An Open-label Study to Evaluate Clinical Performance of Gedea Pessary in Adult Women With Vulvovaginal Candidiasis
Phase: NA
Conditions: Vulvovaginal Candidiasis
Sponsor: Gedea Biotech AB

Clinical Investigation Plan QRS-CL1-003, Version 3.0 
Gedea Pessary 
 
Protocol Version 3.0, 24Oct2018 
LINK Medical Research | Protocol template 
Version 2.0 | Effective date 17Apr2018 
CLINICAL INVESTIGATION PLAN 
AN OPEN-LABEL STUDY TO EVALUATE CLINICAL PERFORMANCE OF GEDEA 
PESSARY IN ADULT WOMEN WITH VULVOVAGINAL CANDIDIASIS 
Study Product: 
Gedea Pessary 
Study Number: 
CL1 
Sponsor: 
Gedea Biotech AB 
Medicon Village 
Scheelevägen 2 
SE-223 81 Lund, Sweden 
Clinical Investigation Plan (CIP) 
Number: 
QRS-CL1-003 
Original CIP Version Date: 
31JUL2018 
CIP Version Number: 
3.0 
CIP Version Date: 
24OCT2018 
Confidentiality Statement 
The information contained in this document is confidential and cannot be disclosed unless 
required by governmental regulation. Persons to whom any portion of the contents of this 
document is disclosed must be informed that the information is confidential and may not 
be further disclosed by them 

Clinical Investigation Plan QRS-CL1-003, Version 3.0 
Gedea Pessary 
 
Protocol Version 3.0, 24Oct2018 
LINK Medical Research | Protocol template 
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INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
Principal Investigator(s): 
NAME 
VO Kvinnosjukvård 
Skånes universitetssjukvård 
SE-221 85, Lund, Sweden 
Telephone: 
TELEPHONE 
 
Facsimile: 
NA 
e-mail: 
NAME 
NAME 
Hoftekliniken 
Drottninggatan 7, 6tr 
SE-252 21, Helsingborg, Sweden 
Telephone: 
TELEPHONE 
Facsimile: 
NA 
e-mail: 
NAME 
NAME 
Annerokliniken 
Galoppvägen 46 
SE-246 50, Löddeköpinge, Sweden 
Telephone: 
TELEPHONE 
Facsimile: 
NA 
e-mail: 
NAME 
Clinical Trial Unit: 
Kliniska Studier Sverige – Forum Söder 
Skånes universitetssjukhus 
Akutgatan 8 
SE-221 85, Lund, Sweden 
Telephone: 
TELEPHONE 
Facsimile: 
NA 
e-mail: 
NAME 
Sponsor: 
Gedea Biotech AB 
Medicon Village 
Scheelevägen 2 
SE-223 81 Lund, Sweden 
Telephone: 
TELEPHONE 
Facsimile: 
NA 
 
 

Clinical Investigation Plan QRS-CL1-003, Version 3.0 
Gedea Pessary 
 
Protocol Version 3.0, 24Oct2018 
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Medical Expert: 
NAME 
VO Kvinnosjukvård 
Skånes universitetssjukvård 
SE-221 85, Lund, Sweden 
Telephone: 
TELEPHONE 
Facsimile: 
NA 
e-mail: 
NAME 
Study Director: 
NAME Gedea Biotech AB 
Medicon Village 
Scheelevägen 2 
SE-223 81 Lund, Sweden 
Telephone: 
TELEPHONE 
Facsimile: 
NA 
e-mail: 
NAME 
Study Statistician: 
NAME 
LINK Medical Research AS Filial 
Norgegatan 2, plan 6 
SE-164 32 Kista, Sweden 
Telephone: 
TELEPHONE 
Facsimile: 
NA 
e-mail: 
NAME 
Contract Research 
Organization (CRO): 
LINK Medical Research AS Filial 
Norgegatan 2, plan 6 
SE-164 32 Kista, Sweden 
Telephone: 
TELEPHONE 
Facsimile: 
NA 
e-mail: 
NAME 
Pharmacovigilance Manager 
NAME 
LINK Medical Research AS 
Gjerdrumsvei 19 
0484 Oslo, Norway 
Telephone: 
TELEPHONE 
Facsimile: 
NA 
e-mail: 
NAME 

Clinical Investigation Plan QRS-CL1-003, Version 3.0 
Gedea Pessary 
 
Protocol Version 3.0, 24Oct2018 
LINK Medical Research | Protocol template 
Version 2.0 | Effective date 17Apr2018 
APPROVAL PAGE 
Sponsor: 
 
 
_______________________________________ 
______________________________ 
NAME Gedea Biotech AB 
 
 
Date: 
 
 
 
Coordinating Investigator: 
 
 
_______________________________________ 
______________________________ 
NAME 
 
Date: 
 
 
 
Statistician: 
 
 
_______________________________________ 
______________________________ 
NAME  
 
 
 
 
 
Date: 
 
 

Clinical Investigation Plan QRS-CL1-003, Version 3.0 
Gedea Pessary 
 
Protocol Version 3.0, 24Oct2018 
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SYNOPSIS 
Name of Sponsor: 
Gedea Biotech AB 
Name of Products: 
Gedea Pessary (commercial name pHyph) 
Name of Active Ingredient: 
Glucono-delta-lactone (GDL) and sodium gluconate (NaG) 
Title of Study: 
An open-label study to evaluate clinical performance of Gedea Pessary in adult women with 
vulvovaginal candidiasis (VVC). 
Clinical Investigation Plan Number: 
QRS-CL1-003 
Investigators and Study Center(s): 
NAME, VO Kvinnosjukvård, Skånes universitetssjukvård, Lund, Sweden 
NAME, Annerokliniken, Löddeköpinge, Sweden 
NAME, Hoftekliniken, Helsingborg, Sweden 
Kliniska prövningsenheten, Kliniska Studier Sverige - Forum Söder, Skånes universitetssjukhus, 
Lund, Sweden 
Classification of Trial: 
Feasibility Clinical Investigation 
Objectives: 
To investigate the clinical performance, tolerability, and safety of the investigational product. 
Methodology: 
This is an open-label, single-armed, multi-center study to evaluate clinical performance, 
tolerability, and safety of Gedea Pessary in 24 adult women with VVC. On Day 0, patients will have 
gynecological examination, vaginal samples taken, and will receive the investigational product to 
be self-administered 2 days apart (Day[s] 0, 2, 4, and 6). Patients will be examined after 7 days 
with respect to VVC signs and symptoms and if not cured, will receive prolonged treatment on 
Day(s) 7, 9, 11, and 13. Patients will be followed-up by telephone up to 29 days after last 
treatment. Vaginal samples will be used for confirming diagnosis and microbiome analyzes. 
Patient questionnaires will be used for assessing VVC symptoms, usability, and adverse events 
(AEs). 
Number of Subjects Planned: 
Twenty-four (24) patients 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria: 
 
Adult, post-menarchal, pre-menopausal women aged 18 years or older 

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 
Diagnosis of VVC, defined as having a white or creamy vaginal discharge plus the following 
findings: 
1. At least 2 of the following signs and symptoms of VVC that are characterized as at 
least moderate: itching, burning, irritation, edema, redness, or excoriation. 
2. Potassium hydroxide (KOH) or saline preparation from the inflamed vaginal 
mucosa or secretions revealing yeast forms (hyphae or pseudohyphae) or budding 
yeasts. 
 
Having decisional capacity and providing written informed consent 
 
Negative urine pregnancy test at screening 
 
Refrain from using any intravaginal products (i.e., contraceptive creams, gels, foams, 
sponges, lubricants, or tampons, etc.) during the study period 
 
Refrain from sexual intercourse or use a condom until Day 7 
 
Signed informed consent and willing and able to comply with all study requirements 
Exclusion Criteria: 
 
Patients with known or apparent signs of other infectious causes of VVC (BV, Trichomonas 
vaginalis, Neisseria gonorrhoeae, Chlamydia trachomatis, Herpes simplex, or human 
papillomavirus) at screening 
 
Patients who are pregnant or breastfeeding 
 
Patients who were treated for VVC within the past 14 days 
 
Patients who are currently receiving antifungal therapy unrelated to VVC or has taken 
antifungal therapy within the past 14 days 
 
Patients who have used pH-modifying vaginal products within the last 14 days 
 
Patients who have received an investigational drug in a clinical investigation within 30 days 
prior to screening 
 
Known/previous allergy or hypersensitivity to any product constituent or fluconazole 
 
Any medical condition that in the Investigator’s judgments would make the patient 
unsuitable for inclusion 
Investigational Product, Dose, and Mode of Administration: 
Gedea Pessary, administered vaginally, containing 300 mg GDL and 367.5 mg NaG. 
Study Duration: 
Up to 5 weeks for each patient, planned first patient in November 2018. 
Criteria for Evaluation: 
Primary endpoints: 
 
Clinical cure rate on Day 7. 
o Defined as the absence of signs and symptoms of VVC in terms of having a 
composite vulvovaginal signs-and-symptoms (CVVS) score equal to or below 3. 
 
Each of the following 6 vulvovaginal signs and symptoms will be 
individually scored using the scoring scale below and then added together 
to determine the CVVS score. 
 
Vulvovaginal signs: erythema, edema, or excoriation 
 
Vulvovaginal symptoms: itching, burning, or irritation 

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 
Scoring Scale: each score should be objectively defined. 
0 = none (absent) 
1 = mild (slight) 
2 = moderate (definitely present) 
3 = severe (marked, intense) 
 
Safety and tolerability, based on reported treatment-emergent AEs 
Secondary endpoints: 
All patients 
 
Proportion of patients having a reduction in CVVS score on Day 7 compared to Day 0 
 
Change in the CVVS score from Day 0 to Day 7 
 
Proportion of patients having a reduction in the sum of the 3 vulvovaginal symptoms 
scores (itching, burning, and irritation) on Day 4 and Day 7, compared to Day 0 
 
Change in the sum of the 3 vulvovaginal symptoms scores (itching, burning, and irritation) 
from Day 0 to Day 4 and Day 7 
 
Usability, measured by patient questionnaire 
For patients not receiving prolonged treatment 
 
Recurrence rate on Day 14 and Day 35, defined as the proportion of patients clinically 
cured on Day 7 and thereafter responding “yes” to a yes/no question from the patient 
questionnaire on whether the symptoms have recurred 
For patients receiving prolonged treatment 
 
Proportion of patients receiving prolonged treatment  
 
Clinical cure rate on Day 14, defined as the absence of signs and symptoms of VVC in 
terms of having a CVVS score equal to or below 3 
 
Proportion of patients having a reduction in CVVS score on Day 14 compared to Day 0 
 
Change in the CVVS score from Day 0 to Day 14 
 
Proportion of patients having a reduction in the sum of the 3 vulvovaginal symptoms 
scores (itching, burning, and irritation) on Day 11, Day 14, Day 21, and Day 42, compared 
to Day 0 
 
Change in the sum of the 3 vulvovaginal symptoms scores (itching, burning, and irritation) 
from Day 0 to Day 11, Day 14, Day 21, and Day 42 
 
Recurrence rate on Day 21, and Day 42, defined as the proportion of patients clinically 
cured on Day 14 and thereafter responding “yes” to a yes/no question from the patient 
questionnaire on whether the symptoms have recurred  
 
Proportion of patients receiving prescription for fluconazole on Day 14 
Exploratory endpoint variables: 
All patients 
 
Effect on vaginal microbiome on Day 0 and Day 7 
 
Vaginal pH on Day 7 
For patients not receiving prolonged treatment 
 
Effect on vaginal microbiome on Day 35 
For patients receiving prolonged treatment 
 
Effect on vaginal microbiome on Day 14 and Day 42 
Safety and Tolerability Endpoints: 
See above, safety and tolerability, based on reported treatment-emergent AEs. 

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Statistical Methods: 
Sample size (n=24) is based on having 90 % power to show that the one-sided 95 % confidence 
interval for the observed cure rate is above 40 %, assuming the true clinical cure rate, as defined in 
this study, to be equal to 70 % in this patient population. 
Clinical performance and safety analyses will be performed against the full analysis set (FAS) 
population, i.e. all patients who have received at least 1 dose of study treatment. The first co-
primary endpoint, the clinical cure rate, will be calculated and presented together with a one-
sided 95 % confidence interval based on the exact binomial distribution, whereas the evaluation of 
the second co-primary endpoint (safety and tolerability) will be based on descriptive statistics and 
data listings. The secondary endpoints will be presented with the appropriate point estimate 
together with the 95% confidence interval. Further, all clinical performance and safety endpoints 
will be presented descriptively. 
Clinical Investigation Plan Approval Date: 
24OCT2018 
 

Clinical Investigation Plan QRS-CL1-003, Version 3.0 
Gedea Pessary 
 
Protocol Version 3.0, 24Oct2018 
LINK Medical Research | Protocol template 
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TABLE OF CONTENTS 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ..................................................... 2 
APPROVAL PAGE ...................................................................................................................... 4 
SYNOPSIS ................................................................................................................................. 5 
TABLE OF CONTENTS ................................................................................................................ 9 
LIST OF ABBREVIATIONS ......................................................................................................... 12 
1 
INTRODUCTION ........................................................................................................... 13 
1.1 
Indication ................................................................................................................ 13 
1.2 
Biofilm and Glucono-Delta-Lactone ........................................................................ 14 
1.3 
Product Description and Previous Experience ........................................................ 15 
1.3.1 
Non-Clinical Data ..................................................................................... 15 
1.3.2 
Clinical Data ............................................................................................. 15 
2 
STUDY OBJECTIVES ...................................................................................................... 16 
2.1 
Primary Objectives .................................................................................................. 16 
2.2 
Secondary Objectives .............................................................................................. 16 
3 
STUDY DESIGN ............................................................................................................. 17 
3.1 
General outline ....................................................................................................... 17 
3.2 
Rationale for Study Design ...................................................................................... 20 
3.2.1 
Risks and Benefits .................................................................................... 20 
3.3 
Recruitment ............................................................................................................ 21 
3.4 
Schedule of Assessments and Procedures .............................................................. 22 
3.5 
Study Visits and Procedures ................................................................................... 24 
3.5.1 
Day 0; Screening and Enrollment ............................................................ 24 
3.5.2 
Day 2; Treatment Administration ............................................................ 24 
3.5.3 
Day 4 (+2 Days); Follow-up Telephone Contact ...................................... 24 
3.5.4 
Day 6; Treatment Administration ............................................................ 25 
3.5.5 
Day 7 (+2 Days); Follow-up Visit .............................................................. 25 
3.5.6 
Day 9; Treatment Administration ............................................................ 26 
3.5.7 
Day 11 (+2 Days); Follow-up Telephone Contact .................................... 26 
3.5.8 
Day 13; Treatment Administration .......................................................... 26 
3.5.9 
Day 14 (± 2 Days); Follow-up Telephone Contact ................................... 26 
3.5.10 
Day 14 (+2 Days); Follow-up Visit ............................................................ 27 
3.5.11 
Day 21 (± 2 Days); Follow-up Telephone Contact ................................... 27 
3.5.12 
Day 35 (± 2 Days); Follow-up Telephone Contact ................................... 27 
3.5.13 
Day 42 (± 2 Days); Follow-up Telephone Contact ................................... 28 
3.6 
Early Withdrawal Procedures ................................................................................. 28 
4 
SELECTION OF STUDY POPULATION ............................................................................. 28 
4.1 
Patient Population and Number of Patients ........................................................... 28 
4.2 
Inclusion Criteria ..................................................................................................... 29 
4.3 
Exclusion Criteria .................................................................................................... 29 
4.4 
Withdrawal and Termination Criteria ..................................................................... 30 
4.5 
Reasons for Withdrawal.......................................................................................... 30 
4.6 
Handling of Withdrawals ........................................................................................ 30 
4.7 
Replacements ......................................................................................................... 31 
4.8 
Sponsor Termination of Study ................................................................................ 31 

