynecological 
problems, eye diseases, skin injuries and some cases of burn. Calendula is used topically as suspension 
or tincture for treating acne, reducing inflammation, controlling bleeding, and soothing irritated tissue. 
This plant is rich in many pharmaceutical active ingredients like carotenoids, flavonoids, glycosides, 
steroids and sterols quinines, volatile oil, and amino acids. The medicinal use of Calendula flower 
preparations for the symptomatic treatment of minor inflammations of the skin or the oral mucosa, 
and as an aid in healing minor wounds is documented in a number of scientific references. (39,40)  
Turmenic extract (Curcuma longa) 
Turmeric is acquired from Curcuma longa L., a tuberous herbaceous perennial plant with yellow 
flowers and wide leaves, which is a member of ginger family and grows in tropical climate. 
In the Cerviron ovules medical device, Turmeric extract is found in a concentration of 0.5%, used to 
promote the natural healing and reepithelization of damaged tissues and to reduce the irritating 
symptoms that occur in non-infectious vulvovaginitis.  
Overall, there is early evidence that turmeric/curcumin products and supplements, both oral and 
topical, may provide therapeutic benefits for skin health. However, currently published studies are 
limited, and further studies will be essential to better evaluate efficacy and the mechanisms involved. 
(41–43) 
The curcumin found in turmeric can help wounds heal by decreasing inflammation and oxidation. It 
also lowers the response of the body to cutaneous wounds. This results in in acceleration of the wound 
healing process. Studies have found that turmeric and collagen can positively impact different 
biological processes relevant to wound healing.  
Curcumin acts on different stages of the natural wound healing process to speed healing. Studies 
provide evidence of the ability of curcumin to reduce the body's natural response to skin wounds, such 
as inflammation and oxidation. (44) Recent literature on the healing properties of curcumin also 
provides evidence of its ability to enhance granulation tissue formation, collagen deposition, tissue 
remodeling, and wound contraction. Curcumin has been shown to have strong modular effects on 
wound healing. Studies have shown that curcumin does this by acting on the inflammatory, 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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proliferative and remodeling phases of the wound healing process and therefore reduces the time 
required to heal wounds. (45) 
In traditional medicine, Turmeric is applied topically for the treatment of acne, wounds, burns, bruises, 
ulcers, eczema, insect bites, parasitic infections, bleeding and skin diseases such as herpes zoster and 
pemphigus. It is used as a paste or ointment (mixed with oil or other substances), in the form of a 
tincture or extract. The healing effects of Curcuma longa extract have been studied in rabbits. The 
group treated with Curcuma longa showed a significantly higher mean value for wound contraction 
compared to the controls. Furthermore, the wounds showed lower inflammation and an increasing 
tendency in collagen formation.  
 
Synthetic amorphous silica  
Synthetic amorphous silica (SAS), in the form of pyrogenic (fumed), precipitated, gel or colloidal SAS, 
has been used in a wide variety of industrial and consumer applications including food, cosmetics and 
pharmaceutical products for many decades. (46) There are no relevant clinical trials and thus the 
pharmacological, immunological or metabolic effects of colloidal silicon dioxide cannot be confirmed. 
In the compositon of Cerviron® ovules ovules, this substance is used as a stabilizing agent. 
Lanolin 
Lanolin is listed in the CosIng database of the European Commission with the function of antistatic, 
hair and skin conditioning (emollient), surfactant cleansing and surfactant emulsifying. Lanolin is 
antistatic, hair and skin conditioning (emollient), surfactant cleansing and surfactant emulsifying. No 
relevant in vitro and in vivo studies and clinical trials for the assessment of pharmacological, 
immunological or metabolic activities are available. For this reason, pharmacological, immunological 
or metabolic effects cannot be confirmed for anhydrous lanolin.  In the composition of Cerviron® 
ovules, this substance is used for the dispersion of the substances in the fat base. 
 
Semi-synthetic glycerides 
As a base ingredient the semi-synthetic glycerides are used, a hard fat composed of mono-, di- and 
triglyceride esters of fatty acids (C10 to C18). Suppocire has been approved as a non-toxic and non-
irritating ingredient in medicinal products. It provides good dispersion and compatibility properties for 
ingredients in the suppository mass as well as softening and diffusion properties for efficient and 
uniform 
release 
of 
the 
ingredients 
(https://www.gattefosse.com/pharmaceuticals-
products/suppocire-nas-50). In a study investigating the suppository parameters breaking hardness, 
disintegration time and release properties of ingredients in vaginal suppositories, Suppocire NA was 
found to be the best lipophilic base in comparison to similar products. (47) 
For detailed investigational device information, please refer to Investigator’s Brochure version 1.0 
dated 04 February 2021. 
3.1.3 
PREVIOUS INTENDED USES OR INDICATIONS FOR USE, IF RELEVANT 
Not applicable. 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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3.1.4 
ANY CHANGES TO THE INVESTIGATIONAL DEVICE DURING THE CLINICAL INVESTIGATION OR 
ANY CHANGES FROM THE IB  
Not applicable. 
3.2 
CLINICAL INVESTIGATION PLAN (CIP) 
During the clinical investigation CIP version 1.0 dated 06 January 2021 was used. The CIP was drafted 
according to ISO 14155:2020. No amendments were performed to this version. A copy of the clinical 
investigation plan is available by request. 
3.2.1 
THE CLINICAL INVESTIGATION OBJECTIVES 
Primary Objectives 
The primary objective was to assess the therapeutic performance and tolerability of Cerviron® Ovules 
in participants with symptomatic, non-specific, non-infectious vaginitis, and endogenous symptomatic 
infections. 
Secondary Objectives 
The secondary objective of this clinical investigation was the assessment of performance of the medical 
device by several additionally clinical outcomes (vaginal discharge, vaginal pH, microscopic 
characteristics of inflammatory cells and characteristics of vaginal microflora). 
Participants also evaluated the degree of satisfaction related to the use of the medical device. 
3.2.2 
THE CLINICAL INVESTIGATION DESIGN  
This present clinical investigation was a non-randomized intervention, single-group assignment, open 
label with the primary purpose of treatment. 
Since Cerviron® vaginal ovules has an innovative composition, was preferred an exploratory approach 
for the design of the present clinical investigation. The main objectives and clinical endpoints were the 
performance and the safety profile of the investigational medical device. 
Fifty (50) participants were recruited during this clinical investigation. 
The primary endpoints were:  
1 
Clinical Performance Assessed by the Investigator after thorough gynaecological examination 
[Time Frame: 3 months] 
Success was defined by resolution (return to participant's usual gynecological conditions, i.e. before 
the episode which warranted inclusion in the study) OR substantial improvement of clinical signs of 
infectious vaginitis (i.e. abnormal vaginal discharge), and/or vaginal symptoms (vaginal burning and/or 
vaginal pain, and/or vaginal irritation and/or pruritus and/or odour). 
Failure was defined by persistence or worsening of symptoms and clinical signs or requirement of an 
alternative or specific treatment.  
2 
Rate of treatment-related Adverse Events in subjects participating in the clinical investigation 
[Time Frame: 3 months]  