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5 
TREATMENTS ............................................................................................................... 31 
5.1 
Investigational Product ........................................................................................... 31 
5.1.1 
Investigational Product Accountability ................................................... 32 
5.2 
Additional Products and Material ........................................................................... 33 
5.2.1 
Rescue Medication .................................................................................. 34 
5.3 
Selection of Investigational Device and Doses ....................................................... 34 
5.4 
Treatments Administered ....................................................................................... 34 
5.5 
Method of Assigning Patients to Treatment Groups .............................................. 34 
5.6 
Blinding ................................................................................................................... 34 
5.7 
Prior and Concomitant Medication ........................................................................ 34 
5.8 
Treatment Compliance ........................................................................................... 34 
6 
CLINICAL PERFORMANCE ............................................................................................. 35 
6.1 
Clinical Performance Assessments ......................................................................... 35 
6.1.1 
Gynecological Examination ..................................................................... 36 
6.1.2 
Patient Questionnaire ............................................................................. 36 
7 
SAFETY AND TOLERABILITY ASSESSMENTS ................................................................... 36 
7.1 
Medical and Surgical History .................................................................................. 36 
7.2 
Clinical Laboratory Evaluation ................................................................................ 36 
7.3 
Untoward Medical Events / Adverse Events ........................................................... 37 
7.4 
Serious Untoward Medical Events / Serious Adverse Events ................................. 38 
7.5 
Definitions of Adverse Event Ratings ...................................................................... 38 
7.5.1 
Severity .................................................................................................... 38 
7.5.2 
Relatedness ............................................................................................. 39 
7.5.3 
Outcome .................................................................................................. 40 
7.6 
Capturing and Reporting of Untoward Medical Events / Adverse Events .............. 41 
7.7 
Reporting of Serious Untoward Medical Events / Serious Adverse Events ............ 41 
7.8 
Follow-up of Untoward Medical Events / Adverse Events ..................................... 42 
7.9 
Device Deficiencies ................................................................................................. 42 
7.10 
Tolerability .............................................................................................................. 42 
7.11 
Pregnancy ............................................................................................................... 42 
8 
DATA HANDLING AND QUALITY ASSURANCE ............................................................... 43 
8.1 
Data Management .................................................................................................. 43 
8.1.1 
Data Collection ........................................................................................ 43 
8.1.2 
The Web-Based Case Report Form .......................................................... 43 
8.1.3 
The Entering of Data into the Electronic Case Report Form ................... 43 
8.1.4 
The Query Process ................................................................................... 43 
8.1.5 
Signing of Data ......................................................................................... 44 
8.1.6 
Database Lock .......................................................................................... 44 
8.2 
Patient Records and Source Data ........................................................................... 44 
8.3 
Record Retention .................................................................................................... 44 
8.4 
Monitoring, Audits, and Inspections ....................................................................... 45 
8.5 
Training of Staff ....................................................................................................... 45 
9 
STATISTICAL METHODS AND PLANNED ANALYSIS ........................................................ 45 
9.1 
Statistical Analysis ................................................................................................... 46 
9.1.1 
Analysis Data Sets and Populations ......................................................... 46 
9.1.2 
Demographic and other Baseline Characteristics ................................... 47 

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9.1.3 
Exposure to Treatment ............................................................................ 47 
9.2 
Primary and Secondary Endpoints Analysis ............................................................ 47 
9.2.1 
Primary Endpoints Analysis ..................................................................... 47 
9.2.2 
Secondary Endpoints Analysis ................................................................. 47 
9.2.3 
Tolerability and Safety Analysis ............................................................... 48 
9.2.3.1 
Local Tolerability ................................................................... 48 
9.2.3.2 
Adverse Events ...................................................................... 48 
9.3 
Sample Size Determination ..................................................................................... 48 
10 
DEVIATIONS FROM THE CLINICAL INVESTIGATION PLAN AND CLINICAL 
INVESTIGATION PLAN VIOLATIONS .............................................................................. 48 
10.1 
Deviations ............................................................................................................... 48 
10.2 
Clinical Investigation Plan Violations ...................................................................... 49 
10.3 
Reporting of Deviations and Clinical Investigation Plan Violations ........................ 49 
11 
SPECIAL REQUIREMENTS AND PROCEDURES ................................................................ 49 
11.1 
Good Clinical Practice ............................................................................................. 49 
11.2 
Ethics ....................................................................................................................... 49 
11.2.1 
Institutional Ethics Review ...................................................................... 49 
11.2.2 
Ethical Conduct of the Clinical Investigation ........................................... 50 
11.2.3 
Patient Information and Consent ............................................................ 50 
11.3 
Patient Protection Procedures ................................................................................ 50 
11.3.1 
Procedures in Case of Medical Emergency ............................................. 50 
11.3.2 
Patient Data Protection ........................................................................... 50 
11.3.3 
Insurance ................................................................................................. 50 
11.4 
Report and Publication ........................................................................................... 50 
11.5 
Confidentiality ......................................................................................................... 51 
12 
CLINICAL INVESTIGATION TIME TABLE AND TERMINATION .......................................... 51 
13 
REFERENCES ................................................................................................................ 52 
 
LIST OF FIGURES 
Figure 1 
Study Flow Chart ........................................................................................................ 19 
Figure 2 
Gedea Pessary and Applicator ................................................................................... 32 
Figure 3 
Vaginal Tablet Applicator Label ................................................................................. 32 
Figure 4 
Investigational Product Label .................................................................................... 32 
 
LIST OF TABLES 
Table 1 
Severe Vulvovaginal Candidiasis, Treatment Cure Rates .......................................... 14 
Table 2 
Schedule of Assessments and Procedures, No Prolonged Treatment ...................... 22 
Table 3 
Schedule of Assessments and Procedures, Prolonged Treatment ............................ 23 
Table 4 
Untoward Medical Events / Adverse Events Categorization ..................................... 37 
 
LIST OF APPENDICES 
Appendix 1 Patient Questionnaire 
Appendix 2 Declaration of Helsinki 
Appendix 3 Investigator Signature Pages 
 

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LIST OF ABBREVIATIONS 
ADE 
Adverse device effect 
AE 
Adverse event 
ASADE 
Anticipated serious adverse device effect 
ATC 
Anatomical therapeutic chemical classification system 
BV 
Bacterial vaginosis 
CI 
Confidence interval 
CIP 
Clinical investigation plan 
CRF 
Case report form 
CRO 
Contract research organization 
CIR 
Clinical investigation report 
CTA 
Clinical trial agreement 
CV 
Curriculum vitae 
CVVS 
Composite vulvovaginal signs and symptoms 
eCRF 
Electronic case report form 
FAS 
Full analysis set 
FDA 
The U.S. Food & Drug Administration 
GCP 
Good clinical practice 
GDL 
Glucono-delta-lactone 
GDPR 
General Data Protection Regulation 
GLP 
Good laboratory practice 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International conference on harmonization 
IEC 
Independent ethics committee 
IPCS 
International programme on chemical safety 
ISF 
Investigator site file 
ISO 
International Organization for Standardization 
MedDRA 
Medical dictionary for regulatory activities 
NaG 
Sodium gluconate 
OTC 
Over-the-counter 
PP 
Per protocol 
RA 
Regulatory authorities 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SD 
Standard deviation 
SDV 
Source data verification 
SOP 
Standard operating procedure 
USADE 
Unanticipated serious adverse device effect 
VVC 
Vulvovaginal candidiasis 
WHODD 
World Health Organization Drug Dictionary 
 

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1 INTRODUCTION 
1.1 
Indication 
Vaginal infection is a huge and today largely underestimated problem, affecting between 70% 
to 75% of women at some point in life, and between 5% to 8% of adult women have recurrent 
vulvovaginal candidiasis (VVC) with ≥ 4 episodes yearly.1 As previously described, current 
antifungal agents for VVC treatment and prevention are prone to resistance development and 
many patients relapse after treatment.2 Also, oral antifungal therapies are not recommended 
during pregnancy due to the potential risk of fetal harm and spontaneous abortions.3,4 
Therefore, treatment guidelines recommend that topical, rather than oral, antifungal therapy is 
used in pregnant women.5 
The vaginal microbiome is a dynamic system with a complex mixture of microorganisms in 
different ratios and quantities, which depend on lactic-acid producing bacteria to maintain a 
weakly acidic environment, see overview.6 Changes to vaginal microflora will increase the 
pH, thereby forming a favorable environment for vaginal pathogens. Vaginal or systemic 
antibiotics treatment is frequently followed by VVC, likely due to the elimination of the 
protective bacterial flora, thereby allowing Candida overgrowth.7-11 Infections are also 
facilitated due to the mucosal effect of increased estrogen levels and a weakened immune 
system during pregnancy.12 Recurrences are more common in pregnant women, and their 
therapeutic response is reduced compared to non-pregnant women.13,14 Further, contraceptive 
pills, menstruation, and diabetes mellitus have been identified as predisposing factors for 
VVC.15,16 Candida albicans is the most prevalent pathogen, which has been reported in 
epidemiological studies as represented in between 85% and 95% of vaginal isolations.17-19 
Candida glabrata is the second most prevalent pathogen.20 
Many women diagnose themselves with VVC and purchase over-the-counter (OTC) 
antimycotics for treatment. However, many misdiagnose themselves, leading to unnecessary 
or inappropriate treatment;21 Ferris and colleagues found that only 34% of women who 
purchased OTC antimycotics for VVC did, in fact, have VVC.22 
Current treatment strategies for uncomplicated or acute VVC include antimycotic vaginal 
creams or pessaries/vaginal tablets such as econazole, clotrimazole, or miconazole for 1 to 
7 days, or single-dose oral fluconazole. Reported clinical cure rates are variable, which may 
reflect different clinical cure definitions between studies. Clinical cure rates over 27 to 
38 days for intravaginal imidazoles (clotrimazole, terconazole, butoconazole, or miconazole) 
are 64% to 87%.2,23 Short-term clinical cure rates have been reported to be 85%,2 but also as 
low as 35% seven days after treatment.24 Mycological cure rates for oral fluconazole in 
uncomplicated VVC are 96% after 7 days, 90% after 14 days, and 86% after 28 days.24 
Severe VVC is characterized by extensive vulvar edema, excoriations, and fissure formation. 
Short courses of treatment, which are normally effective in uncomplicated VVC, are often not 
sufficient.21 Recommendations for treating severe and complicated VVC include 2 to 3 oral 
doses of fluconazole, oral itraconazole for 3 days, boric acid vaginal insert for 2 weeks, or 
topical therapy for 7 to 14 days.21,25,26 See Table 1 for severe VVC treatment cure rates. 
Recurrent VVC is characterized by ≥ 4 yearly episodes, and treatment usually entails 
intensive initial therapy to induce clinical and mycological remission, followed by 6-month 
systemic fluconazole maintenance therapy.21,27,28 While treatment guidelines for recurrent 

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VVC are consistent, recommended treatments are not particularly effective in the long term2,27 
as 30% to 50% of patients experience recurrence after treatment discontinuation.21 
There are limited data regarding the antifungal susceptibility of the Candida causing VVC as 
VVC cultures are rarely performed. The prevalence of fluconazole-resistance among 
C. albicans isolates has been reported to be between 2.1% and 21% in different studies.29-32 
Fluconazole or itraconazole resistance is found in a larger proportion of non-albicans Candida 
species; resistance to fluconazole was found in 15% of C. glabrata isolates and 42% of 
Candida krusei isolates, and resistance to itraconazole was found in 74% and 58% of 
C. glabrata and C. krusei isolates, respectively.31 
In summary, current treatment and prevention strategies for infections in the genital area are 
limited, and there is a need for novel treatment and prevention alternatives which are safe 
during pregnancy and with low risk of resistance development. 
Table 1 Severe Vulvovaginal Candidiasis, Treatment Cure Rates 
 
Terconazole 
Clotrimazole 
Fluconazole 
Clinical Cure Rate 
 
 
 
 
7-14 days after treatment 
81% 
89% 
76%-89% 
 
30-35 days after treatment 
60% 
72% 
56%-78% 
Mycological Cure rate 
 
 
 
 
7-14 days after treatment 
79% 
78% 
71%-74% 
 
30-35 days after treatment 
62% 
54% 
53%-56% 
Relapse rates after 30 to 35 days were between 13%-26%, see33,34 for details. 
1.2 
Biofilm and Glucono-Delta-Lactone 
It is estimated that approximately 80% of pathogen infections in humans are related to the 
formation of biofilm, i.e., a complex 3-dimensional structure of pathogens attached to cell 
walls and to other pathogens. It has been shown that biofilm formation is required for VVC, 
and that biofilm is coupled to treatment failure, recurrent infections, and enhancing spread of 
antimicrobial resistance.35,36 Biofilm formation is dependent both on pH and the availability 
of alternative carbohydrate sources. The vulvovaginal tract is generally acidic and rich in 
lactic acid and acetic acid. Interestingly, it has been shown that the addition of gluconic acid 
strongly diminished the biofilm formation in Vibrio cholera.37 Prokaryotes, such as 
V. cholera, uses gluconic acid as a carbon source using the Entner-Doudoroff pathway. 
Similarly, gluconic acid, as well as glucono-delta-lactone (GDL) can be utilized by yeasts and 
other eukaryotes in the pentose phosphate pathway. 
Biofilms are characterized by a transformation of planktonic cells to form hyphae, which can 
invade the mucous membrane and induce inflammation.38 The hyphal form, i.e., filamentous 
cells, can invade tissue and induce inflammation, mediated by Candidalysin, a cytotoxic 
peptide toxin that destroys the epithelial cells of the vagina.39 Thus, it is reasonable to assume 
that GDL functions as an indicator of a favorable environment for several pathogens, such as 
Candida, which favors planktonic cells over hyphae, resulting in reduced biofilm formation. 
We have shown that GDL can significantly reduce the biofilm formation in C. albicans and 
other Candida species. The effect on biofilm formation is not only due to a lowering of the 
pH, as treatment with GDL inhibits the formation of biofilm even at pH 6. For comparison, 
biofilm formation was measured at different pH levels in phosphate buffer, with significantly 