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The safety of CERVIRON® as measured by the rate of treatment-related adverse events, including 
serious adverse events (SAEs), in subjects participating in the clinical investigation. 
The secondary endpoints were: 
1 
Change in Vaginal Discharge Aspect during Clinical Exam, Assessed by the Investigator [Time 
Frame: at 1, 2 and 3 months]  
The vaginal discharge was assessed by the treating physician using a score between 0 and 4, as follows: 
0=absent  
1=mild: insufficient for speculum collection  
2=moderate: sufficient for speculum collection  
3=abundant: visible at the introitus even before speculum introduction  
4=purulent, abnormal discharge: visible at the introitus even before speculum 
introduction  
2 
Change in vaginal pH values [Time Frame: at 1, 2 and 3 months]  
The determination of pH values was performed using the Veneris pH Tests for vaginal infections.  
3 
Change in vaginal microflora and Lactobacilli count [Time Frame: 3 months]  
The change in Lactobacillus species was shown through laboratory microscopy.  
4 
Change in vaginal inflammation [Time Frame: 3 months]  
The change in inflammatory and parabasal cells was performed through laboratory microscopy.  
5 
Participant Satisfaction (Likert Scale) [Time Frame: 3 months] 
The degree of satisfaction when using the medical device was assessed using a five-point Likert Scale. 
3.2.3 
THE ETHICAL CONSIDERATIONS 
The present clinical investigation was conducted in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki.  
These principles protect the rights, safety and well-being of human subjects, which are the most 
important considerations and shall prevail over interests of science and society. These principles were 
understood, observed, and applied at every step in the clinical investigation by the Investigator, the 
Investigator’s nominated staff, the Sponsor personnel and the Contract Research Organization 
personnel. 
All parties involved in the conduct of the clinical investigation shared the responsibility for its ethical 
conduct in accordance with their respective roles in the clinical investigation. 
The present clinical investigation was conducted in accordance with the provisions of the International 
Standard ISO 14155:2020 Clinical Investigation of medical devices for human subjects - Good Clinical 
Practice. These principles address Good Clinical Practice for the design, conduct, recording and 
reporting of clinical investigations carried out in human subjects to assess the safety and performance 
of medical devices. These principles were understood, observed, and applied at every step in the 
clinical investigation. 

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Prior to commencing the clinical investigation, the Sponsor obtained documentation of the EC’s 
approval/favorable opinion. The present clinical investigation did not begin until the required 
approval/favorable opinion from the EC or regulatory authority have been obtained. 
3.2.4 
THE DATA QUALITY ASSURANCE 
The collected data was subjected to multiple checks for correctness (entry errors). Every information 
has been verified by an SDV (Source Data Verification) process, performed by the study monitors. Data 
clarification queries have been implemented to obtain clean data. 
All data collected through the data management system, by eCRFs, were checked for completeness 
and extreme values (outlier) presence. The data was collected using the electronic platform 
OpenClinica. OpenClinica is compliant with FDA and EMA regulations, including 21 CFR Part 11, HIPAA, 
GDPR, ICH-GCP), as well as with data practices and security standards (ISO, SOC). Any anomalies found 
were forwarded by the study monitor to the Investigator. Such data queries were solved with priority, 
in no more than 3 days from the query’s opening. It was the statistician’s decision to use/accept the 
revised data for the subsequent statistical analyses. 
Data for the present clinical investigation is stored according to Annex E of ISO 14155:2020. 
All statistical analyses were performed using the R statistical software (version 4.1.1) with a few extra 
statistical packages added, all of which have been revised and updated to the latest version. The final 
analysis was completed after all subjects have finalized the study, all queries have been resolved, and 
the database has been locked. 
The overall type I error will be preserved at 5%. Data from unscheduled visits was not included in the 
analysis. 
Statistical analyses were conducted on all subjects who have successfully completed the study without 
a CIP deviation that is regarded as impacting the assessment of the key variables (as per CIP). 
Quantitative variables (i.e., demographic) if normally distributed were described through mean ± 
Standard Deviation (SD), otherwise median, minimum, maximum, and interquartile range were 
showed. Qualitative variables were evaluated using frequencies and percentages. 
To evaluate changes of proportions over time before and after the treatment, for categorical variables 
two-proportions z test were performed. 
The quality and completeness of the collected data were evaluated preliminary compared to data 
analysis. No study participant has been involved in violation of inclusion/exclusion criteria. 
3.2.5 
THE PARTICIPANT POPULATION 
The target population for this clinical investigation was comprised of females suffering from 
symptomatic vulvovaginitis, either non-specific or caused by an endogenous imbalance in the vaginal 
microflora, with abnormal vaginal secretion and with characteristics signs and symptoms, such as 
pruritus, erythema, burning, pain, odor, dysuria and dyspareunia. 
Vulnerable subjects were not enrolled in this clinical investigation. 
 
 

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3.2.5.1 INCLUSION/EXCLUSION CRITERIA 
3.2.5.1.1 Inclusion criteria for subject selection 
The inclusion criteria have been verified at the screening visit (day -3). Each potential subject had to 
satisfy all the following criteria before being enrolled in the clinical investigation: 
• 
Adult females, aged 18 years to 65 years; 
• 
Subjects presenting two or more vaginal symptoms such as leucorrhoea, pruritus, burning 
sensation, erythema, pain, odour, dysuria, or dyspareunia; 
• 
Subjects with a diagnosis of either non-infectious vaginitis, or endogenous, symptomatic 
infection; 
• 
Negative for Gardnerella vaginalis, Candida albicans, Trichomonas vaginalis; 
• 
Subjects willing to provide signed informed consent to clinical investigation participation. 
3.2.5.1.2 Exclusion criteria for subject selection 
The exclusion criteria have been verified at the screening visit (day -3). Subjects fulfilling one or more 
of the following exclusion criteria have not been included in the clinical investigation: 
• 
Subjects in menstrual period or suffering from menorrhagia; 
• 
Colpectomy; 
• 
Subjects with undiagnosed abnormal genital bleeding; 
• 
Subject with vulvar, vaginal or cervical cancer; 
• 
Known, active sexually transmitted infection (STI) in partner, as per anamnesis; 
• 
Subjects with HIV or other immunodeficiency; 
• 
Subjects with any pathology of the female reproductive organs; 
• 
Known allergy or hypersensitivity to the medical device ingredients; 
• 
Subjects using spermicides; 
• 
Subjects using diaphragm; 
• 
Concomitant topical or systemic anti-infective treatment; 
• 
Unable to comply with visit procedures; 
• 
Subjects included in other clinical investigations. 
3.2.6 
THE TREATMENT AND TREATMENT ALLOCATION SCHEDULE 
This present clinical investigation was a non-randomized intervention, open label, single group 
assignment with the primary purpose of treatment. 
Cerviron vaginal ovules ® is an adjuvant treatment for acute and chronic vulvovaginitis of mechanical 
etiology, caused by changes of vaginal pH and/or changes of the vaginal microflora. It favours the 
healing and re-epithelialization processes and reduces the proliferation of endogenous pathogens. 
Composition per ovule 
Cerviron® is composed of: Bismuth subgallate 100 mg, hydrolyzed Collagen 15 mg, Thyme extract 
(Thymus vulgaris) 10 mg, Goldenseal extract (Hydrastis canadensis) 10 mg, Marigold extract (Calendula 
officinalis) 10 mg, Turmeric extract (Curcuma longa) 10 mg, and Hexylresorcinol 2 mg. 
After the final eligibility check performed by the treating physician (after the collection of the vaginal 
swabs) the participant was instructed regarding the medical device usage. 