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less effect. The reduced biofilm formation caused by GDL was accompanied by a significant 
reduction of hyphal cells, the pathogenic form of C. albicans, as shown by time-lapse 
microscopy. Furthermore, GDL treatment was found to remove also mature biofilm (biofilm 
grown for 2 days before treatment, data not shown). 
1.3 
Product Description and Previous Experience 
1.3.1 
Non-Clinical Data 
Glucono-delta-lactone is a normal intermediate in glucose metabolism through the pentose 
phosphate cycle in mammals. Animal studies show that GDL gives similar weight increase as 
glucose in rats on low-calorie diets.40 Furthermore, several studies on humans have been 
performed using oral doses between 3 g and 50 g of GDL with no signs of toxicity.41 The 
investigated studies showed no evidence for carcinogenicity, teratogenicity, or genotoxicity of 
GDL, nor D-gluconic acid or the magnesium, potassium, calcium, or sodium salts thereof. In 
addition, both the U.S. Food & Drug Administration (FDA) and the World Health 
Organization International Programme on Chemical Safety (ICPS) accepts GDL as a safe 
food additive.42,43 
In this study, GDL and sodium gluconate (NaG) have been formulated as a slow-release 
vaginal tablet/ pessary. Sodium gluconate is the sodium salt of the anion of gluconic acid and 
in a water solute, both GDL and NaG are in equilibrium with gluconic acid. Biological 
evaluation of the pessary has been performed in accordance with International Organization 
for Standardization (ISO) 10993 (Biological Evaluation of Medical Devices). The biological 
evaluation included: cytotoxicity testing (direct cell contact test, ISO 10993-5); in vivo 
irritation (vaginal acute irritation, ISO 10993-10); and sensitization (local lymph node assay, 
ISO 10993-10). The tests have been performed by Eurofins Medical Device Testing (Munich, 
Germany) in compliance with the principles of good laboratory practice (GLP). The 
cytotoxicity test, which is performed in vitro as a direct cell contact test, classified the test 
item as slight to moderate cytotoxic (scale 1‒2 on a 3-grade scale). The in vitro cytotoxicity 
test is a prerequisite to continue with the in vivo irritation and sensitization studies. In the in 
vivo irritation test, no signs of irritation or necrosis were observed in the macroscopic 
assessment after treatment with Gedea Pessary. Also, there were no indicators for irritation of 
the vaginal mucosa in the histopathology assessment. The sensitization test showed no signs 
of sensitization after treatment with Gedea Pessary. Thus, it can be concluded that the product 
fulfilled the current biocompatibility requirements for medical devices. For further pre-
clinical data, refer to the Investigator’s brochure (IB). 
1.3.2 
Clinical Data 
The GDL-and-NaG containing investigational device, Gedea Pessary (commercial name 
pHyph), has not been tested in previous clinical trials. Products containing polymerized lactic 
acid have comparable properties to Gedea Pessary, as lactic acid and GDL have the same 
ability to inhibit bacterial biofilm formation and lower the pH to a similar extent, see IB. One 
such product, Laccure Pessary (Laccure AB, Helsingborg, Sweden), is buffered to pH 3.5, 
whereas Gedea Pessary is buffered to pH 3.6. Laccure Pessary has been tested in a clinical 
trial of 126 patients with confirmed bacterial vaginosis (BV), where 93 patients were treated 
with 1 or 2 doses of Laccure Pessary and 33 patients formed the control group.44 The study 
showed an 80% cure rate for the single-dose treatment. No serious adverse events (SAEs) 
occurred. The majority of adverse events (AEs) reported were of mild intensity and brief. The 

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most common events were vaginal itching or vaginal burning, experienced by 10 patients. No 
differences were seen between groups. The treatment had no visually detectable negative 
impact on the vaginal mucosa. 
Based on published studies on current treatments for VVC, all vaginal and local antimycotics 
are generally well tolerated.2 Local irritation is the most frequent adverse event reported in 
conjunction with topical azole therapy, and headache is the most frequently reported adverse 
event of oral imidazoles.23,34 Nausea and diarrhea has been reported as treatment-emergent 
AEs in a study with oral fluconazole, both at a rate of 1.9%.24 
Collectively, pre-clinical data indicate that GDL and NaG are safe and may be an effective 
topical treatment for VVC and a GDL-and-NaG containing slow-release pessary is to be 
investigated in this clinical trial. 
2 STUDY OBJECTIVES 
2.1 
Primary Objectives 
To investigate the clinical performance, tolerability, and safety of the investigational product. 
Primary endpoints: 
 Clinical cure rate on Day 7. 
o Defined as the absence of signs and symptoms of VVC in terms of having a 
composite vulvovaginal signs-and-symptoms (CVVS) score equal to or 
below 3.1 
 Each of the following 6 vulvovaginal signs and symptoms will be 
individually scored using the scoring scale below and then added 
together to determine the CVVS score. 
o Vulvovaginal signs: erythema, edema, or excoriation 
o Vulvovaginal symptoms: itching, burning, or irritation 
 Scoring Scale: each score should be objectively defined. 
0 = none (absent) 
1 = mild (slight) 
2 = moderate (definitely present) 
3 = severe (marked, intense) 
 Safety and tolerability, based on reported treatment-emergent AEs. 
2.2 
Secondary Objectives 
To further investigate the clinical performance of the investigational product. 
Secondary endpoints: 
All patients 
 Proportion of patients having a reduction in CVVS score on Day 7 compared to Day 0. 
 Change in the CVVS score from Day 0 to Day 7. 
 Proportion of patients having a reduction in the sum of the 3 vulvovaginal symptoms 
scores (itching, burning, and irritation) on Day 4 and Day 7, compared to Day 0. 

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 Change in the sum of the 3 vulvovaginal symptoms scores (itching, burning, and 
irritation) from Day 0 to Day 4 and Day 7. 
 Usability, measured by patient questionnaire. 
For patients not receiving prolonged treatment 
 Recurrence rate on Day 14 and Day 35, defined as the proportion of patients clinically 
cured on Day 7 and thereafter responding “yes” to a yes/no question from the patient 
questionnaire on whether the symptoms have recurred. 
For patients receiving prolonged treatment 
 Proportion of patients receiving prolonged treatment.  
 Clinical cure rate on Day 14, defined as the absence of signs and symptoms of VVC in 
terms of having a CVVS score equal to or below 3. 
 Proportion of patients having a reduction in CVVS score on Day 14 compared to 
Day 0. 
 Change in the CVVS score from Day 0 to Day 14. 
 Proportion of patients having a reduction in the sum of the 3 vulvovaginal symptoms 
scores (itching, burning, and irritation) on Day 11, Day 14, Day 21, and Day 42, 
compared to Day 0. 
 Change in the sum of the 3 vulvovaginal symptoms scores (itching, burning, and 
irritation) from Day 0 to Day 11, Day 14, Day 21, and Day 42. 
 Recurrence rate on Day 21, and Day 42, defined as the proportion of patients clinically 
cured on Day 14 and thereafter responding “yes” to a yes/no question from the patient 
questionnaire on whether the symptoms have recurred. 
 Proportion of patients receiving prescription for fluconazole on Day 14. 
Exploratory endpoint variables: 
All patients 
 Effect on vaginal microbiome on Day 0 and Day 7. 
 Vaginal pH on Day 7. 
For patients not receiving prolonged treatment 
 Effect on vaginal microbiome on Day 35. 
For patients receiving prolonged treatment 
 Effect on vaginal microbiome on Day 14 and Day 42. 
3 STUDY DESIGN 
3.1 
General outline 
This is an open-label, single-armed, multi-center study to evaluate clinical performance, 
tolerability, and safety of Gedea Pessary in 24 adult women with VVC. Patients seeking 
treatment can be screened for study participation. Included patients will have gynecological 
examination, including collection of CVVS data, vaginal samples taken, and will receive the 

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investigational product to be self-administered at Day(s) 0, 2, 4, and 6. Patients will again be 
examined after 7 days and CVVS data will be collected. Prolonged treatment at Day(s) 7, 9, 
11, and 13 will be given to patients not cured at Day 7; including re-examination at 
Day 14. Patients will be followed up by telephone up to 29 days after last treatment 
administration. Vaginal samples will be used for confirming diagnosis and microbiome 
analyzes. Patient questionnaires will be used for assessing VVC symptoms, usability, and 
AEs.

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Figure 1 Study Flow Chart 
Gynecological 
Examination 
(VVS)
VS
Day 0
Day 4
Day 7
Day 11
CVVS
VS
Day 7
Site visit
VVS
Day 14
Telephone
VVS
VS
Day 35
Telephone
Day 0
Screening Visit (site)
Treatment
Gynecological 
Examination 
(VVS)
VS
Day 4
Telephone
Treatment
Screening Visit (Site)
Site visit
Telephone
Telephone
Patients not receiving prolonged treatment
Patients receiving prolonged treatment
Day 2
Day 6
Day 2
Day 6
Day 9
VVS
Day 14
Site visit
CVVS
VS
VVS
Day 21
Telephone
VVS
Day 42
Telephone
VVS
VS
Day 13
VVS
CVVS
VS
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
 
VVS = Vulvovaginal Symptoms, VS = Vaginal Swab, CVVS = Composite Vulvovaginal Signs and Symptoms 
Patients not receiving prolonged treatment applies to patients cured at Day 7. If not cured, the flow chart patients receiving prolonged treatment applies. Patients will here receive fluconazole 
if not cured at Day 14. Adverse events will be assessed throughout the study 

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3.2 
Rationale for Study Design 
As described in Section 1.1, VVC is a major clinical concern, and new effective interventions 
not associated with antibiotic resistance and major drug interactions would be valuable 
additions to the current treatment arsenal. This study aims to investigate the clinical 
performance and safety of the Gedea Pessary containing GDL and NaG in treating VVC. 
Previous in vitro data show that GDL inhibits both bacterial and fungal biofilm formation, 
and transforms Candida to a non-adhesive form (see Section 1.2). In addition, a device 
comparable to Gedea Pessary with regards to its pH-lowering and biofilm-inhibiting 
properties, used for treating BV, have shown high cure rates.44 Data also indicate that GDL is 
tolerable and does not pose any special risk to humans (Section 1.3.1). 
Based on this, it may be argued that a trial involving patients is justified due to the widespread 
clinical problem of VVC and the issues involving current therapies (see Section 1.1). Further, 
due to that the pessary has not been evaluated clinically prior to this study and the lack of 
proper comparators, a single-arm design has been chosen, allowing evaluation of clinical 
performance on a smaller number of patients. Due to the open-label design, risks for 
introducing assessor bias have been minimized by the use of well-defined and documented 
scales, as well as objective laboratory assessments. 
The dose of 300 mg GDL and 376.5 mg NaG administered 2 days apart on Day(s) 0, 2, 4, and 6a 
was chosen based on pre-clinical data, specifically an in vitro dissolution test of the Gedea 
Pessary using a vaginal fluidic model (see IB). Measurements of pH in the in vitro dissolution 
test showed a pH-decrease duration of approximately 45 hours. 
3.2.1 
Risks and Benefits 
The investigational device, Gedea Pessary has been evaluated in accordance with ISO 10993 
(Biological Evaluation of Medical Devices). The evaluation included: cytotoxicity testing 
(Direct cell contact test, ISO 10993-5); in vivo irritation (Vaginal acute irritation; 
ISO 10993-10); and sensitization (local lymph node assay, ISO 10993-10). The in vitro 
cytotoxicity test, classified the test item as slight to moderate cytotoxic (scale 1‒2 on a 3-
grade scale); the in vivo irritation test as well as the in vivo sensitization test showed no signs 
of irritation, necrosis or sensitization after treatment with Gedea Pessary. 
The vaginal pessary may, in similarity with other vaginally administered products, cause 
temporary minor discomfort at insertion. The vaginal sampling procedures are similar to 
sampling procedures used in clinical practice are unlikely to cause any major inconvenience 
to patients. In the Laccure pessary study,44 there were no SAEs and vaginal itching was the 
most common AE. 
There is a risk that patients will have no clinical benefit from the investigational device. This 
may cause patients to experience symptoms including vaginal itching, burning or soreness, 
pain during sexual intercourse, pain or discomfort when urinating, or abnormal vaginal 
discharge longer than necessary.1,45 However, fluconazole will be offered on Day 14 if any 
symptoms should still be present, thus avoiding any risk associated with long-term untreated 
VVC. 
 
a And on Day(s) 7, 9, 11, and 13 if receiving prolonged treatment  

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Subjects included in the study must refrain from using other intravaginal products, thus 
mitigating the risk of interactions with concomitant vaginally-administered products. The 
investigational device acts locally on the vaginal mucosa and most likely will most likely not 
affect any concomitant systemic treatment. 
Taken together, as the anticipated levels of discomfort are transient and mild, and that risks 
associated with VVC are avoidable, the use of the investigational product appears to offer 
clinical benefits at a reasonable risk level. 
3.3 
Recruitment 
Patients will be recruited at study sites’ gynecological clinics. Post-menarchal, pre-
menopausal females 18 years or older seeking for VVC symptoms may be informed verbally 
and in writing about the study and screened following signed informed consent. Patients may 
also be pre-informed about the study by the use of advertisement through social media; these 
patients will directly book appointments with the clinic. The recruitment of patients will start 
only after the approval of the clinical investigation plan (CIP) by the regulatory authorities 
(RA) and the independent ethics committee (IEC). No study procedures will be performed 
unless the patient has provided written informed consent to study participation. See also 
Section 4.1. 

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3.4 
Schedule of Assessments and Procedures 
Table 2 Schedule of Assessments and Procedures, No Prolonged Treatment 
Evaluations 
Day 0 
Day 2 
Day 4 
(+2 days) 
Day 6 
Day 7 
(+2 days) 
Day 14 
(±2 days) 
Day 35 
(±2 days) 
Screening 
 
Follow-up 
 
Follow-up 
Follow-up 
Follow-up 
Visit 1 
 
Visit 2 
 
Visit 3 
Visit 4 
Visit 5 
Visit 
 
Telephone 
 
Visit 
Telephone 
Telephone 
Informed Consent 
X 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
Pregnancy Test (Urinary) 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Concomitant Medications 
X 
 
X 
 
X 
X 
X 
Gynecological Examination 
including vulvovaginal signs 
X 
 
 
 
X 
 
 
Vulvovaginal Symptoms 
X 
 
X 
 
X 
X 
X 
Recurrence 
 
 
 
 
 
X 
X 
Fungal Microscope 
Assessment 
X 
 
 
 
X 
 
 
Vaginal Swab for Culture  
X 
 
 
 
 
 
 
Vaginal Swab for 
Sequencing* 
X 
 
 
 
X 
 
X 
Treatment 
X 
X 
X 
X 
 
 
 
Vaginal pH 
X 
 
 
 
X 
 
 
Usability 
 
 
 
 
X 
 
 
Adverse Events 
X 
 
X 
 
X 
X 
X 
Product Accountability 
 
 
 
 
X 
 
 
* Self-swab at Day 35. 