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As per Instructions for use, the recommended dose prescribed was 1 Cerviron® ovule inserted vaginally 
with a total number of 15 days. The investigational device, the instructions for use and the primary 
and secondary packaging were designed following the requirements of national and EU regulations 
and indicated that the investigational device is intended exclusively for use in the present clinical 
investigation. Accountability forms were kept separately and were reported by Investigator for each 
participant at each study visit.  
Each participant followed a treatment schema of 3 months (a total of 45 days of treatment). 
In case of pregnancy, in general, no specific cautions are necessary. Due to insufficient data regarding 
the using of the medical device during pregnancy, a specialist should be consulted in case of 
administration to pregnant women. 
There were no cases of pregnancy during our investigation. 
3.2.7 
ANY CONCOMITANT MEDICATIONS AND TREATMENTS 
Vaginal tampons usage was prohibited during the clinical investigation because tampons can absorb 
some of the active substances and as such, they can prevent the ovule from exhibiting its full 
performance. 
Also, a list of restricted concomitant medications was defined in CIP Attachment (Prohibited 
Concomitant Medication and Treatments) for the purpose of distinguishing between the efficacy of 
the medical device in questions and other therapies that can exert the same therapeutic effect. The 
prohibited concomitant medication list is shown below: 
1. Vaginal creams, ointments, lubricants; 
2. Use of other anti-infectious treatments, either systemic or local; 
3. Use of hydrocortisone cream or other local, anti-inflamatory therapy; 
4. Vaginal tampons; 
5. Use of an etonogestrel/ethinyl estradiol vaginal ring (Nuvaring® 152 ) or other intrauterine 
device; 
6. Oral or vaginal antibiotic therapy or other vaginal therapies (like douching, spermicide); 
7. Oral or vaginal probiotics (e.g. vaginal lactobacilli). 
Without these exceptions in terms of concomitant medications, the treating physician was free to add, 
withdraw, or alter doses of any kind of medication at his/her own discretion based on standard medical 
practice. All concomitant medication and treatments were recorded in the appropriate study 
documents (the eCRF and source data). 
3.2.8 
DURATION OF FOLLOW-UP 
The clinical investigation included subjects under treatment with Cerviron® vaginal ovules for 
approximately 3 months. 
Each enrolled subject performed 4 visits. The screening visit (SV) took place with 3-0 days before the 
baseline visit (day 0). On day 0 the subjects received the medical device. 
The study participants had 4 visits at the investigational site, at 30 days interval each. The study visit 
flow-chart is listed in Figure 2. 

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Figure 2. Study Flow Chart 
3.2.8.1  THE STATISTICAL ANALYSIS  
Quantitative variables (i.e., demographic) if normally distributed were described through mean ± 
Standard Deviation (SD), otherwise median, minimum, maximum, and interquartile range were 
showed. Qualitative variables were evaluated using frequencies and percentages. To evaluate changes 
of proportions over time before and after the treatment, for categorical variables a two-proportions z 
test were performed. 
The quality and completeness of the collected data were evaluated preliminary compared to data 
analysis.  
No participant subject has been involved in violation of inclusion/exclusion criteria. 
Statistical analysis and generation of tables, figures, and patient data listings were performed using R 
statistical software version 4.1.1 according to the standard operating procedures used during the 
clinical investigation performance (SOPs).  
All variables were analyzed in an explorative manner using descriptive statistics only. Summary 
statistics consisted of frequency tables for categorical variables. For continuous variables, descriptive 
statistics (number of available observations, mean and median, standard deviation [SD], minimum, and 
maximum) were tabulated unless specified otherwise.  
3.2.8.2 THE CLINICAL INVESTIGATION HYPOTHESIS OR PASS/FAIL CRITERIA 
The primary hypothesis is that, after 3 months after using the medical device, the clinical symptoms 
will be improved by 100.00% of the treated participants (50 out of 50 evaluable subjects). As secondary 
hypotheses we assume that several additionally clinical outcomes will be improved with 100.00% of 
the participants using the medical device. 
The intended performance that will be verified during this clinical investigation is the medical device’s 
effect in symptomatic, non-specific, non-infectious vaginitis, and endogenous symptomatic infections 
treatment. 
3.2.8.3  SAMPLE SIZE CALCULATION 
During September 2020 - January 2021, we performed a review of the scientific literature to find similar 
investigations to determine the minimal clinically difference between Baseline and a similar period of 
treatment of 90 days. In a similar study, conducted by Murina, 44 samples were collected to achieve a 
power of 80% and one-sided significance of 5% for detecting a difference of 0.25 between marginal 
proportions. (48) 
50 participants 
planned 
SCREENING 
0 – 3 days 
VISIT 1 
VISIT 2 
VISIT 3 
VISIT 4 
30 days 
30 days 
30 days 

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To confirm the sample size in the Murina study, we decided to repeat the calculation, and according 
to Cohen's (1988) calculation formula, considering a drop-out rate of about 10%, we estimated a 
representative sample around 50 participants. 
3.2.8.4 STATISTICAL ANALYSIS METHODS 
All statistical analyses were performed using the R statistical software (version 4.1.1) with a few extra 
statistical packages added, all of which have been revised and updated to the latest version. The final 
analysis was completed after all subjects have finalized the study, all queries have been resolved, and 
the database has been locked. 
The overall type I error was preserved at 5%. Statistical analyses were conducted on all subjects who 
have successfully completed the study without a CIP deviation that is regarded as impacting the 
assessment of the key variables (as per CIP). 
4. 
RESULTS 
4.1 CLINICAL INVESTIGATION INITIATION/CONCLUSION AND SUBJECTS BASELINE CHARACTERISTICS 
The Clinical Investigation Initiation was performed during a Site Initiation Visit conducted at each of 
the selected sites approved by the National Ethics Committee. The sites and the Principal Investigators 
are listed below: 
Name: 
Associated Professor Daniela-Oana Toader, MD 
Centre: 
Clinical Investigational Site 01 
Institutul National pentru Sanatatea Mamei si Copilului “Alessandrescu-
Rusescu” Obstetrics-Gynecology “Polizu” 
Department of Obstetrics-Gynecology III 
38-52 Gheorghe Polizu Street, District 1 
011061 Bucharest, Romania 
Name: 
Associated Professor Izabella Petre, MD 
Centre: 
Clinical Investigational Site 02 
Spitalul Clinic Judetean de Urgenta “Pius Brinzeu” Timisoara 
Department of Obstetrics-Gynecology II 
12 Victor Babes Boulevard 
300226 Timisoara, Romania 
4.2 CLINICAL INVESTIGATION CLOSE-OUT 
The Clinical Investigation completion was performed on March 3rd, 2022, once all the data of all 
participants enrolled were collected, checked for correction and the database lock was done. 

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4.3 DISPOSITION OF SUBJECTS 
A total number of 50 subjects were screened and 47 participants were considered eligible for the 
completion of this study. The 47 fully met the inclusion and exclusion criteria, signed the Inform 
Consent, and performed the Baseline visit. 
Out of 50 subjects enrolled in the clinical study, three subjects did not meet the inclusion and exclusion 
criteria, as a result they were not included in the clinical trial. All 47 participants completed all visits. 
The safety population included the 47 subjects that took the treatment; more precisely 39 subjects 
had a 100% compliance, 6 subjects had a 75% compliance, and 2 participants had a 50% compliance. 
The ITT population included 47 subjects that received the treatment of the study medical device. 
The Per Protocol Set population, subjects who completed all the visits without major protocol 
deviations, was 47 subjects. The distribution of participants on the two sites is listed in Table 3. 
 
Site Number 
No of 
screened 
participants 
No of 
enrolled 
participants 
First 
participant 
IN 
First 
participant 
OUT 
Last 
participant 
IN 
Last 
participant 
OUT 
Site 01 
15 
15 
15.07.2021 
25.09.2021 
01.09.2021 
28.11.2021 
Site 02 
35 
32 
27.04.2021 
10.07.2021 
27.11.2021 
28.02.2022 
Table 3. The distribution of study participants. 
4.4 DEMOGRAPHY AND OTHER BASELINE CHARACTERISTICS 
The following table 4 shows the demography of the study participants. 
Baseline characteristics 
Experimental 
 
n 
% 
Age (years): mean [range] 
47 
41.23 [22 – 64] 
Gender 
 
 
    Female 
47 
100.00 
    Male 
0 
0.00 
Ethnicity 
 
 
    Caucasian 
47 
100.00 
Childbirth potential 
 
 
    Yes 
36 
76.60 
    No 
11 
23.40 
 
 