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Table 3 Schedule of Assessments and Procedures, Prolonged Treatment 
Evaluations 
Day 0 
Day 2 
Day 4 
(+2 days) 
Day 6 
Day 7 
(+2 days) 
Day 9 
Day 11 
(+2 days) 
Day 13 
Day 14 
(+2 days) 
Day 21 
(±2 days) 
Day 42 
(±2 days) 
Screening 
 
Follow-up 
 
Follow-up 
 
Follow-up 
 
Follow-up 
Follow-up 
Follow-up 
Visit 1 
 
Visit 2 
 
Visit 3 
 
Visit 4 
 
Visit 5 
Visit 6 
Visit 7 
Visit 
 
Telephone 
 
Visit 
 
Telephone 
 
Visit 
Telephone 
Telephone 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (Urinary) 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Gynecological Examination 
including vulvovaginal signs 
X 
 
 
 
X 
 
 
 
X 
 
 
Vulvovaginal Symptoms 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Recurrence 
 
 
 
 
 
 
 
 
 
X 
X 
Fungal Microscope 
Assessment 
X 
 
 
 
X 
 
 
 
X 
 
 
Vaginal Swab for Culture  
X 
 
 
 
 
 
 
 
 
 
 
Vaginal Swab for 
Sequencing* 
X 
 
 
 
X 
 
 
 
X 
 
X 
Treatment 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vaginal pH 
X 
 
 
 
X 
 
 
 
 
 
 
Usability 
 
 
 
 
X 
 
 
 
X 
 
 
Adverse Events 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Product Accountability 
 
 
 
 
X 
 
 
 
X 
 
 
* Self-swab at Day 42. 
 

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3.5 
Study Visits and Procedures 
3.5.1 
Day 0; Screening and Enrollment 
Patients seeking treatment for symptoms relating to VVC may be informed about the study 
and, if agreeing to participate, sign the informed consent form (ICF). After enrollment, 
patients will have gynecological examinations performed, where the Investigator or an 
authorized designee will assess the presence of vulvovaginal signs (erythema, edema, or 
excoriation) and ask about symptoms (itching, burning, or irritation) and score each sign and 
symptom, as described in Section 6.1. 
Vaginal samples will be examined by microscope to reveal yeast forms (hyphae or 
pseudohyphae) or budding yeast. Two (2) vaginal secretion samples will also be collected by 
swab. One (1) of the samples will be cultured to verify presence of Candida and 1 sample will 
be used for sequencing analysis of the vaginal microbiome prior to treatment (Section 7.2). If 
the Investigator assesses that the patient has VVC, based on examination and the KOH test, 
the patient will receive the investigational product to be self-inserted vaginally at home on 
Day 0. Additional doses will also be dispensed to be administered by patients on Day(s) 2, 4, 
and 6. In addition, the Investigator will measure vaginal pH. 
Procedures performed: 
 Informed consent 
 Eligibility criteria 
 Pregnancy test (urinary) 
 Recording of: 
o medical history, 
o concomitant medication, and 
o adverse events 
 Gynecological examination by Investigator or authorized designee evaluating signs 
(erythema, edema, or excoriation) and symptoms (itching, burning, or irritation) of 
VVC according to the scoring scale 
 Fungal KOH microscope assessment 
 Vaginal swab for: 
o culture, and 
o sequencing 
 Vaginal pH 
 Treatment dispensing and self-administration by patients 
3.5.2 
Day 2; Treatment Administration 
Procedures performed: 
 Treatment self-administration by patients 
3.5.3 
Day 4 (+2 Days); Follow-up Telephone Contact 
On Day 4, patients will self-administer the investigational product and will be contacted by 
telephone by the Clinical Trial Unit. Telephone contact up to Day 6 will be allowed if Day 4 
falls on a weekend. The treatment should nevertheless be self-administered on Day 4. Patients 

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will be asked questions from the patient questionnaire about: VVC symptoms (itching, 
burning, or irritation); concomitant medications; and AEs, if any. 
Procedures performed: 
 Treatment self-administration by patients 
 Symptoms of VVC (itching, burning, or irritation) evaluated by patients according to 
the scoring scale 
 Recording of: 
o concomitant medications, and 
o adverse events 
3.5.4 
Day 6; Treatment Administration 
Procedures performed: 
 Treatment self-administration by patients 
3.5.5 
Day 7 (+2 Days); Follow-up Visit 
Patients will visit the clinic on Day 7 to have gynecological examination performed. The 
Investigator or an authorized designee will assess the presence of vulvovaginal signs 
(erythema, edema, or excoriation) and symptoms (itching, burning, or irritation) and score 
each sign and symptom. 
Vaginal samples will be examined by microscope to reveal yeast forms (hyphae or 
pseudohyphae) or budding yeast and secretion samples collected by swab to be used for 
sequencing analysis of the vaginal microbiome. Vaginal pH will also be assessed. 
If VVC symptoms are still present, patients will have prolonged treatment and receive 
additional doses of investigational product to be administered at home on Day(s) 7, 9, 11, 
and 13. 
In addition, patients will be asked questions from the patient questionnaire to assess: usability; 
concomitant medications; and AEs, if any. 
Procedures performed: 
 Gynecological examination by Investigator or authorized designee evaluating signs 
(erythema, edema, or excoriation) and symptoms (itching, burning, or irritation of 
VVC according to the scoring scale 
 Fungal KOH microscope assessment 
 Vaginal swab for sequencing 
 Vaginal pH 
 Recording of: 
o concomitant medications, 
o adverse events, and 
o usability 
 Treatment dispensing and self-administration by patients if receiving prolonged 
treatment 

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3.5.6 
Day 9; Treatment Administration 
Applicable to patients receiving prolonged treatment 
Procedures performed: 
 Treatment self-administration by patients 
3.5.7 
Day 11 (+2 Days); Follow-up Telephone Contact 
Applicable to patients receiving prolonged treatment 
Patients receiving prolonged treatment on Day 7 will self-administer the investigational 
product and will be contacted by the Clinical Trial Unit by telephone on Day 11. Telephone 
contact up to Day 13 will be allowed if Day 11 falls on a weekend. The treatment should 
nevertheless be self-administered on Day 11. Patients will be asked questions from the patient 
questionnaire about: VVC symptoms (itching, burning, or irritation), concomitant 
medications; and AEs, if any. 
Procedures performed: 
 Treatment self-administration by patients 
 Symptoms of VVC (itching, burning, or irritation) evaluated by patients according to 
the scoring scale 
 Recording of: 
o concomitant medications, and 
o adverse events 
3.5.8 
Day 13; Treatment Administration 
Applicable to patients receiving prolonged treatment 
Procedures performed: 
 Treatment self-administration by patients 
3.5.9 
Day 14 (± 2 Days); Follow-up Telephone Contact 
Applicable to patients NOT receiving prolonged treatment 
Patients not receiving additional doses of investigational product on Day 7 will be contacted 
by the Clinical Trial Unit by telephone on Day 14. Patients will be asked questions from the 
patient questionnaire about VVC symptoms (itching, burning, or irritation), recurrence, 
concomitant medications, and AEs, if any. 
Procedures performed: 
 Vulvovaginal candidiasis recurrence 
 Symptoms (itching, burning, or irritation) of VVC evaluated by patients according to 
the scoring scale 
 Recording of: 
o concomitant medications, and 
o adverse events 

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3.5.10 Day 14 (+2 Days); Follow-up Visit 
Applicable to patients receiving prolonged treatment 
Patients receiving prolonged treatment at Day 7 due to still-present VVC symptoms will visit 
the site on Day 14 to have gynecological examination performed and vulvovaginal signs 
(erythema, edema, or excoriation) and symptoms (itching, burning, or irritation) assessed by 
the Investigator or an authorized designee. Patients will receive fluconazole should symptoms 
still be present. 
Vaginal samples will be examined by microscope to reveal yeast forms (hyphae or 
pseudohyphae) or budding yeast and secretion samples collected by swab to be used for 
sequencing analysis of the vaginal microbiome.  
In addition, patients will be asked questions from the patient questionnaire to assess usability 
and AEs, if any. 
Procedures performed: 
 Gynecological examination by Investigator or authorized designee evaluating signs 
(erythema, edema, or excoriation) and symptoms (itching, burning, or irritation) of 
VVC according to the scoring scale 
 Fungal KOH microscope assessment 
 Vaginal swab for sequencing 
 Recording of: 
o concomitant medications, 
o adverse events, and 
o usability 
3.5.11 Day 21 (± 2 Days); Follow-up Telephone Contact 
Applicable to patients receiving prolonged treatment 
Patients receiving prolonged treatment on Day 7 will be contacted by the Clinical Trial Unit 
by telephone on Day 21. Patients will be asked questions from the patient questionnaire 
pertaining to VVC symptoms (itching, burning, or irritation). Questions on concomitant 
medications, recurrence, and AEs, if any, will also be asked. 
Procedures performed: 
 Vulvovaginal candidiasis recurrence 
 Symptoms (itching, burning, or irritation) of VVC evaluated by patients according to 
the scoring scale 
 Recording of: 
o concomitant medications, and 
o adverse events 
3.5.12 Day 35 (± 2 Days); Follow-up Telephone Contact 
Applicable to patients NOT receiving prolonged treatment 
On Day 35, the Clinical Trial Unit will contact patients not receiving prolonged treatment and 
ask questions from the patient questionnaire relating to VVC symptoms (itching, burning, or 
irritation). Patients will also be asked questions on concomitant medications, recurrence, and 

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AEs, if any. In addition, patients will self-collect vaginal samples by swab for sequencing and 
send samples by post to laboratory. 
Procedures performed: 
 Vulvovaginal candidiasis recurrence 
 Symptoms (itching, burning, or irritation) of VVC evaluated by patients according to 
the scoring scale 
 Vaginal swab for sequencing 
 Recording of: 
o concomitant medications, and 
o adverse events 
3.5.13 Day 42 (± 2 Days); Follow-up Telephone Contact 
Applicable to patients receiving prolonged treatment 
Patients receiving prolonged treatment will be contacted over telephone by the Clinical Trial 
Unit on Day 42 and asked questions from the patient questionnaire relating to VVC symptoms 
(itching, burning, or irritation). Patients will also be asked questions on recurrence, 
concomitant medications, and AEs, if any. Patients will collect vaginal samples by self-swab 
to be sent by post to laboratory for sequencing. 
Procedures performed: 
 Vulvovaginal candidiasis recurrence 
 Symptoms (itching, burning, or irritation) of VVC evaluated by patients according to 
the scoring scale 
 Vaginal swab for sequencing 
 Recording of: 
o concomitant medications, and 
o adverse events 
3.6 
Early Withdrawal Procedures 
See Section 4.6 for withdrawal procedures. Patients refusing to visit the site for follow-up 
visits shall be contacted by telephone, if possible, to collect answers to the patient 
questionnaire, and AEs, if any. Patients receiving fluconazole on Day 14 will be followed up 
for safety assessments. 
4 SELECTION OF STUDY POPULATION 
4.1 
Patient Population and Number of Patients 
This study will include patients with VVC. Twenty-four (24) patients are planned to be 
treated under this CIP. 
Post-menarchal, pre-menopausal females aged 18 years or older seeking treatment for 
symptoms of VVC at study sites’ gynecological clinics may be informed about the study and 
asked about their willingness to participate. 

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Patients may also contact the site directly and book appointments after seeing study 
advertisement on social media. 
The Investigator must always use IEC-approved patient information that must not be changed 
without prior Sponsor and IEC approvals, see Section 11 for further details. 
Patients who have signed the ICF shall be listed on a screening-and-inclusion log together 
with an assigned screening number. Patients not fulfilling all inclusion criteria as described in 
Section 4.2, or fulfilling any of the exclusion criteria listed in Section 4.3, shall be considered 
screening failures. Screening failure reasons shall be stated in both the Screening Visit 
electronic case report form (eCRF) pages and the screening-and-inclusion log. 
4.2 
Inclusion Criteria 
Inclusion and exclusion criteria in the fungal study should follow the FDA Vulvovaginal 
signs-and-symptoms score: 
 Adult, post-menarchal, pre-menopausal women aged 18 years or older 
 Diagnosis of VVC, defined as having a white or creamy vaginal discharge plus the 
following findings: 
 At least 2 of the following signs and symptoms of VVC that are characterized 
as at least moderate: itching, burning, irritation, edema, redness, or 
excoriation. 
 Potassium hydroxide (KOH) or saline preparation from the inflamed vaginal 
mucosa or secretions revealing yeast forms (hyphae or pseudohyphae) or 
budding yeasts. 
 Having decisional capacity and providing written informed consent. 
 Negative urine pregnancy test at screening. 
 Refrain from using any intravaginal products (i.e., contraceptive creams, gels, foams, 
sponges, lubricants, or tampons, etc.) during the study period. 
 Refrain from sexual intercourse or use a condom until Day 7 
 Signed informed consent and willing and able to comply with all study requirements. 
4.3 
Exclusion Criteria 
 Patients with known or apparent signs of other infectious causes of VVC (BV, 
Trichomonas vaginalis, Neisseria gonorrhoeae, Chlamydia trachomatis, Herpes 
simplex, or human papillomavirus) at screening. 
 Patients who are pregnant or breastfeeding. 
 Patients who were treated for VVC within the past 14 days. 
 Patients who are currently receiving antifungal therapy unrelated to VVC or has taken 
antifungal therapy within the past 14 days. 
 Patients who have used pH-modifying vaginal products within the last 14 days. 
 Patients who have received an investigational drug in a clinical investigation within 
30 days prior to screening. 
 Known/previous allergy or hypersensitivity to any product constituent or fluconazole. 

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 Any medical condition that in the Investigator’s judgments would make the patient 
unsuitable for inclusion. 
4.4 
Withdrawal and Termination Criteria 
Subjects shall be informed through the ICF about their rights to withdraw from the study at 
any time, without prejudice to further treatment or medical care. The Investigator may, at his 
or her discretion, withdraw a patient from the study and discontinue study treatment and 
assessments at any time. The specific reasons for discontinuing a patient from the study shall 
be documented in the eCRF. 
4.5 
Reasons for Withdrawal 
Reasons for patient withdrawal include, but are not limited to: 
Informed consent 
withdrawal: 
The patient may withdraw from the study or be withdrawn by a legal 
representative, if applicable, at any time without stating a reason and 
without prejudice to further treatment or medical care. 
Safety reasons: 
The Investigator or Sponsor may withdraw patients if judged that an 
AE poses an unacceptable risk or consequence to the patient. 
Medical reasons: 
The Investigator may withdraw patients if judged that a medical 
condition poses an unacceptable risk or consequence for the patient to 
continue in the study. The rationale and the medical condition 
responsible for the Investigator-initiated withdrawal shall be 
documented. 
Lost to follow-up: 
Reasonable efforts shall be made to reach patients not returning for 
scheduled visits or not being reachable by telephone. Such efforts may 
include, e.g., calling the patient at least 3 times at different hours and 
leaving voice messages. 
Other reasons: 
Includes but are not limited to failure of the patient to comply with 
study procedures or requirements 
4.6 
Handling of Withdrawals 
If a patient withdraws from the study before study completion, the reason for withdrawal 
should be sought and recorded on the eCRF. If the withdrawal is due to the performance or 
safety of the investigational device, the Investigator will ask for permission to follow-up 
patients outside of the study. If a withdrawal occurs during a study visit, the eCRF for that 
specific visit shall be completed as far as possible. 
Any AEs should be followed up until the AE is resolved or the Investigator decides that the 
AE is stable and needs no further follow-up. The last day for follow-up will be the study 
Day 35 if not receiving prolonged treatment or Day 42 if receiving prolonged treatment. AEs 
ongoing at study Day(s) 35 or 42 shall be assessed as chronic or stable. Wherever possible, 
end-of-study assessments should be carried out at the time of withdrawal. 