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Baseline characteristics 
Experimental 
 
n 
% 
Subject in menopause 
 
 
    Yes 
9 
19.15 
    No 
38 
80.85 
Subject pregnant 
 
 
    Yes 
0 
0.00 
    No 
47 
100.00 
History of cancer 
 
 
    Yes 
2 
4.26 
    No 
45 
95.74 
Sex life 
 
 
    Yes 
44 
93.62 
    No 
3 
6.38 
Reproductive life 
 
 
    Yes 
25 
53.19 
    No 
22 
46.81 
Tobacco consumption 
 
 
    Yes 
20 
42.55 
    No 
27 
57.45 
Alcohol consumption 
 
 
    Yes 
0 
0.00 
    No 
47 
100.00 
Physical activity 
 
 
    Yes 
32 
68.09 
    No 
15 
31.91 
Rest/Day 
 
 
    Yes 
34 
72.34 
    No 
13 
27.66 
Hydration 
 
 
    Yes 
36 
76.60 
    No 
11 
23.40 
Table 4. Demographic data of all study participants 

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4.5 CLINICAL INVESTIGATION PLAN COMPLIANCE 
During the study period no major protocol deviation and/or issue were reported regarding the clinical 
investigation plan. 
4.6. DATA QUALITY ASSURANCE 
The collected data was subjected to multiple checks for correctness (entry errors). Every information 
was verified by an SDV process, performed by the study monitors. Data Clarification Forms were 
implemented to obtain clean data. 
The database lock was performed after the study’s statistician approved all the data for correctness 
and completeness.  
4.7 PRIMARY OUTCOMES 
The following primary outcomes were collected in this study: Clinical Performance Assesses by the 
Investigator After Thorough Gynecological Examination and Participant’s Interview at End of 
Treatment Visit, after 3 months.  
Success was defined by resolution (return to participant’s usual gynecological conditions, i.e., before 
the episode which warranted inclusion in the study) or substantial improvement of clinical signs of 
infections vaginitis (i.e., abnormal vaginal discharge), and/or vaginal symptoms (vaginal burning and/or 
vaginal pain, and/or vaginal irritation and/or pruritus and/or odor). As per CIP, failure was defined by 
persistence or worsening of symptoms and clinical signs or requirement of an alternative or specific 
treatment. 
The Presence of Vaginal Symptoms Score Change between Baseline and Final Visit is detailed in Table 
5.  
Baseline score 
Visits 
 
Baseline 
Final 
Yes Answer 
47 
13 
No Answer 
0 
34 
Total number of subjects 
47 
47 
Table 5. The Presence of Vaginal Symptoms score change between baseline and final visit. 
The primary hypothesis is that, after 3 months after using the medical device, the clinical symptoms 
will be improved by 100.00% of the treated participants. 
For 34 out of 47 participants (72.34%) treated with Cerviron©, the medical device had a beneficial 
effect on the score of Vaginal Symptoms, while for only 13 participants (27.66%) the score remained 
the same. Performing a test for equality of proportions with continuity correction, at 5% significance 
level, and considering a null hypothesis that is no statistically significant difference between baseline 
visit and final visit, we evidenced that the differences between these values were statistically 
significant (p < 0.001, 95% CI [57.42% - 87.25%]). 

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A very important aspect of Cerviron© treatment is that it reduces the symptoms of vaginitis after 30 
days. Thus, for 9 out of 47 patients (19.15%) who were treated, the medical device had a beneficial 
effect on the score of Vaginal Symptoms (p < 0.05, 95% CI [5.77% - 32.52%]) measured at Visit 2 (30 
days). This improvement in vaginal score is much more evident at 60 days when 25 out of 47 patients 
(53.19%) showed an improvement in symptoms (p < 0.001, 95% CI [36.80% - 69.58%]). 
Even if between Visit 3 (60 days) and Visit 4 (90 days) there is a reduction of the score of 19.5%, more 
precisely the score improves for 9 patients, this improvement is not statistically significant (p = 0.081). 
The effect of Vaginal Symptoms changes between visits for Cerviron© is graphically presented in Figure 
3. 
 
Figure 3. Change from baseline for Vaginal Symptoms – comparison between Visits 
The variables collected by Investigators were the Vaginal Symptoms and the vaginal swab results. The 
Investigators collected through Patient’s interview the presence or absence of the following 
symptoms: leucorrhea, pruritus, burn, rash, pain, odour, dysuria, dyspareunia. The vaginal swab results 
were delivered by the Bioclinica central laboratory. (Table 6). 
 
Vaginal 
Symptoms 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
 
YES 
NO 
YES 
NO 
YES 
NO 
YES 
NO 
Leucorrhea 
45 
(93.62%) 
2 
(4.26%) 
26 
(55.32% 
21 
(44.68) 
16 
(34.04%) 
31 
(65.96% 
12 
(25.53%) 
35 
(74.47%) 
Pruritus 
8 
(17.02%) 
39 
(82.98%) 
44 
(93.62% 
3 
(6.38%) 
1 
(2.13%) 
46 
(97.87%) 
1 
(2.13%) 
46 
(97.87%) 
Burn 
6 
(12.77%) 
41 
(87.23%) 
1 
(2.13%) 
46 
(97.87%) 
0 
(0.00%) 
47 
(100.00%) 
0 
(0.00%) 
47 
(100.00%) 
Rash 
9 
(19.15%) 
38 
(80.85%) 
2 
(4.26%) 
45 
(95.74%) 
0 
(0.00%) 
47 
(100.00%) 
0 
(0.00%) 
47 
(100.00%) 

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Pain 
24 
(51.06%) 
23 
(48.94% 
3 
(6.38%) 
44 
(93.62%) 
1 
(2.13%) 
46 
(97.87%) 
0 
(0.00%) 
47 
(100.00%) 
Bad smell 
13 
(27.66%) 
34 
(72.34%) 
7 
(14.89%) 
40 
(85.11%) 
3 
(6.38%) 
44 
(93.62%) 
3 
(6.38%) 
44 
(93.62%) 
Dysuria 
8 
(17.02%) 
39 
(82.98%) 
4 
(8.51%) 
43 
(91.49%) 
5 
(10.64%) 
42 
(89.36%) 
0 
(0.00%) 
47 
(100.00%) 
Dyspareunia 
15 
(31.91%) 
32 
(68.09%) 
9 
(19.15%) 
38 
(80.85%) 
3 
(6.38%) 
44 
(93.62%) 
1 
(2.13%) 
46 
(97.87%) 
Vaginal 
swab 
results* 
45 
(95.74%) 
2 
(4.26%) 
45 
(95.74%) 
2 
(4.26%) 
40 
(85.11%) 
7 
(14.89%) 
42 
(89.36%) 
5 
(10.64%) 
* 1 – Normal Vaginal Swab Results, 0 – Pathological Vaginal Swab Results 
Table 6. The Presence or absence of symptoms related to Vaginal Symptoms – comparison between 
Visits 
At the same time, the effectiveness of Cerviron© on each symptom related to the vaginitis was studied 
separately. Thus, it was observed that treatment for 90 days with Cerviron© significantly reduced the 
following symptoms:  Leucorrhea (p <0.001), Pruritus (p < 0.05), Burn (p < 0.05), Rash (p < 0.05), Pain 
(p < 0.001), Bad smell (p < 0.05), Dysuria (p < 0.05), and Dyspareunia (p < 0.001). 
In Figure 4 the evolution of each symptom from Baseline, and throughout all the study visits is 
represented. 
 
Figure 4. Vaginal Symptoms and Vaginal swab results – comparison between visits 
4.8 AE, SAES 
During the study conduct, safety was assessed at every visit. Three study participants (with study codes 
0203, 0213 and 0224) were reported with mild, grade-1 vaginal infection. Study participant no. 0203 
experienced a Streptococcus infection while study participants 0213 and 0224 experienced E. Coli 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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infection that resolved over time with oral antibiotics and the treatment with Cerviron© was continued, 
as per the treating physician recommendation. 
At the end of study, no treatment-related AEs or SAEs were reported. 
4.8.1 DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT ADVERSE EVENTS 
4.8.1.1 DEATHS 
No deaths occurred during the clinical investigation. 
4.8.1.2 OTHER SERIOUS ADVERSE EVENTS 
No serious adverse events (SAEs) occurred during the clinical investigation. 
4.8.1.3 OTHER SIGNIFICANT ADVERSE EVENTS 
No significant adverse events (AEs) were reported during this clinical investigation. 
4.8.1.4 NARRATIVES OF DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT 
ADVERSE EVENTS 
Not applicable. 
4.8.1.5 ANALYSIS AND DISCUSSION OF DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER 
SIGNIFICANT ADVERSE EVENTS 
No deaths or significant AEs were reported during the present clinical investigation. 
4.8.1.6 CLINICAL LABORATORY EVALUATION 
The Clinical Laboratory evaluation was performed in the Hospital Laboratory for site 01 while a private 
practice was preferred for site 02. 
4.8.1.7 VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATION RELATED TO SAFETY 
No other observation related to safety was reported during the present clinical investigation. 
4.8.1.8 ANALYSIS OF LOCAL AND SYSTEMIC REACTIONS 
No systemic reactions were reported during the present clinical investigation. 
4.8.1.9 SAFETY CONCLUSION 
The safety analysis set included all study participants who were exposed to Cerviron© (N=47).  
The intravaginal administration of Cerviron© in participants with symptomatic, non-specific, non-
infectious vaginitis, and endogenous symptomatic infections proved safe for the study participants and 
not accompanied by any significant adverse events.  
At the end of study, no treatment-related AEs were reported. 
Cerviron© vaginal ovules exert a very good tolerability with the vaginal mucosa and vaginal epithelium. 
Cerviron© may be a better choice also for pregnant women with aerobic vaginitis, under the 
supervision of the gynecologist. Future research is needed to confirm its tolerability profile during 
pregnancy. 

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4.9 SECONDARY OUTCOMES 
As secondary hypotheses we assume that several additionally clinical outcomes will be improved with 
100.00% of the participants using the medical device. 
4.9.1 CHANGE IN VAGINAL DISCHARGE ASPECT 
The vaginal discharge was assessed by the treating physician using a score as follows: absent, mild: 
(insufficient for speculum collection), moderate (sufficient for speculum collection), abundant (visible 
at the introitus even before speculum introduction), purulent discharge (visible at the introitus even 
before speculum introduction but with a purulent aspect). The change in vaginal discharge aspect 
during Visit 1-Visit 4 is reflected in Table 7. 
Change in Vaginal 
Discharge Aspect 
Visit 1 
Visit 2 
Visit 3 
Visit4 
Absent 
0 (0.00%) 
2 (4.26%) 
8 (17.02%) 
9 (19.15%) 
Mild 
6 (12.77%) 
26 (55.32%) 
21 (44.68%) 
13 (27.66%) 
Moderate 
37 (78.22%) 
19 (40.43%) 
18 (38.30%) 
25 (53.19%) 
Abundant 
4 (8.51% 
0 (0.00%) 
0 (0.00%) 
0 (0.00%) 
Purulent 
0 (0.00%) 
0 (0.00%) 
0 (0.00%) 
0 (0.00%) 
Table 7. Change in Vaginal Discharge Aspect score between each visit 
Due to the small proportions of some visits, such as Visit 1 for Absent (0.00%), Abundant (8.51%) and 
Purulent (0.00%) symptoms, and finally (visit 4), for Abundant (0.00%) and Purulent (0.00%) symptoms, 
to highlight the difference between baseline and final visit, data reduction was used, thus, neglecting 
the small and statistically insignificant proportions. Thus, for the participants, the categories of 
symptoms were reconsidered in Table 8, as follows:  
1. Mild symptoms. Participants with Absent and Mild symptoms were included in a new category 
called Mild;  
2. Moderate symptoms. Participants with Moderate and Abundant symptoms have been 
included in a new category called Moderate;  
3. Purulent symptoms, even if not found, were left in the same way. 
 
 
 
 
 
 
 
 
 
 
Table 8. Change in Vaginal Discharge Aspect score between visit 1 and visit 4 
Vaginal Discharge Aspect 
score 
Visits 
 
Baseline 
Final 
    Mild symptoms 
6 
21 
    Moderate symptoms 
41 
20 
    Purulent symptoms 
0 
0 
Total number of subjects 
47 
47 

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McNemar’s Chi-squared test with continuity correction was performed to assess the status-quo of the 
Vaginal Discharge Aspect score between the baseline and final visit (Visit 4). At a 5% significance level 
and considering a null hypothesis that is no statistically significant difference between baseline visit 
and final visit, we evidenced that the differences between these values were statistically significant (p 
< 0.05). 
4.9.2 CHANGE IN VAGINAL PH VALUES 
The determination of pH values between Visits 1-Visit 4 is showed in Table 9. 
 
Change in vaginal pH values 
Visit 1 
Visit 2 
Visit 3 
Visit4 
Normal 
38 (80.85%) 
41 (87.23%) 
44 (93.62% 
47 (100.00%) 
Abnormal 
9 (19.15%) 
6 (12.77%) 
3 (6.38%) 
0 (0.00%) 
Table 9. Change in Vaginal pH Values between visit 1 and visit 4 
Performing test for equality of proportions without continuity correction to assess the change of the 
Vaginal pH values between the baseline and final visit (Visit 4). At a 5% significance level and 
considering a null hypothesis that is no statistically significant difference between baseline visit and 
final visit, we evidenced that the differences between these values were statistically significant  
(p < 0.05). There are limitations in performing the proportionality test because the proportion of 
participants with an abnormal pH is small (9 participants). It is observed that after the 3 months of 
treatment with Cerviron© all participants presented a normal pH. 
4.9.3 CHANGE IN VAGINAL MICROFLORA AND LACTOBACILLI COUNT 
The change in Lactobacillus species as shown by microscopy is presented in Table 10. 
 
Vaginal 
microflora 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
p-value 
 
YES 
NO 
YES 
NO 
YES 
NO 
YES 
NO 
 
Lactobacilli 
25 
(53.19%) 
22 
(46.81%) 
27 
(57.45%) 
20 
(42.55%) 
27 
(57.45%) 
20 
(42.55%) 
30 
(63.83%) 
17 
(36.17%) 
= .131* 
Leukocytes 
37 
(78.72%) 
10 
(21.28%) 
39 
(82.98%) 
8 
(17.02%) 
36 
(76.60%) 
11 
(23.40%) 
38 
(80.85%) 
9 (19.15%) 
= 1* 
Enterobact. 
0 (0.00%) 
47 
(100.00%) 
1 
(2.13%) 
46 
(97.87%) 
0 
(0.00%) 
47 
(100.00%) 
0 
(0.00%) 
47 
(100.00%) 
NA 
Squamous 
epithelial cells 
3 (6.38%) 
44 
(93.62%) 
5 
(10.64%) 
42 
(89.36%) 
0 
(0.00%) 
47 
(100.00%) 
0 
(0.00%) 
47 
(100.00%) 
= .241** 
Gardnerella 
vaginalis 
0 (0.00%) 
47 
(100.00%) 
0 
(0.00%) 
47 
(100.00%) 
0 
(0.00%) 
47 
(100.00%) 
2 
(4.26%) 
45 
(95.74%) 
= .475** 

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Trich. 
vaginalis 
0 (0.00%) 
47 
(100.00%) 
0 
(0.00%) 
47 
(100.00%) 
0 
(0.00%) 
47 
(100.00%) 
0 
(0.00%) 
47 
(100.00%) 
NA 
Candida 
1 (2.13%) 
46 
(97.87%) 
0 
(0.00%) 
47 
(100.00%) 
0 
(0.00%) 
47 
(100.00%) 
2 
(4.26%) 
45 
(95.74%) 
= 1* 
Yeast cells 
and filaments 
3 (6.38%) 
44 
(93.62%) 
6 
(12.77%) 
41 
(87.23%) 
4 
(8.51%) 
43 
(91.49%) 
2 
(4.26%) 
45 
(95.74%) 
= 1* 
* p – value was obtained with Mc’Nemar test with continuity correction 
** p – value was obtained with 2-sample test for equality of proportions with continuity correction 
Table 10. Change in vaginal microflora from Visit 1 to Visit 4 
From the data presented in Table 9 it is observed that some improvements are seen in the vaginal 
microflora but without statistical significance. 
4.9.4 CHANGE IN VAGINAL INFLAMMATION 
The change in inflammatory and parabasal cells by laboratory microscopy was statistically significant, 
with a number of 32 study participants recording an improvement. 
Response 
Visits 
 