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4.7 
Replacements 
Withdrawn or discontinued patients shall not be replaced or re-entered into the study 
4.8 
Sponsor Termination of Study 
Although the Sponsor has every intention of completing the study, the Sponsor reserves the 
right to discontinue the study at any time for clinical or administrative reasons. In such a case, 
Investigators will be informed of additional procedures to be followed to ensure that adequate 
consideration is given to the protection of patient’s interest. 
If the study is prematurely terminated or suspended for any reason, the Investigator has to 
inform the patients and to assure appropriate patient follow-up. The Sponsor should promptly 
inform the study sites, and the RA on the termination or suspension and the reason(s) for the 
termination or suspension. The IEC should also be informed promptly and provided with the 
reason(s) for the termination or suspension by the Sponsor or by the Investigator, as specified 
by the applicable regulatory requirements. 
5 TREATMENTS 
5.1 
Investigational Product 
The investigational product, Gedea Pessary (commercial name pHyph), is a GDL-and-NaG 
containing pessary to be administered vaginally with a CE-marked vaginal tablet applicator 
(Schägner GmbH, Steinmauern, Germany). The device is intended to treat vaginal Candida 
infections, see Figure 2 and Figure 3 for product image and applicator label. Gedea Pessary is 
a Class IIa medical device according to MDD 93/42/EEC (the Swedish regulation SFS 
1993:584 and LVFS 2003:11). 
NOTE: The terms investigational product, Gedea Pessary, investigational device, pessary, 
and vaginal pessary are used interchangeably in the CIP 
Gedea Pessary is a white, convex, bullet-shaped tablet, approximately 2 cm in length, 
contract-manufactured by Galenica AB (Malmö, Sweden). The pessary is slow-release 
formulated, administering 300 mg GDL and 367.5 mg NaG over 45 hours. Each patient will 
administer a total of 4 pessaries in the study or 8 if receiving prolonged treatment. The 
investigational products will be packed in blister packs containing 4 pessaries labeled with 
Gedea Pessary and batch number. Blisters will be packed together with 4 vaginal tablet 
applicators in a cardboard-box labeled with Gedea Pessary, for investigational use only, 
production date, and expiry date (Figure 4). 
It is the responsibility of the Investigator to ensure that the investigational products are stored 
in their original packaging in a secure location with access only by authorized personnel, 
separate from other medications. The investigational product shall be stored at room 
temperature (15°C -25°C), protected from direct sunlight or freezing. The investigational 
products must not be used outside of the study. For further reference, refer to the IB. 
Instructions for use will be distributed at the first visit, advising patients on how to use the 
product together with the applicator. Briefly, patients will be instructed to: wash their hands 
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as is comfortable (without forcing), or until half of the applicator is inside; discard the 
applicator after use; not use tampons or other vaginal products while using this product. 
Figure 2 Gedea Pessary and Applicator 
 
Figure 3 Vaginal Tablet Applicator Label 
 
Figure 4 Investigational Product Label 
 
5.1.1 
Investigational Product Accountability 
The investigational products may be released to the Investigator when the clinical trial 
agreement (CTA) has been signed by all involved parties and appropriate approvals has been 
given from the IEC. 
The Investigator is responsible for full traceability of the investigational product from the 
manufacturer to patients until return or disposal. This shall be ensured by use of product 
accountability records, documenting: 
 Product quantity at storage, and 
 Deliveries to-and-from storage. 

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Shipping records of investigational product deliveries from the manufacturer shall be kept at 
study sides, including at least the following information: 
 Investigational product name and quantity received, 
 Delivery date, 
 Batch number, and 
 Expiry date. 
Dispensing logs shall be kept at study sites, documenting at least the following information: 
 Investigational product name, 
 Batch number, 
 Expiry date, 
 Dispense date, 
 Number of units used, 
 Patient receiving the investigational product, and 
 Number of units remaining in stock. 
Any nonfunctioning devices or applicator shall be documented. All unused or expired 
investigational products must be returned to the Sponsor for destruction unless otherwise 
stated in writing by the Sponsor. Any used, or opened unused materials must not be reused. 
5.2 
Additional Products and Material 
The Sponsor will provide kits for vaginal swabs for culturing and sequencing. The Sponsor 
will provide the study sites with pH meters for vaginal pH analysis. Study sites will provide 
urine pregnancy tests (urinary human chorionic gonadotropin [U-HCG]) and other materials, 
as applicable. 
The Investigator is responsible for full traceability of the vaginal swabs from the 
manufacturer to patients until return or disposal. This shall be ensured by use of 
accountability records documenting quantity at storage and deliveries to and from storage. 
Shipping records of vaginal swab-kit deliveries from the manufacturer shall be kept at study 
sides, including at least the following information: 
 Swab kit batch number and quantity received, 
 Delivery date, and 
 Expiry date. 
Dispensing logs shall be kept at study sites, documenting at least the following information: 
 Swab kit batch number, 
 Expiry date, 
 Dispense date, 
 Number of units used, 
 Patient receiving the swab kit, and 
 Number of units remaining in stock. 

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All unused or expired swab kits must be returned to the Sponsor for destruction unless 
otherwise stated in writing by the Sponsor. Any used, or opened unused materials must not be 
reused. 
5.2.1 
Rescue Medication 
Fluconazole will be used as rescue medication in this investigation, and patients will receive a 
prescription for fluconazole if considered necessary to relieve their VVC symptoms on 
Day 14. Patients withdrawing at any point in the investigation may receive fluconazole if 
considered necessary by the Investigator. The dose of fluconazole will be decided by the 
Investigator on an individual basis. The use of rescue medication will be recorded in the 
eCRF. 
5.3 
Selection of Investigational Device and Doses 
Refer to Section 3.2 
5.4 
Treatments Administered 
The pessary will be self-administered vaginally by the patient. The pessary should be inserted 
high into the vagina. The pessary should be used with the co-supplied vaginal tablet 
applicator. The patients should insert the applicator gently and deeply into the vagina, and 
then slowly depress the plunger to release the pessary. Instructions for use will be distributed 
to patients at the first site visit. See also Section 5.1. 
5.5 
Method of Assigning Patients to Treatment Groups 
Not applicable 
5.6 
Blinding 
Not applicable 
5.7 
Prior and Concomitant Medication 
Information about any concomitant medication, including OTC medications and vitamins 
taken by patients during the study and within 14 days prior to inclusion shall be documented 
in the eCRF. The generic name or trade name, dosage, and reason for use shall be recorded 
for all medications. 
NOTE: Antifungal medication during the study and within 14 days prior to inclusion is 
strictly prohibited 
See Appendix 1, Section 3 for specific questions. 
5.8 
Treatment Compliance 
Patients will be asked about investigational product administration by telephone on Day 4 and 
at the site on Day 7, and also on Day(s) 11 (telephone) and 14 (site) if receiving prolonged 
treatment. No other measurements of treatment compliance will be made. 

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6 CLINICAL PERFORMANCE 
6.1 
Clinical Performance Assessments 
Assessments described below in Section 6.1.1, gynecological examination, will be used to 
collect the following 6 vulvovaginal signs and symptoms: 
 Vulvovaginal signs of: erythema, edema, and excoriation; and 
 Vulvovaginal symptoms of itching, burning, and irritation. 
The intensity of each of the signs and symptoms will be scored as: 
0 = none (absent), 
1 = mild (slight), 
2 = moderate (definitely present), or 
3 = severe (marked, intense). 
The scores will be added together and the sum defined as the CVVS score. 
A CVVS score equal to or below 3 on Day 7 will be defined as clinical cure, and is a co-
primary study endpoint together with safety and tolerability evaluation. 
The CVVS score will also be used for the following secondary endpoints: 
 Proportion of patients having a reduction in CVVS score on Day 7 compared to Day 0. 
 Change in the CVVS score from Day 0 to Day 7. 
 Recurrence rate at Day 14 and Day 35, defined as the proportion of patients clinically 
cured at Day 7 and thereafter responding “yes” to a yes/no question from the patient 
questionnaire on whether the symptoms have recurred. 
 Proportion of patients receiving prolonged treatment. 
 Clinical cure rate on Day 14, defined as the absence of signs and symptoms of VVC in 
terms of having a CVVS score equal to or below 3. 
 Proportion of patients having a reduction in CVVS score on Day 14 compared to 
Day 0. 
 Change in the CVVS score from Day 0 to Day 14. 
 Recurrence rate at Day 21, and Day 42, defined as the proportion of patients clinically 
cured at Day 14 and thereafter responding “yes” to a yes/no question from the patient 
questionnaire on whether the symptoms have recurred. 
 Proportion of patients receiving prescription for fluconazole at Day 14. 
Assessments described in Section 6.1.2, patient questionnaire, will be used to assess the 
following secondary endpoints: 
 Proportion of patients having a reduction in the sum of the 3 vulvovaginal symptoms 
scores (itching, burning, and irritation) on Day 4 and Day 7, compared to Day 0. 
 Change in the sum of the 3 vulvovaginal symptoms scores (itching, burning, and 
irritation) from Day 0 to Day 4 and Day 7. 
 Usability, measured by patient questionnaire. 

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 Proportion of patients having a reduction in the sum of the 3 vulvovaginal symptoms 
scores (itching, burning, and irritation) on Day 11, Day 14, Day 21, and Day 42, 
compared to Day 0. 
 Change in the sum of the 3 vulvovaginal symptoms scores (itching, burning, and 
irritation) from Day 0 to Day 11, Day 14, Day 21, and Day 42. 
6.1.1 
Gynecological Examination 
Patients will have gynecological examinations by the Investigator or authorized designee on 
Day(s) 0 and 7; or Day(s) 0, 7, and 14 if receiving prolonged treatment, in order to assess 
vulvovaginal signs of erythema, edema, and excoriation. During the examinations, patients 
will also be asked about any vulvovaginal symptoms of itching, burning, and irritation. 
NOTE: The Investigator will always assess vulvovaginal signs of erythema, edema, and 
excoriation. Vulvovaginal symptoms of itching, burning, and irritation will always 
be assessed by patients themselves and asked about by the Investigator at site visits. 
6.1.2 
Patient Questionnaire 
The questionnaire can be found in Appendix 1. 
The Clinical Trial Unit will call the patients on Day(s) 4, 14 and 35; or Day(s) 4, 11, 21, 
and 42 if receiving prolonged treatment; and ask questions from the patient questionnaire 
relating to vulvovaginal symptoms (itching, burning, or irritation), usability, concomitant 
medications, and AEs, if any. 
Questions from Section 1 in the patient questionnaire relating to vulvovaginal symptoms of 
itching, burning, and irritation will be asked to patients over telephone on Day(s) 4, 14, 
and 35; or Day(s) 4, 11, 21, and 42 if receiving prolonged treatment. A recurrence question 
will be asked to patients at Days(s) 14 and 35 if not receiving prolonged treatment and at 
Days(s) 21 and 42 if receiving prolonged treatment. 
Questions from Section 2 in the patient questionnaire relating to usability in will be asked to 
patients on Day 7, and Day 14 if receiving prolonged treatment. 
Questions from Section 3 and Section 4 in the patient questionnaire relating to concomitant 
medications and AEs, respectively, will be asked to patients at each visit/telephone contact. 
7 SAFETY AND TOLERABILITY ASSESSMENTS 
7.1 
Medical and Surgical History 
Medical and surgical history will be collected during the Screening Visit. 
7.2 
Clinical Laboratory Evaluation 
Vaginal samples will be collected by vaginal swab on Day(s) 0 and 7 by the Investigator and 
on Day 35 by patients (also on Day 14 by Investigator and Day 42 by patients if receiving 
prolonged treatment). Collected samples will be used accordingly: 
 The potassium hydroxide (KOH) test for fungus from samples from Day(s) 0, 7, 
and 14 if receiving prolonged treatment. Briefly, vaginal samples are covered with 

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10% ‒ 20% KOH and inspected by microscope. Presence of hyphae indicate Candida 
and will serve as an immediate, preliminary VVC diagnosis. 
 Samples collected on Day 0 will be sent to laboratory and cultured to confirm the VVC 
diagnosis. Time for lab results is approximately 1 week; patients will be included 
based on the KOH test as described above. 
 Sequencing of samples collected on Day(s) 0, 7, and 35 (by patients). If receiving 
prolonged treatment, samples will by collected on Day(s) 0, 7, 14, and 42 (by patients). 
These samples will be analyzed after study completion to assess effects of the 
investigational product on the vaginal microbiome. 
Patients’ vaginal pH will be measured for assessments of investigational product in vivo 
duration on Day(s) 0 and 7. Vaginal pH lower at follow-up visits compared to Day 0 indicate 
appropriate release duration. 
7.3 
Untoward Medical Events / Adverse Events 
The definitions are the definitions in the current version of the ISO 14155. The categorization 
will adhere to the following table in ISO 14155; 
Table 4 Untoward Medical Events / Adverse Events Categorization 
ADVERSE EVENTS 
Non-device related 
Device-or-procedure related 
Non-serious 
Adverse Event (AE)a 
(3.2) 
Adverse Device Effect 
(ADE) 
(3.1) 
Serious 
Serious Adverse Event 
(SAE)b 
(3.37)  
Serious Adverse Device Effect 
(SADE) 
(3.36)  
Anticipated 
Unanticipated 
Anticipated Serious 
Adverse Device Effect 
(ASADE) 
(3.42, Note) 
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
(3.42) 
References in parentheses refer to sections in the standard ISO 14155:2011 
a Includes all categories. 
b Includes all categories that are serious 
Adverse events are any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the investigational medical device. 
The AE may be directly related to the use of an investigational medical device and are then 
called an adverse device effect (ADE). This includes events due to insufficient or incomplete 
instructions, use, implantation, or dysfunction of the tested product. Misuse and errors while 
using the product are also included in the ADE definition. 
The following events are not considered untoward medical events / AEs: 

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 Medical interventions planned before study initiation given that the status of the 
participant has not worsened since signing the consent form or the intervention has had 
to be done at an earlier date. 
 All conditions or diseases known at the time when the subject signs the informed 
consent form, are not considered untoward medical events / AEs. These will be 
registered in the medical history CRF page. 
7.4 
Serious Untoward Medical Events / Serious Adverse Events 
An SAE is an AE that lead to serious deterioration in the health of the subject, that resulted in 
one or more of the below: 
 death, or 
 an immediately life-threatening illness or injury, or 
 a permanent impairment of a body structure or a body function, or 
 in-patient or prolonged hospitalization, or 
 requires intervention to prevent life-threatening illness, or injury or permanent 
impairment to a body structure or a body function, or 
 led to fetal distress, fetal death or a congenital abnormality or birth defect. 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the 
current CIP, without serious deterioration in health, is not considered an SAE. 
A serious adverse device effect (SADE) is an ADE that has resulted in any of the 
consequences characteristic of a SAE. 
An unanticipated serious adverse device effect (USADE) is a SADE, which by its nature, 
incidence, severity, or outcome has not been identified in the current version of the risk 
analysis report 
NOTE: Anticipated serious adverse device effect (ASADE) is an effect, which by its 
nature, incidence, severity, or outcome has been identified in the risk analysis 
report. The classification of an untoward medical event as USADE or ASADE will 
be done retrospectively. The event will initially be captured as an SAE. 
7.5 
Definitions of Adverse Event Ratings 
7.5.1 
Severity 
Untoward medical events / AEs will be rated concerning their severity. The rating will be 
done by the Investigator. The rating used will be the following: 
Mild: 
Transient symptoms, no interference with daily activities of the participant; 
Moderate: Clear symptomatology that moderately affects the daily activities of the 
participant; or 
Severe: 
Symptoms that clearly affects or hinders daily activities of the participant. 