Baseline 
Final 
    Yes 
32 
15 
    No 
15 
32 
Total number of subjects 
47 
47 
Table 11. Change in vaginal inflammation score between baseline and final visit 
McNemar’s Chi-squared test with continuity correction was performed to assess the difference of the 
Vaginal Inflammation score between the baseline and final visit (Visit 4). At a 5% significance level and 
considering a null hypothesis that is no statistically significant difference between baseline visit and 
final visit, we evidenced that the differences between these values were statistically significant (p < 
0.001). 
4.9.5 PARTICIPANT SATISFACTION 
The degree of satisfaction when using the medical device was assessed using a five-point Likert Scale, 
as very satisfied, satisfied, neutral, unsatisfied, and very unsatisfied. 
The evaluation of participant satisfaction was summarized in the following Table 12 and Figure 5.  
 
Participant 
Satisfaction 
Very 
Satisfied 
Satisfied 
Neutral 
Unsatisfied 
Very 
Unsatisfied 
SCORE 
39 (82.98%) 
6 (12.77%) 
2 (4.26%) 
0 (0.00%) 
0 (0.00%) 
Table 12. Participants response regarding Medical Device Usage Satisfaction  

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Figure 5. Participant Satisfaction Score – Likert Scale 
Thirty-nine study participants (82.98%) were very satisfied, 6 participants (12.77%) were satisfied, and 
2 participants (4.26%) were neutral. No participants declared themselves unsatisfied or very 
unsatisfied. 
4.9.6 EXPLORATORY ANALYSIS 
4.9.6.1. PERFORMANCE IN POSTMENOPAUSAL WOMEN 
4.9.6.1.1 
DYSURIA 
A normal feature of natural aging is the postmenopausal syndrome. Menopause is one of the most 
significant events in a woman's life bringing a broad spectrum of physiological changes caused mainly 
by the lack of estrogens. The hypoestrogenic state results in hormonal and anatomical changes in the 
genitourinary tract, with vaginal dryness, dysuria and dyspareunia being some of the most frequent 
symptoms that can have a great impact on the quality of life of the affected women.  
The effectiveness of Cerviron© at 30 days and 90 days on specific symptoms, such as dysuria and 
dyspareunia in menopausal versus non-menopausal patients, has also been investigated. At the same 
time, a correlation was suggested between the evolution of symptoms and the response to treatment 
between these groups. During the clinical investigation, there were 9 participants with 
postmenopausal syndrome enrolled. Participants that accused dysuria and their symptom evolution 
between visits are represented in Table 13. 
 
 
 
 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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Patient groups 
Vaginal symptom: Dysuria 
 
Baseline 
After 30 days 
Final Visit (90 days) 
 
Presence 
Absence 
Presence 
Absence 
Presence 
Absence 
   Menopause 
3 
6 
3 
6 
0 
9 
   No Menopause 
5 
33 
1 
37 
0 
38 
Table 13. Comparison between menopausal and non-menopausal patients with Dysuria at Visit 1, 
Visit 2, and Visit 4 
In the first group, there were 9 menopausal patients, of which at baseline 3 patients had dysuria 
(33.33%), and 6 patients did not show this symptom. The second group consisted of non-menopausal 
patients (N = 38). At baseline, 5 patients (13.16%) had dysuria, while 33 patients did not have this 
condition (Table 13). 
In the first stage, the proportion of menopausal patients who responded to Cerviron© treatment after 
30 days was determined. It was observed that the proportion of patients in this group remained 
unchanged after 30 days of treatment (p = 1). 
In the second stage, the proportion of non-menopausal patients who responded to treatment after 30 
days was determined. From the analyzed data it was observed that the proportion in this group 
decreased from 13.16% (N = 5) at baseline to 2.63% (N =1) after 30 days. This decrease of 10.53 
percentage points between the two groups is not statistically significant (p = 0.202). 
At the final visit, after 90 days of treatment, it is observed from table 13 that both menopausal and 
non-menopausal patients have an identical response to treatment. Basically, the effectiveness of 
Cerviron© after 90 days of treatment is identical in the two groups. 
4.9.6.1.2 DYSPAREUNIA 
From out of 9 menopausal patients, 4 patients (44.45%) had baseline dyspareunia as a symptom, and 
11 out of 38 non-menopausal patients (28.96%) also had this condition. 
After 30 days of treatment with Cerviron©, it was observed that although there was a 22.22% (N = 2) 
reduction in symptoms in the group of menopausal patients, this was not statistically significant (p = 
0.617). 
In the group of non-menopausal patients, after 30 days of treatment, it was found that there was a 
reduction in dyspareunia in 4 patients (10.53%). However, this reduction is not statistically significant 
(p = 0.418). 
In contrast, at the final visit versus baseline in the group of menopausal patients the reduction was 
from 4 cases to 0 cases of dyspareunia, but from a statistical point of view this reduction is not 
significant (p = 0.378), and in the group of women who do not at menopause the cases decreased from 
28.95% (N = 11) at baseline to 2.63% (N = 1) (p < 0.05). 
The evolution of dyspareunia is represented in Table 14. 
 
 
 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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Patient groups 
Vaginal symptom: Dyspareunia 
 
Baseline 
After 30 days 
Final Visit (90 days) 
 
Presence 
Absence 
Presence 
Absence 
Presence 
Absence 
   Menopause 
4 
5 
2 
7 
0 
9 
   No Menopause 
11 
27 
7 
31 
1 
37 
Table 14. Comparison between menopausal and non-menopausal patients with Dyspareunia at Visit 
1, Visit 2, and Visit 4 
In postmenopausal women, irritation and trauma occurring during sexual intercourse are the result of 
the hypoestrogenic environment of urogenital tract tissue, with thicker vaginal epithelium and lamina 
propria, atrophy of smooth muscles, reduction of vaginal-area blood flow, and loss of tissue elasticity 
causing bothersome symptoms. For postmenopausal women, during the clinical investigation a 
significant improvement was seen in the most bothersome symptoms (dysuria and dyspareunia) as 
shown. However, there is no correlation between this physiological condition and the response to 
treatment with Cerviron©. Both menopausal and non-menopausal women have a similar response to 
treatment at 30 days of treatment (p = 0.795) and at the end of the treatment period (p = 0.998). 
4.9.6.1.3 
CHANGE IN VAGINAL INFLAMMATION SCORE 
The response to treatment with Cerviron© in terms of the score of vaginal inflammation in menopausal 
subject versus non-menopausal subjects was considered. The change in vaginal inflammation score is 
represented in Table 15. 
Patient groups 
Change in Vaginal Inflammation Score 
 
Baseline 
Final Visit (90 days) 
 
Presence 
Absence 
Presence 
Absence 
  Menopause 
7 
2 
1 
8 
  No Menopause 
25 
13 
14 
24 
Table 15. Comparison between menopausal and non-menopausal patients in terms of changes in 
vaginal inflammatory score 
At baseline, 7 from 9 patients (77.78%) in the menopausal group had a symptom of vaginal 
inflammation, and in the group of non-menopausal patients, 25 patients (65.79%) out of a total of 38 
had symptoms. 
After 90 days of treatment with Cerviron©, the score improved significantly in both groups studied. 
Thus, in the group of menopausal patients the inflammatory symptoms were reduced to 1 case 
(11.11%) (p < 0.05), while in the other group there were 14 cases (36.84%) (p <0.05). 
However, there is no correlation between menopausal and non-menopausal women (p = 0.166) in 
terms of improving vaginal inflammation score. 
The medical device can therefore be considered a safe and effective alternative for the treatment of 
specific signs and symptoms in postmenopausal women (dysuria, dyspareunia and vaginal 
inflammation), especially when hormonotherapy is not recommended. 
 

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4.9.6.2 PERFORMANCE IN BALANCING VAGINAL PH IN SEXUALLY ACTIVE PATIENTS 
It has also been determined whether sexual activity can have any effect on changes in vaginal pH and 
on the effectiveness of treatment with Cerviron©. Figure 6 shows the evolution of pH in sexually active 
patients during the 90 days of treatment. After 30 days of treatment, a slight decrease was observed 
in cases with abnormal pH from 20.45% (N = 9) to 13.64% (N = 6). 
In contrast, at 60 days of treatment, the rate of patients with abnormal pH decreased to only 6.82% (N 
= 3), which shows that treatment with this medical device is effective (p < 0.05). 
At the end of the clinical investigation, all patients in this group had normal vaginal pH. 
 
Figure 6. PH changes between visits in the group of participants with sexual activity  
5.  
DISCUSSIONS AND OVERALL CONCLUSIONS 
The purpose of this study was to investigate the therapeutic performance and tolerability of Cerviron© 
in participants with symptomatic, non-specific, non-infectious vaginitis, and endogenous symptomatic 
infections. The effects were assessed as changes between Baseline, Visit 2, Visit 3, and Final Visit in the 
following primary performance outcomes: clinical performance after thorough gynecological 
examination and participant’s interview at end of treatment visit (regarding the presence of vaginal 
symptoms) and rate of treatment-related AE in subjects participating in the clinical investigation.  
The primary objective of the clinical investigation was met. For 34 (72.34%) study participant using 
Cerviron® the medical device had a beneficial effect on the score of vaginal symptoms, while for only 
13 participants (27.66%) the score remained the same (p < 0.001) over the 3 treatment sessions (each 
of 15 days). 
As secondary performance outcomes, the clinical investigation proposed several paraclinical 
investigations (vaginal discharge, vaginal pH, microscopic characteristics of inflammatory cells and 
vaginal microflora characteristics).  

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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The symptoms for which patients were enrolled in the study have certainly improved. No persistence 
or worsening of symptoms /clinical signs were noted in any participant. The presence of vaginal 
symptoms has improved statistically significant from Baseline to the 90-day Visit. The medical device 
also significantly improved the vaginal discharge aspect score, pH values, and vaginal inflammation 
symptoms. Treatment success (evaluated through participant questionnaires) was relevant in the 
assessment of the degree of satisfaction with the medical device usage. In terms of the degree of 
satisfaction offered, participants in the largest proportion (around 96%) said they were satisfied with 
this medical device. Only 2 participants declared themselves neutral in terms of satisfaction. 
In terms of safety, the medical device was used according to the data supplied by the Manufacturer 
on the labelling, in the instructions and/or in Investigator’s Brochure. Three patients experience mild 
vaginal Cocci and E. Coli infections and the study team decided to continue the treatment with 
Cerviron©. At the final study visit, no study participants presented treatment-related AEs or SAEs, 
which makes the medical device safe to administer. 
Data from the secondary variables supported the results from the primary variable, as follows: 
• 
Change in vaginal discharge aspect. The difference in change for Vaginal Discharge Aspect 
between baseline visit and final visit was statistically significant at 5% significance level  
(p < 0.05). 
The vaginal discharge aspect is useful in the management of vaginal infections. The change in vaginal 
discharge aspect was assessed by the investigator as an objective finding and was verified by laboratory 
examination during every study visit. The vaginal discharge aspect improved during the medical device 
usage. While at the Baseline visit, participants were evaluated with abundant discharge (N=4), 
moderate discharge (N=37) and mild discharge (N=6), after 90 days, some participants had no vaginal 
discharge (N=9), and other participants were reported with mild vaginal discharge (N=13) or moderate 
discharge (N=25). As such, Cerviron© ovules proves its performance in improving the vaginal discharge 
aspect after 3 months of usage. 
• 
Change in vaginal pH values. Determination of pH values compared to its normal values (3.8 – 
4.5). The difference in change of Vaginal pH values between the baseline and final visit, at 5% 
significance level was statistically significant (p < 0.05). 
The vagina has a dynamic microbial ecosystem with varying vaginal pH levels. An imbalance in that 
ecosystem can alter the vaginal pH and upscale to the point of causing medical attention. It is observed 
that after the 3 months of treatment with Cerviron© all participants presented a normal pH. The normal 
vaginal pH level (between 3.8 – 4.5) is very important for its protective role in blocking yeast and 
bacteria multiplication. Thus, the supportive role of the medical device in preventing reinfection is 
proven on the basis of its effective role in correction of the unbalanced vaginal pH. 
The vaginal pH can be affected by overall health conditions, such as age, taking antibiotics, vaginal 
hydration status, vaginal douching, unprotected sex, variations in the menstrual cycle, daily diet. (49) 
The semen is relatively alkaline, with a pH value of approximately 8.0. and can alter the vaginal pH 
during unprotected intercourse. As such, the vaginal defense system is altered, causing a change in 
vaginal pH that remains elevated even after 10–14 h. (50) This alteration leaves the vagina les 
protected against infection. Several applications of Cerviron© will maintain a healthy vaginal 
environment and conserve the microbial ecosystem. Moreover, Cerviron© can be used as an adjuvant 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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treatment in patients requiring antibiotic treatment in order to maintain a healthy, more acidic vaginal 
pH level.  
• 
Change in vaginal microflora and Lactobacilli count. The change in Lactobacilli species 
throughout the study was not statistically significant (p > 0.05). 
The common vaginal microbiome, the Lactobacilli species, can produce acidic pH and bacteriocins to 
kill other bacteria in the vagina. Lactobacilli can produce an acidic environment in the vagina, which is 
designed to protect women from sexually transmitted pathogens and opportunistic infections. During 
the present clinical investigation, some improvements were found in vaginal microflora and 
Lactobacilli count, but they were not statistically significant.  
• 
Change in vaginal inflammation. The difference in change in vaginal inflammation between 
baseline and final visit, at 5% significance level was statistically significant (p < 0.001). 
Vaginal inflammation is often present in the diagnosis of vaginitis, especially in desquamative 
inflammatory vaginitis. Signs and symptoms include abundant discharge, vestibulo-vaginal irritation, 
and dyspareunia. The physical examination of vaginal walls shows signs of inflammation with increased 
erythema and petechiae. The vaginal sample is characterized by the absence of clue cells, hyphae, 
trichomonads and lactobacilli with increased number of parabasal cells. Parabasal cells are typically 
round or oval in shape with a high nuclear/cytoplasmic ratio.  
Cerviron© medical device reduces vaginal inflammation as shown by laboratory microscopy.  The 
change in inflammatory and parabasal cells was relevant, with a number of 32 study participants 
recording an improvement. 
In conclusion, Cerviron® ’s clinical performance as adjuvant treatment in non-specific or symptomatic 
vaginitis was demonstrated throughout the present 90-days clinical investigation. Administration of 
Cerviron© significantly alleviates the symptoms of symptomatic, non-specific, non-infectious vaginitis, 
and its administration can be considered safe. Cerviron® can be used as long-term supportive therapy, 
either as a stand-alone treatment or in combination with other oral therapies with antibiotics, 
antifungals or antivirals. Cerviron® supportive therapy may be prescribed for 10 or 15 consecutive 
days. While balancing the vaginal pH, Cerviron reduces vaginal inflammation and improves the vaginal 
discharge aspect after 3 months of therapy. 
Cerviron® beneficial effects were correlated with participants’ different baseline characteristics, such 
as premenopausal or menopausal status, normal hydration and nutrition status and age. There was no 
statistical difference reported between the groups. Cerviron® was safely administrated across all age 
groups, with or without a healthy diet and hydration.  
Regarding sexual activity, Cerviron® can be safely administered to both sexually active women as well 
as to abstinent women.  
Despite the fact that during the clinical investigation no pregnancy cases were managed, the usage of 
Cerviron® is recommended under the close supervision of the gynecologist. As shown, Cerviron® can 
be safely applied in different forms of vaginitis. When added to the standard-of-care in aerobic 
vaginitis, Cerviron® will restore the vaginal pH, will reduce inflammation and will reduce the 
proliferation of aerobic bacteria. A good management of aerobic vaginitis during pregnancy 
significantly improves perinatal outcomes and can prevent treatment failures and severe 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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complications, such as pelvic inflammatory disease, infertility, miscarriage, chorioamnionitis, 
premature rupture of membranes and preterm delivery. (52)  
Further studies need to be planned to confirm the tolerability profile of Cerviron® in pregnant 
participants.  
6.  
ABBREVIATED TERMS AND DEFINITIONS 
AE 
Adverse Event 
CIP 
Clinical Investigation Plan 
CNBMDM 
National Ethics Commitee (Comisia Nationala De Bioetica a Medicamentului si a 
Dispozitivelor Medicale) 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
eCRF 
Electronic Case Report Form 
GCP 
Good Clinical Practice 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
ISO 
International Organization for Standardization 
LC50 
Lethal Concentration 50 
MMP 
Matrix Metalloproteinases 
NEC 
National Ethics Committee 
PHI 
Personal Health Identifiers 
PI 
Principal Investigator 
Ppm 
Parts Per Million 
SAE 
Serious Adverse Event 
SDV 
Source Data Verification 
SAR 
Serious Adverse Reaction 
SOC 
Service Organization Control 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
7.  
ETHICS 
The clinical investigation and its updates were reviewed by the National Ethics Committee from 
Romania (CNBMDM). A list of the NEC members is available by request. The study was conducted in 
accordance with the ethical principles that have their origins in the Declaration of Helsinki. The 
Participant Information and Consent was obtained prior to participant enrollment (at Screening Visit) 