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7.5.2 
Relatedness 
The Investigator’s assessment of an AE's relationship to the device is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. The likely relationship of an AE to the device should be assessed by the Investigator 
according to the following definitions: 
Not Related: 
Relationship to the device or procedures can be excluded when: 
 the event is not a knowna side effect of the product category the 
device belongs to or of similar devices and procedures; 
 the event has no temporal relationship with the use of the 
investigational device or the procedures; 
 the serious event does not follow a known response pattern to the 
medical device (if the response pattern is previously known) and is 
 biologically implausible; 
 the discontinuation of medical device application or the reduction of 
the level of activation/exposure – when clinically feasible – and 
reintroduction of its use (or increase of the level of 
activation/exposure), do not impact on the serious event; 
 the event involves a body-site or an organ not expected to be 
affected by the device or procedure; 
 the serious event can be attributed to another cause (e.g. an 
underlying or concurrent illness/ clinical condition, an effect of 
another device, drug, treatment or other risk factors); 
 the event does not depend on a false result given by the 
investigational device used for diagnosisb, when applicable; 
 harms to the subject are not clearly due to use error; 
 In order to establish the non-relatedness, not all the criteria listed 
above might be met at the same time, depending on the type of 
device/procedures and the serious event. 
Unlikely: 
The relationship with the use of the device seems not relevant and/or the 
event can be reasonably explained by another cause, but additional 
information may be obtained. 
Possible: 
The relationship with the use of the investigational device is weak but 
cannot be ruled out completely. Alternative causes are also possible (e.g. an 
underlying or concurrent illness/ clinical condition or/and an effect of 
another device, drug or treatment). Cases were relatedness cannot be 
 
a When the event is not a known side effect of the product category the device belongs to or of similar 
devices and procedures, generally is considered “not related”. Yet, the unexpected effect shall not be 
excluded from evaluation and reporting. 
b If an investigational device gives an incorrect diagnosis, the patient might, for example, receive an 
unnecessary treatment and incur all the risks that accompany that treatment, or might be incorrectly 
diagnosed with a serious disease. In other cases, the patient might not receive an effective treatment 
(thereby missing out on the benefits that treatment would confer), or might not be diagnosed with the 
correct disease or condition. 

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assessed or no information has been obtained should also be classified as 
possible. 
Probable: 
The relationship with the use of the investigational device seems relevant 
and/or the event cannot reasonably explained by another cause, but 
additional information may be obtained. 
Causal 
Relationship: 
The serious event is associated with the investigational device or with 
procedures beyond reasonable doubt when: 
 the event is a known side effect of the product category the device 
belongs to or of similar devices and procedures; 
 the event has a temporal relationship with investigational device 
use/application or procedures; 
 the event involves a body-site or organ that 
o the investigational device or procedures are applied to; 
o the investigational device or procedures have an effect on; 
 the serious event follows a known response pattern to the medical 
device (if the response pattern is previously known); 
 the discontinuation of medical device application (or reduction of the 
level of activation/exposure) and reintroduction of its use (or 
increase of the level of activation/exposure), impact on the serious 
event (when clinically feasible); 
 other possible causes (e.g. an underlying or concurrent illness/ 
clinical condition or/and an effect of another device, drug or 
treatment) have been adequately ruled out; 
 harm to the subject is due to error in use; 
 the event depends on a false result given by the investigational 
device used for diagnosisa, when applicable; 
 In order to establish the relatedness, not all the criteria listed above 
might be met at the same time, depending on the type of 
device/procedures and the serious event. 
7.5.3 
Outcome 
The outcome or the result of the untoward medical event / AE for a participant will be rated 
by the Investigator as; 
Resolved: 
Fully recovered spontaneously or after medical or surgical intervention, i.e., 
the status is the same as the pre-study status. 
 
a If an investigational device gives an incorrect diagnosis, the patient might, for example, receive an 
unnecessary treatment and incur all the risks that accompany that treatment, or might be incorrectly 
diagnosed with a serious disease. In other cases, the patient might not receive an effective treatment 
(thereby missing out on the benefits that treatment would confer), or might not be diagnosed with the 
correct disease or condition. 

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Resolved 
with 
sequelae: 
As a result of the event the participant has remaining significant symptoms or 
loss of function as, but not limited to, blindness, deafness, or paralysis. All 
untoward medical events that the participant has not fully recovered from and 
has significant remaining symptoms or loss of function should be handled as 
serious untoward medical events / SAEs. 
Ongoing: 
The status of the participant has not improved and the symptoms are 
unchanged. 
Death 
 
Unknown: 
The status of the participant is unknown. This term is to be used only when no 
other term applies, e.g., when the participant is lost to follow-up. 
7.6 
Capturing and Reporting of Untoward Medical Events / Adverse Events 
Patients shall be asked about AEs at all visits (both site visits and telephone contacts). 
Questions for collecting AEs are specified in Appendix 1, Section 4. 
Adverse events can also be obtained from: 
 Signs and symptoms from patient examinations, 
 Laboratory values, or 
 Spontaneous reports by subjects or their relatives. 
All AEs and ADEs, will be captured in the section for AEs in the eCRF or in case of serious 
events in the section for SAEs, SADEs, or USADEs. 
All events fulfilling the definition of untoward medical event will be captured and reported 
from the time when the participant signs the ICF and to the last visit in the study or until the 
participant has left the study. Untoward medical events may need follow-up after the last visit 
in the study before being rated as recovered or given a final status according to the definitions 
above. 
7.7 
Reporting of Serious Untoward Medical Events / Serious Adverse 
Events 
The Investigator will report any SAE to the Sponsor authorized representative immediately 
but not later than within 24 hours after awareness that the event has occurred by 
completing the SAE eCRF pages. 
Further reportable events, according to MEDDEV 2.7.3 rev. 3 have to be reported by the 
Sponsor/authorized representative to the National Competent Authority (NCA) where the 
event occurred using an SAE Report Table. 
The following events are considered reportable: 
 Any SAE 
 Any device deficiency (See Section 7.9) that might have led to a SAE if: 
o suitable action had not been taken or 
o intervention had not been made or 
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 New findings/updates in relation to already reported events. 
The following timelines apply in case of: 
 Serious public health threat: 
o Immediately, but not later than 2 calendar days after awareness by Sponsor. 
 Death or unanticipated serious deterioration in state of health: 
o Immediately, but not later than 2 calendar days after awareness by Sponsor. 
 Others: 
o Immediately, but not later than 7 calendar days after awareness by Sponsor. 
7.8 
Follow-up of Untoward Medical Events / Adverse Events 
Any AE that is ongoing when the patient is withdrawn from the investigation should be 
followed-up until the AE is resolved or the Investigator decides that the AE is stable and 
needs no further follow-up. The last day for follow-up will be the study Day 35/42. AEs 
ongoing at study Day 35/42 shall be assessed as chronic or stable. 
7.9 
Device Deficiencies 
A device deficiency will in this study be defined as an inadequacy of a medical device with 
respect to its identity, quality, durability, reliability, safetya, or performance. 
All device deficiencies related to the identity, quality, durability, reliability, safety or 
performance of an investigational medical device shall be documented in the eCRF. Device 
deficiencies include malfunctions, use errors, and inadequate labeling. 
7.10 Tolerability 
Based on AEs 
7.11 Pregnancy 
Subjects must be instructed to immediately inform the Investigator if any pregnancy should 
occur from the time of signing the informed consent form and 6 weeks onwards. Any 
confirmed study-subject pregnancy shall be reported by the Investigator on a Pregnancy 
Report Form immediately but not later than 24 hours of awareness and submitted to the 
Sponsor-authorized representative. Subjects becoming pregnant will be withdrawn from the 
study and followed until delivery, additional information on the infant will be collected until 
the infant is 1 month old. Adverse events in connection with the pregnancy, in the fetus, and 
in the infant up to 1 month of age will be reported. Any abortions (including elective 
abortions) together with abortion rationale should be reported and handled as SAEs; as well as 
any complications relating to the pregnancy, fetus, and infant fulfilling any criteria for 
seriousness. Procedures and timelines for AE/SAE reporting applies to reporting of 
AEs/SAEs in the pregnant subject, the fetus, and the infant. 
 
a Inadequacy of device safety refers to properties of the device that could have or have led to an AE. 

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8 DATA HANDLING AND QUALITY ASSURANCE 
8.1 
Data Management 
Data management based on GCP refers to the activities defined to achieve safe routines to 
efficiently enter patient information into a database, avoiding errors. 
The data management routines include procedures for handling of CRF, eCRF and database 
set-up and management, data entry, data verification and validation (quality control of 
database), and documentation of the performed activities, including information of 
discrepancies in the process. The eCRF/ data entry screens, and the database/programs will be 
designed in accordance with the CIP and LINK standard operating procedure (SOP) system. 
8.1.1 
Data Collection 
The clinical investigation data will be collected via eCRF completed by the Investigator or 
other qualified personnel at the site, and by the Clinical Trial Unit. Together these constitute a 
remote electronic data system, which complies with the associated requirements of EN ISO 
14155:2011. 
8.1.2 
The Web-Based Case Report Form 
Clinical data (including AEs and concomitant medications) will be entered into a 21 CFR Part 
11-compliant eCRF (Viedoc4™). The eCRF includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, 
or inaccurate. Clinical data will be entered directly from the source documents, unless the 
eCRF is considered source. 
Authorized trial site personnel designated by the Investigator will complete data collection. 
Appropriate training and security measures will be completed with the Investigator and all 
authorized trial site personnel prior to get access to live version of the eCRF and any data 
being entered into the system for any trial patient. 
The CRF specification provided in this CIP will be the basis for the set-up of the eCRF in 
Viedoc4™. However minor deviations might be necessary due to technical issues that cannot 
be foreseen during the CIP writing process. 
8.1.3 
The Entering of Data into the Electronic Case Report Form 
The eCRFs should always reflect the latest observations on the patients participating in the 
trial. Therefore, the eCRFs should be completed as soon as possible during or after the 
patient’s visit. The Investigator must verify that all data entries in the eCRFs are accurate and 
correct. If some assessments are not done, or if certain information is not available, not 
applicable or unknown, the Investigator should indicate this in the eCRF. The Investigator 
will be required to electronically sign off all collected data. 
8.1.4 
The Query Process 
The Monitor will review the eCRFs and evaluate them for completeness and consistency. 
Each eCRF will be compared with the respective source documents to ensure that there are no 
discrepancies between critical data. All entries, corrections, and alterations are to be made by 
the Investigator or authorized designee. The Monitor cannot enter data in the eCRFs. Once 

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clinical data have been submitted to the central server via the eCRF, corrections to the data, 
made by the site personnel, will be audit trailed, meaning that the reason for change, the name 
of the person who made the change, together with date and time will be logged. Roles and 
rights of the site personnel responsible for entering clinical data into the eCRF will be 
determined in advance. If additional corrections are needed, the responsible Monitor or Data 
Manager will raise a query in the eCRF. The appropriate investigational personnel will 
answer the queries in the eCRF. 
8.1.5 
Signing of Data  
Electronic CRF records will be automatically appended with the identification of the creator, 
by means of their unique User ID. Specified records will be electronically signed by the 
Investigator to document his/her review of the data and acknowledgement that the data are 
accurate. This will be facilitated by means of the Investigator’s unique User ID and password. 
Date and time stamps will be added automatically at time of electronic signature. 
8.1.6 
Database Lock 
All changes will be fully recorded in a protected audit trail, and a reason for the change will 
be required. Once all data have been entered, verified, and validated; and all queries are 
solved, medical coding approved, and SAE reconciliation performed; the database will be 
locked. 
8.2 
Patient Records and Source Data 
The data may be recorded directly in the eCRF, which will then be considered as source data. 
The origin of source data in the investigation will be further specified in a separate document 
(“Origin of Source Data”). 
It is the responsibility of the Investigator to record essential information in the medical 
records in accordance with national regulations and requirements, including, but not limited 
to: 
 Study code, 
 Patient screening number and/or patient number, 
 That informed consent for participating in the study was obtained, signed and dated by 
subjects, 
 All visits during the investigation period, 
 All AEs/ADEs SAEs/SADEs, and 
 Treatments and medications. 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data recorded in the CRFs. 
8.3 
Record Retention 
The Investigator will retain copies of the records for a period of 15 years from the close-out 
visit. The Investigator must take measures to prevent accidental or premature destruction of 
these documents. In all cases, the Investigator must contact the Sponsor prior to disposing of 
any records related to the clinical investigation. Included in records to be retained are the 

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patients’ medical records, signed CIP, copies of paper CRFs (if applicable), signed ICFs, IEC 
approval letters, product accountability records, correspondence concerning the clinical 
investigation, and any other documents to identify the patients (including the Patient 
Identification Log). The electronic data retention period is of at least 15 years. Archiving of 
data is performed according to industry standards such as in PDF/A format. 
In addition, if the Investigator is no longer able to fulfill the role of Investigator (e.g. if he/she 
retires), a new Investigator will be appointed in consultation with the Sponsor. 
8.4 
Monitoring, Audits, and Inspections 
During the investigation, the Monitor will have regular contacts with the investigational site. 
These contacts will include visits to confirm that the facilities remain adequate to specified 
standards and that the investigational team are carrying out the procedures stated in the CIP. 
All data must be accurately recorded in the eCRF and source data verified (comparison of 
eCRF data with the patient’s medical records and other records at the investigational site). 
The eCRF and other records must be accessible during the visit. 
The Monitor or other Sponsor personnel will be available between visits if the Investigator or 
other staff at the site needs information or advice. 
Authorized representatives of the Sponsor or RA may visit the site to perform audits or 
inspections, including source data verification. 
8.5 
Training of Staff 
A delegation log will be completed for each investigational site team member to indicate 
which activities the Investigator has authorized them to perform. This must be updated prior 
to a new or existing team member undertaking any new responsibility. 
The Investigator will ensure that appropriate training relevant to the clinical investigation is 
given to the medical, nursing and other staff involved and that new information of relevance 
to the performance of this clinical investigation is forwarded to the staff involved. 
9 STATISTICAL METHODS AND PLANNED ANALYSIS 
The statistical planning, analysis and reporting work will follow LINK SOP system. All 
analyses described below will be performed using SAS Version 9.4.46 
For continuous data, number of missing and non-missing records, mean, standard deviation, 
median, 25th and 75th percentiles, minimum and maximum will be presented. All mean, 
median, confidence interval (CI), and standard deviation (SD) values will be formatted to one 
more decimal place than the measured value. Minimum and maximum values will be 
presented with the same number of decimal places as the measured value. Categorical data, 
including both nominal and ordered variables, as well as binary variables, will be presented 
by frequencies and percentages. Percentage values will be presented with 1 decimal place. In 
case of any hypothesis testing, p-values will be presented using a maximum of 4 decimal 
places. 
The statistical analysis will be based on the observed data. However, if missing data, due to 
patient withdrawals or other reasons, or outliers, are considered to be an issue, measures will 
be taken in order to reduce bias or, in case bias is unavoidable, conservatively direct the bias. 