CLINICAL INVESTIGATION REPORT CYRON/01/2021 
 
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in most cases by the Principal Investigator or the delegated that were also the consulting physician and 
a member of the clinical site team.  
A sample of the participant consent form is available by request. 
Data Protection 
Participants were assigned a unique identifier by the sponsor. Any participant records or datasets that 
were transferred to the sponsor contain the identifier only. Participant names or any information 
which would make the participant identifiable were not transferred. Sponsor staff that required access 
to personal data agreed to keep confidentiality. Only the relevant data to fulfil the objectives of the 
study were collected. Study participants were informed that they have the right to request access to 
their personal data and the right to request rectification of incorrect or incomplete data. No personal 
details were recorded during the clinical investigation, except for the data included in the medical 
charts. 
8.  
INVESTIGATORS AND ADMINISTRATIVE STRUCTURE OF CLINICAL INVESTIGATION 
This clinical investigation was conducted in Romania, in a hospital-based setting, in two investigational 
centres, located in Bucharest and Timisoara, Romania. 
The details of the clinical sites, affiliation, principal investigators and subinvestigators’ names can be 
found below: 
Clinical site 
Affiliation 
Name 
Surname 
Site 01 
INSTITUTUL 
NATIONAL 
PENTRU 
SANATATEA MAMEI SI COPILULUI " 
ALESSANDRESCU-RUSESCU" 
Obstetrics-Ginecology „Polizu” 
Department of Obstetrics-Gynecology III 
38-52 Gheorghe Polizu Street, District 1 
011061 Bucharest, Romania 
Daniela-Oana 
 
Raluca 
Toader 
 
Olaru 
Site 02 
SPITALUL CLINIC JUDEȚEAN DE URGENȚĂ 
“PIUS BRINZEU” TIMISOARA 
Department of Obstetrics-Gynecology II 
12 Victor Babeș Boulevard 
300226 Timisoara, Romania 
Izabella 
 
Lavinia 
Petre 
 
Stelea 
Table 16. Clinical sites and affiliation 
8.1 SITE PERFORMANCE 
Site 01 INSTITUTUL NATIONAL PENTRU SANATATEA MAMEI SI COPILULUI " ALESSANDRESCU-
RUSESCU" BUCHAREST (Principal Investigator Dr. Daniela-Oana Toader) 
The site screened 15 patients. All 15 patients received the medical device CERVIRON. The site 
conducted the trial according to ICH-GCP and study protocol requirements. There were no critical or 
major findings identified. The eCRF was completed in a timely manner for patients 101-115 for all the 
visits. Primary and secondary objectives, safety and concomitant medication were reported as per CIP. 

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Patient 108 is reported with 3 unreturned, unadministered ovules. Three patients (101, 105 and 109) 
out of 15 did not return the used boxes of the clinical investigation medical device.  
During the study, the PI has had excellent oversight and implication. 
SITE 02 SPITALUL CLINIC JUDEȚEAN DE URGENȚĂ “PIUS BRINZEU” TIMISOARA (Principal Investigator 
Dr. Izabella Petre) 
The site screened 35 patients. Only 32 patients met the inclusion and exclusion criteria. Three patients 
(0206, 0215 and 0218) were screen-failure. There were 8 onsite monitoring visits performed between 
24 May 2021 - 28 Feb 2022. 
For participant 0213 Visit 1 was performed on 19.05.2021 and visit 2 was performed in a serious delay, 
on 24.09.2021. The PI explained that the patient was detached with work. Also, participants no. 0216 
and 0217 have a delay of 3 months between Visit 1 and Visit 2. There were no critical or major findings 
identified. The eCRF was generally completed with some delays from the study team.  The site team 
members were compliant with GCP principles, CIP and the current clinical trials legislation. During the 
study, the PI has had a good oversight and implication. 
 

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ANNEX 1. STUDY-RELATED ESSENTIAL DOCUMENTATION 
ANNEX 2. THE EC FAVOURABLE OPINION AND ESSENTIAL CORRESPONDENCE 
 

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Page 53 of 53 
 
AUTHORS AND SPONSOR SIGNATURE PAGE 
 
Statement of 
Agreement 
 
I have written this report and confirm that to the best of my knowledge it 
accurately describes the conduct and results of the clinical investigation 
entitled “A Prospective, Open-Label, Pilot, Multicentric Clinical 
Investigation to Evaluate the Performance and Safety of Cerviron® ovules 
in the Local Treatment of Non-Specific or Endogenous, Symptomatic 
Vaginitis” (Version 1.0 dated 05 Apr 2022). 
 
  Pharm. Ramona Petrita 
 
 
Medical Writer’s Name 
Date 
Medical Writer’s Signature 
 
Statement of 
Agreement 
 
I have written this report and confirm that to the best of my knowledge it 
accurately describes the conduct and results of the clinical investigation 
entitled “A Prospective, Open-Label, Pilot, Multicentric Clinical 
Investigation to Evaluate the Performance and Safety of Cerviron® ovules 
in the Local Treatment of Non-Specific or Endogenous, Symptomatic 
Vaginitis” (Version 1.0 dated 05 Apr 2022). 
 
  Pharm. Alexandru - Remus Pinta 
 
 
Biostatistician’s Name  
 
Date 
    Biostatistician’s Signature  
 
 
 
Statement of 
Agreement 
 
I have read this report and confirm that to the best of my knowledge it 
accurately describes the conduct and results of the clinical investigation 
entitled “A Prospective, Open-Label, Pilot, Multicentric Clinical 
Investigation to Evaluate the Performance and Safety of Cerviron® ovules 
in the Local Treatment of Non-Specific or Endogenous, Symptomatic 
Vaginitis” (Version 1.0 dated 05 Apr 2022). 
 
  Pharm. Ema Peta 
 
 
Sponsor’s Name 
Date 
Sponsor’s Signature 
05- Apr - 2022 
06 - Apr - 2022 
07 - Apr - 2022