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Details on the presentation of descriptive statistics, analytical methods, and handling of 
statistical issues will be given in the statistical analysis plan (SAP). 
9.1 
Statistical Analysis 
The clinical performance endpoints will be presented with the appropriate point estimate 
together with the 95% confidence interval. Any possible statistical testing will be performed 
using an overall significance level of 5%. 
Although there are two co-primary endpoints, no adjustment of e.g. p-values or confidence 
intervals will be applied. This is for two reasons, the first being that the evaluation of the 
second co-primary endpoint (safety and tolerability) will only be based on descriptive 
statistics and data listings, and the second is that both co-primary endpoints have to show 
favorable results. For all other statistical analyses of the secondary endpoints, no adjustment 
due to multiple testing will be performed. 
Statistical analysis will be based on all data, however, results will also be presented by site. 
If the stated assumptions that the statistical evaluation is built upon can be questioned, 
suitable alternative methods may be applied. For example, a 95% confidence interval based 
on a non-parametric method may be applied if assumption of data belonging to the normal 
distribution seems not to hold. This, together with further details on the statistical analysis and 
identification of any possible exploratory or subgroup analysis, will be given in the SAP. 
Sensitivity analyses may be performed to evaluate the robustness of the results. 
Any deviations or changes to the study protocol specified statistical analyses will be 
documented and justified in the SAP and the Clinical Investigation Report (CIR). 
9.1.1 
Analysis Data Sets and Populations 
The two different analysis datasets that will be considered for analysis is as below: 
Full Analysis Set (FAS): This is the primary population and comprises all patients entering 
the study and having received at least 1 dose of study treatment. Analyses of clinical 
performance will be performed against this population. 
Per Protocol (PP) Population - This will include all FAS patients without any major protocol 
deviation, i.e. patients who have completed the study and sufficiently complied with the study 
protocol, have available primary endpoint data and have received the study treatment 
according to protocol. The final definition of a major protocol deviation will be decided and 
defined at the clean file meeting. If a relevant number of patients are excluded from the PP 
population, then selected outputs will be provided for the PP population. 
All safety analyses will be performed against the FAS. All patients included in the FAS will 
be accounted for, including those who did not complete the study along with the reasons for 
withdrawal. 
Subject disposition table presenting the number and percentage of patients reaching each 
study milestone will be reported. The reasons for withdrawal from the study will be tabulated. 
Patients who not qualify for the FAS population will be listed. 

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9.1.2 
Demographic and other Baseline Characteristics 
All demographic and other baseline data will be summarized descriptively. Demographic and 
baseline assessments will be presented descriptively using the principles stated in Section 9 
above. 
Medical history will be coded according to MedDRA classification and will be presented by 
system organ class and preferred term as part of the baseline data. 
Prior or concomitant medications will be coded using WHODD and summarized by ATC 
class. 
Prior medications will be identified as those with a start date before Day 0 and will be 
presented as part of the baseline data. The concomitant medications will be defined as those 
with a start date equal to or after Day 0. 
9.1.3 
Exposure to Treatment 
Treatment compliance data, see Section 5.8, will be presented descriptively.  
9.2 
Primary and Secondary Endpoints Analysis 
9.2.1 
Primary Endpoints Analysis 
 Clinical cure rate on Day 7 will be calculated and presented together with a one-sided 
95 % confidence interval based on the exact binomial distribution. 
 Safety and tolerability will be assessed according to Section 9.2.3. 
9.2.2 
Secondary Endpoints Analysis 
Below is the list of all secondary endpoints (highlighted in italics) and other related variables, 
together with information on variable types, followed by additional information on the 
planned statistical analysis and presentation of the endpoints. Note that the analyses of the 
secondary endpoints will be performed on different patient categories as described in 
Section 2.2. 
a) 
CVVS score (can take integer values in the interval 0-18) 
a1) 
Vulvovaginal signs: erythema (can take integer values in the interval 0-3) 
a2) 
Vulvovaginal signs: edema (can take integer values in the interval 0-3) 
a3) 
Vulvovaginal signs: excoriation (can take integer values in the interval 0-3) 
a4) 
Sum of all vulvovaginal signs score (can take integer values in the interval 0-9) 
a5) 
Vulvovaginal symptoms: itching (can take integer values in the interval 0-3) 
a6) 
Vulvovaginal symptoms: burning (can take integer values in the interval 0-3) 
a7) 
Vulvovaginal symptoms: irritation (can take integer values in the interval 0-3) 
a8) 
Sum of all vulvovaginal symptoms score (can take integer values in the interval 0-9) 
b1) Cure rate on Day 14 (based on values yes/no on the individual level, i.e. binary 
variable) 
b2) Proportion endpoints (based on values yes/no on the individual level, i.e. binary 
variables) 
c)  
Change in CVVS score (can take values from -18 to +14) 
d)  
Change in sum of all vulvovaginal symptoms score (can take values from -9 to +8) 
e) 
Recurrence rates (based on values recurrence=yes/no on the individual level, i.e. a 
binary variable) 

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f) 
Usability, measured by patient questionnaire (the questionnaire contains 4 specific 
yes/no (i.e. binary) variables, and a 5th question, “How do you generally regard the 
treatment?”, rated on a 1-10 integer scale). 
In summary, the secondary endpoints: 
 b1), b2), e), and the first 4 questions in f) are considered as binary variables 
 c),d), and the 5th question in f) are considered as continuous variables 
The binary endpoints categorized as b1), b2), and e) above, will be calculated and presented 
together with a two-sided 95 % confidence interval based on the exact binomial distribution. 
Two-sided 95% confidence intervals will be presented for endpoints c), and d) using a 
parametric method assuming normally distributed data, i.e. arithmetic mean will be presented 
together with the 95% confidence limits. 
Further, all study endpoints (primary, secondary, and exploratory), as well as the related 
variables specified in the list above, will be presented descriptively. 
9.2.3 
Tolerability and Safety Analysis 
As part of the local tolerability and safety assessments, the following will be evaluated: 
 Tolerability, 
 Adverse events and SAEs, and 
 Rate of withdrawals from the study and/or the study treatment. 
9.2.3.1 Local Tolerability 
Based on AEs 
9.2.3.2 Adverse Events 
The AEs will be presented descriptively by means of frequency and percentages to evaluate 
both the rate of incidence and event occurrence among the different treatment groups. The 
descriptive tables will be presented with respect to intensity, seriousness, and relationship to 
the treatment. 
9.3 
Sample Size Determination 
Assuming the true cure rate is equal to 70 %, 22 patients are needed to obtain 90 % chance 
(90 % power) to show that the one-sided 95 % CI for the observed cure rate is above 40 %. 
To compensate for a small number of non-evaluable patients, 24 patients will be included. 
10 DEVIATIONS FROM THE CLINICAL INVESTIGATION PLAN AND CLINICAL 
INVESTIGATION PLAN VIOLATIONS 
The Investigator is not allowed to deviate from the CIP, except in an emergency. 
10.1 Deviations 
A deviation is a planned departure from the requirements of the CIP in order to deal with 
unforeseen circumstances. 

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Non-emergency Deviations: 
In the event of a non-emergency deviation, prior approval 
by the Sponsor is required. If the deviation may affect the 
rights, safety, or welfare of participants or the scientific 
integrity of the clinical investigation, IEC approval is also 
required prior to implementation. 
Emergency Deviations: 
Emergency deviations required for the safety and welfare of 
the patient will be implemented by the Investigator and 
notified to the Sponsor as soon as possible after 
implementation. 
The Sponsor is responsible for analyzing deviations and assessing their significance. 
Corrective action will be implemented to avoid repeated deviations, which may include 
suspending the clinical investigation and/or amending the CIP. 
10.2 Clinical Investigation Plan Violations 
Clinical Investigation Plan violations are deviations made without permission as a result of 
error or fraud/misconduct. Where the Monitor or Sponsor identifies that the Investigator is out 
of compliance, this will be notified to the Investigator in writing, with a request to correct the 
source of the deviation immediately. Corrective action will be implemented to avoid repeated 
non-compliance, which will usually include re-training and may include terminating the 
clinical investigation at the site. 
10.3 Reporting of Deviations and Clinical Investigation Plan Violations 
Depending on the nature of the deviation, they will either be recorded by the Investigator on 
the eCRF or documented by the Monitor and signed by the Investigator. Emergency 
deviations and violations which may affect the rights, safety or welfare of participants; or the 
scientific integrity of the clinical investigation will be notified to the IEC as soon as possible 
after the Sponsor has become aware of them. 
11 SPECIAL REQUIREMENTS AND PROCEDURES 
11.1 Good Clinical Practice 
This clinical investigation will be conducted in accordance with Note for Guidance on Good 
Clinical Practice: CPMP/ICH/135/95, January 1997 (where applicable to medical devices) 
and the principles of the European Standard EN ISO 14155:2011 Clinical Investigation of 
Medical Devices for Human Patients – Good Clinical Practice. 
11.2 Ethics 
11.2.1 Institutional Ethics Review 
The final CIP, including the final version of the patient information and consent form, must 
be approved or given a favorable opinion in writing by an IEC before enrollment of any 
patient into the investigation. The Investigator is responsible for informing the IEC of any 
amendment to the CIP as per local requirements. 

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11.2.2 Ethical Conduct of the Clinical Investigation 
The clinical investigation will be conducted in compliance with applicable regulatory 
requirements and with the ethical principles of the latest revision of the Declaration of 
Helsinki as adopted by the World Medical Association (Appendix 2). 
11.2.3 Patient Information and Consent 
All patients will receive written and verbal information regarding the investigation prior to 
any investigation-related procedures. This information will emphasize that the participation in 
the investigation is voluntary and that the patient may withdraw from the investigation at any 
time and for any reason. All patients will be given the opportunity to ask questions about the 
investigation and will be given sufficient time to decide whether to participate in the 
investigation. 
Before any clinical investigation-related procedures are undertaken, the ICF will be signed 
and dated by the patient (or their legally acceptable representative and/or witness, as 
applicable) and by the Investigator, or the qualified designee who gave the patient the verbal 
and written information. 
If any data is transferred to EEA countries outside Sweden, the data will not identify any 
persons taking part in the clinical investigation in accordance with the EU General Data 
Protection Regulation (GDPR). 
11.3 Patient Protection Procedures 
11.3.1 Procedures in Case of Medical Emergency 
The Investigator is responsible for ensuring that procedures and expertise are available to 
cope with medical emergencies during the clinical investigation. 
11.3.2 Patient Data Protection 
The written patient information explains that the data will be stored in a computer database, 
maintaining confidentiality in accordance with national data legislation, and that authorized 
representatives of the investigational site, Sponsor, RA, or an IEC require access to those 
parts of the medical records relevant to the clinical investigation, including medical history, 
for verification of data and appropriate conduct of the clinical investigation. 
Confidentiality of patient data will be maintained at all times. Patient anonymity will be 
guaranteed and documentation relating to a patient will be kept in a secure location. 
11.3.3 Insurance 
The Sponsor has arranged the appropriate product liability and clinical trials insurance to 
cover the requirements of this clinical investigation. 
11.4 Report and Publication 
A final report of the investigation (a “Clinical Investigation Report” [CIR]) should be 
completed, even if the investigation is prematurely terminated. The report will be prepared by 
the Sponsor according to the guideline presented in Annex C of ISO 14155-1:2011(E). 
All publications and presentations must be based upon the CIR. 

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All information supplied by the Sponsor in connection with this investigation will remain the 
sole property of the Sponsor and is to be considered confidential information. No confidential 
information will be disclosed to others without obtaining prior written consent from the 
Sponsor and will not be used except in the performance of this investigation. 
The Investigator may publish results from this investigation; however as some of the 
information regarding the investigational medical device and development activities may be 
of a strictly confidential nature, the Sponsor must first be given the opportunity to review any 
publication manuscript prior to submission to journals, meetings or conferences. 
The Sponsor may choose to publish or present data from this investigation. If an Investigator 
is offered first authorship, he/she will be asked to comment and approve the publication. The 
author order will be determined out of number of completed subjects. The Sponsor has the 
right to use the results for registration and internal presentation and for promotion. 
11.5 Confidentiality 
All processing of personal data will be stored confidential and handled according to 
legislations concerning the protection of personal data. Patients will be identified only by 
code. The informed consent form shall contain information about what personal data to be 
collected in the study and that this will be kept confidential. The provided information shall 
be sufficient to enable all subjects to give their consent not only to the participation in the 
study, but also to the processing of personal data. See also Section 11.3.2. 
12 CLINICAL INVESTIGATION TIME TABLE AND TERMINATION 
Clinical investigation start (first patient first visit):  10 Nov 2018 
Inclusion completed (last patient first visit):  
10 Jan 2019 
Last patient out (last patient last visit):  
 
February 2019 

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Mendling W, Brasch J, Cornely OA, et al. Guideline: vulvovaginal candidosis 
(AWMF 015/072), S2k (excluding chronic mucocutaneous candidosis). Mycoses. 
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Alsaad AM, Kaplan YC, Koren G. Exposure to fluconazole and risk of congenital 
malformations in the offspring: A systematic review and meta-analysis. Reprod 
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Howley MM, Carter TC, Browne ML, et al. Fluconazole use and birth defects in the 
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Spinillo A, Capuzzo E, Acciano S, De Santolo A, Zara F. Effect of antibiotic use on 
the prevalence of symptomatic vulvovaginal candidiasis. Am J Obstet Gynecol. 
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Glover DD, Larsen B. Relationship of fungal vaginitis therapy to prior antibiotic 
exposure. Infectious diseases in obstetrics and gynecology. 2003;11(3):157-160. 
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Pirotta MV, Gunn JM, Chondros P. "Not thrush again!" Women's experience of post-
antibiotic vulvovaginitis. The Medical journal of Australia. 2003;179(1):43-46. 
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Bluestein D, Rutledge C, Lumsden L. Predicting the occurrence of antibiotic-induced 
candidal vaginitis (AICV). Family practice research journal. 1991;11(3):319-326. 
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Wilton L, Kollarova M, Heeley E, Shakir S. Relative risk of vaginal candidiasis after 
use of antibiotics compared with antidepressants in women: postmarketing 
surveillance data in England. Drug safety. 2003;26(8):589-597. 
12. 
Cotch MF, Hillier SL, Gibbs RS, Eschenbach DA. Epidemiology and outcomes 
associated with moderate to heavy Candida colonization during pregnancy. Vaginal 
Infections and Prematurity Study Group. Am J Obstet Gynecol. 1998;178(2):374-380. 
13. 
Dennerstein GJ, Ellis DH. Oestrogen, glycogen and vaginal candidiasis. Aust N Z J 
Obstet Gynaecol. 2001;41(3):326-328. 
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Tarry W, Fisher M, Shen S, Mawhinney M. Candida albicans: the estrogen target for 
vaginal colonization. J Surg Res. 2005;129(2):278-282. 
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Geerlings S, Fonseca V, Castro-Diaz D, List J, Parikh S. Genital and urinary tract 
infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res 
Clin Pract. 2014;103(3):373-381. 
16. 
Spinillo A, Capuzzo E, Nicola S, Baltaro F, Ferrari A, Monaco A. The impact of oral 
contraception on vulvovaginal candidiasis. Contraception. 1995;51(5):293-297. 
17. 
Landers DV, Wiesenfeld HC, Heine RP, Krohn MA, Hillier SL. Predictive value of 
the clinical diagnosis of lower genital tract infection in women. Am J Obstet Gynecol. 
2004;190(4):1004-1010. 
18. 
Sobel JD. Epidemiology and pathogenesis of recurrent vulvovaginal candidiasis. Am J 
Obstet Gynecol. 1985;152(7 Pt 2):924-935. 

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19. 
Sobel JD. Recurrent vulvovaginal candidiasis. A prospective study of the efficacy of 
maintenance ketoconazole therapy. N Engl J Med. 1986;315(23):1455-1458. 
20. 
Powell AM, Gracely E, Nyirjesy P. Non-albicans Candida Vulvovaginitis: Treatment 
Experience at a Tertiary Care Vaginitis Center. J Low Genit Tract Dis. 2016;20(1):85-
89. 
21. 
Workowski KA, Bolan GA, Centers for Disease C, Prevention. Sexually transmitted 
diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1-137. 
22. 
Ferris DG, Nyirjesy P, Sobel JD, Soper D, Pavletic A, Litaker MS. Over-the-counter 
antifungal drug misuse associated with patient-diagnosed vulvovaginal candidiasis. 
Obstetrics and gynecology. 2002;99(3):419-425. 
23. 
Martin Lopez JE. Candidiasis (vulvovaginal). BMJ clinical evidence. 2015;2015. 
24. 
Mikamo H, Matsumizu M, Nakazuru Y, Okayama A, Nagashima M. Efficacy and 
safety of a single oral 150 mg dose of fluconazole for the treatment of vulvovaginal 
candidiasis in Japan. Journal of infection and chemotherapy : official journal of the 
Japan Society of Chemotherapy. 2015;21(7):520-526. 
25. 
Colombo AL, Guimaraes T, Camargo LF, et al. Brazilian guidelines for the 
management of candidiasis - a joint meeting report of three medical societies: 
Sociedade Brasileira de Infectologia, Sociedade Paulista de Infectologia and 
Sociedade Brasileira de Medicina Tropical. Braz J Infect Dis. 2013;17(3):283-312. 
26. 
van Schalkwyk J, Yudin MH, Infectious Disease C. Vulvovaginitis: screening for and 
management of trichomoniasis, vulvovaginal candidiasis, and bacterial vaginosis. 
Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et 
gynecologie du Canada : JOGC. 2015;37(3):266-274. 
27. 
Matheson A, Mazza D. Recurrent vulvovaginal candidiasis: A review of guideline 
recommendations. Aust N Z J Obstet Gynaecol. 2017;57(2):139-145. 
28. 
Mendling W, Caserini M, Palmieri R. O06.6 A Randomised, Double-Blind, 
Controlled Study to Assess the Efficacy and Safety of Nifuratel in the Treatment of 
Trichomoniasis. Sexually Transmitted Infections. 2013;89(Suppl 1):A38.31-A38. 
29. 
Bauters TG, Dhont MA, Temmerman MI, Nelis HJ. Prevalence of vulvovaginal 
candidiasis and susceptibility to fluconazole in women. Am J Obstet Gynecol. 
2002;187(3):569-574. 
30. 
Mathema B, Cross E, Dun E, et al. Prevalence of vaginal colonization by drug-
resistant Candida species in college-age women with previous exposure to over-the-
counter azole antifungals. Clin Infect Dis. 2001;33(5):E23-27. 
31. 
Richter SS, Galask RP, Messer SA, Hollis RJ, Diekema DJ, Pfaller MA. Antifungal 
susceptibilities of Candida species causing vulvovaginitis and epidemiology of 
recurrent cases. J Clin Microbiol. 2005;43(5):2155-2162. 
32. 
Sobel JD, Zervos M, Reed BD, et al. Fluconazole susceptibility of vaginal isolates 
obtained from women with complicated Candida vaginitis: clinical implications. 
Antimicrob Agents Chemother. 2003;47(1):34-38. 
33. 
Li T, Zhu Y, Fan S, Liu X, Xu H, Liang Y. A randomized clinical trial of the efficacy 
and safety of terconazole vaginal suppository versus oral fluconazole for treating 
severe vulvovaginal candidiasis. Med Mycol. 2015;53(5):455-461. 
34. 
Zhou X, Li T, Fan S, et al. The efficacy and safety of clotrimazole vaginal tablet vs. 
oral fluconazole in treating severe vulvovaginal candidiasis. Mycoses. 2016;59(7):419-
428. 

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35. 
Harriott MM, Lilly EA, Rodriguez TE, Fidel PL, Noverr MC. Candida albicans forms 
biofilms on the vaginal mucosa. Microbiology (Reading, England). 2010;156(Pt 
12):3635-3644. 
36. 
Muzny CA, Schwebke JR. Biofilms: An Underappreciated Mechanism of Treatment 
Failure and Recurrence in Vaginal Infections. Clin Infect Dis. 2015;61(4):601-606. 
37. 
Patra T, Koley H, Ramamurthy T, Ghose AC, Nandy RK. The Entner-Doudoroff 
pathway is obligatory for gluconate utilization and contributes to the pathogenicity of 
Vibrio cholerae. Journal of bacteriology. 2012;194(13):3377-3385. 
38. 
Sudbery PE. Growth of Candida albicans hyphae. Nature reviews Microbiology. 
2011;9(10):737-748. 
39. 
Moyes DL, Wilson D, Richardson JP, et al. Candidalysin is a fungal peptide toxin 
critical for mucosal infection. Nature. 2016;532(7597):64-68. 
40. 
Eyles R, Lewis HB. The Utilization of d-Glucono-δ-Lactone by the Organism of the 
Young White Rat. The Journal of Nutrition. 1943;26(3):309-317. 
41. 
Prescott FJ, Shaw JK, Bilello JP, Cragwall GO. Gluconic Acid and Its Derivatives. 
Industrial & Engineering Chemistry. 1953;45(2):338-342. 
42. 
International Programme on Chemical Safety (IPCS). Glucono-Delta-Lactone and the 
Calcium, Magnesium, Potassium, and Sodium Salts of Gluconic Acid. 1999; 
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43. 
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44. 
Fredstorp M, Jonasson AF, Barth A, Robertsson J. A new effective, user friendly 
bacterial vaginosis treatment: a randomized multicenter open-label parallel-group two-
part study with a novel sustained-release pessary containing oligomeric lactic acid. J 
Infect Non Infect Dis. 2015(1):005. 
45. 
Goncalves B, Ferreira C, Alves CT, Henriques M, Azeredo J, Silva S. Vulvovaginal 
candidiasis: Epidemiology, microbiology and risk factors. Critical reviews in 
microbiology. 2016;42(6):905-927. 
46. 
SAS Institute Inc. Base SAS® 9.4 Procedures Guide: Statistical Procedures, Second 
Edition. Cary, NC: SAS Institute Inc.; 2013. 

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Appendix 1 
Patient Questionnaire 
Section 1. Vulvovaginal Symptoms 
Day(s) 0, 4, 7, 14, and 35; or Day(s) 0, 4, 7, 11, 14, 21 and 42 if receiving prolonged 
treatment. Questions will be asked by the Investigator at Day(s) 0, 7, and 14 (for patients 
receiving prolonged treatment); and by the Clinical Trial Unit at remaining days. 
Scoring of symptoms 
 
0 = none 
(absent) 
1 = mild 
(slight) 
2 = moderate 
(definitely present) 
3 = severe 
(marked, intense) 
Irritation  
 
 
 
Itching 
 
 
 
 
Burning  
 
 
 
 
The question “Have the symptoms returned, so that you need to seek medical care?” (yes/no) 
will be asked at Day(s) 14 and 35 if not receiving prolonged treatment and at Day(s) 21 and 
42 if receiving prolonged treatment. 
Section 2. Usability 
Day 7 and Day 14 if receiving prolonged treatment: 
Is the vaginal tablet easy to use? 
 Yes 
 No 
 If no, provide reason: ________________________ 
Do you find the use of the vaginal tablet gentle? 
 Yes 
 No 
 If no, provide reason: ________________________ 
Is the treatment odor free? 
 Yes 
 No 
Is the treatment smear-free and dripless? 
 Yes 
 No 
How do you generally regard the treatment? 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not satisfied 
Very satisfied  

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Section 3. Concomitant Medications 
Day(s) 4, 7, 14, and 35; or Days(s) 4, 7, 11, 14, 21, and 42 if receiving prolonged treatment); 
patients will be asked: “since the last study visit or telephone contact, have you changed dose 
or taken any new medication? 
Section 4. Adverse Events 
The following question will be asked at each patient contact: “since the last visit / telephone 
contact, have you had any health problems?” 
 
 

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Appendix 2 
Declaration of Helsinki 
WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving 
Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1.        The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. 
           The Declaration is intended to be read as a whole and each of its constituent paragraphs should be applied 
with consideration of all other relevant paragraphs. 
2.        Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The 
WMA encourages others who are involved in medical research involving human subjects to adopt these 
principles.  
General Principles 
3.        The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient 
will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician 
shall act in the patient's best interest when providing medical care.” 
4.        It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, 
including those who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfilment of this duty. 
5.        Medical progress is based on research that ultimately must include studies involving human subjects. 
6.        The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best proven interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality. 
7.        Medical research is subject to ethical standards that promote and ensure respect for all human subjects and 
protect their health and rights. 
8.        While the primary purpose of medical research is to generate new knowledge, this goal can never take 
precedence over the rights and interests of individual research subjects. 
9.        It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects. The responsibility for the protection of research subjects must always rest with the physician or 
other health care professionals and never with the research subjects, even though they have given consent. 
10.      Physicians must consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. 

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11.      Medical research should be conducted in a manner that minimises possible harm to the environment. 
12.      Medical research involving human subjects must be conducted only by individuals with the appropriate 
ethics and scientific education, training and qualifications. Research on patients or healthy volunteers 
requires the supervision of a competent and appropriately qualified physician or other health care 
professional. 
13.      Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14.      Physicians who combine medical research with medical care should involve their patients in research only 
to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if the 
physician has good reason to believe that participation in the research study will not adversely affect the 
health of the patients who serve as research subjects. 
15.      Appropriate compensation and treatment for subjects who are harmed as a result of participating in 
research must be ensured. 
Risks, Burdens and Benefits  
16.      In medical practice and in medical research, most interventions involve risks and burdens. 
         Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research subjects. 
17.      All medical research involving human subjects must be preceded by careful assessment of predictable 
risks and burdens to the individuals and groups involved in the research in comparison with foreseeable 
benefits to them and to other individuals or groups affected by the condition under investigation. 
          Measures to minimise the risks must be implemented. The risks must be continuously monitored, assessed 
and documented by the researcher.  
18.      Physicians may not be involved in a research study involving human subjects unless they are confident 
that the risks have been adequately assessed and can be satisfactorily managed. 
           When the risks are found to outweigh the potential benefits or when there is conclusive proof of definitive 
outcomes, physicians must assess whether to continue, modify or immediately stop the study.            
Vulnerable Groups and Individuals 
19.      Some groups and individuals are particularly vulnerable and may have an increased likelihood of being 
wronged or of incurring additional harm. 
           All vulnerable groups and individuals should receive specifically considered protection. 
20.      Medical research with a vulnerable group is only justified if the research is responsive to the health needs 
or priorities of this group and the research cannot be carried out in a non-vulnerable group. In addition, 
this group should stand to benefit from the knowledge, practices or interventions that result from the 
research. 
Scientific Requirements and Research Protocols  
21.      Medical research involving human subjects must conform to generally accepted scientific principles, be 
based on a thorough knowledge of the scientific literature, other relevant sources of information, and 
adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for 
research must be respected. 
22.      The design and performance of each research study involving human subjects must be clearly described 
and justified in a research protocol. 
           The protocol should contain a statement of the ethical considerations involved and should indicate how 
the principles in this Declaration have been addressed. The protocol should include information regarding 
funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for subjects and 
information regarding provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. 
           In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 

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Research Ethics Committees 
23.      The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins. This committee must be transparent in its 
functioning, must be independent of the researcher, the sponsor and any other undue influence and must 
be duly qualified. It must take into consideration the laws and regulations of the country or countries in 
which the research is to be performed as well as applicable international norms and standards but these 
must not be allowed to reduce or eliminate any of the protections for research subjects set forth in this 
Declaration.  
           The committee must have the right to monitor ongoing studies. The researcher must provide monitoring 
information to the committee, especially information about any serious adverse events. No amendment to 
the protocol may be made without consideration and approval by the committee. After the end of the 
study, the researchers must submit a final report to the committee containing a summary of the study’s 
findings and conclusions.  
Privacy and Confidentiality  
24.      Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their 
personal information. 
Informed Consent  
25.      Participation by individuals capable of giving informed consent as subjects in medical research must be 
voluntary. Although it may be appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a research study unless he or she freely 
agrees. 
26.      In medical research involving human subjects capable of giving informed consent, each potential subject 
must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, 
institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the 
discomfort it may entail, post-study provisions and any other relevant aspects of the study. The potential 
subject must be informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific information 
needs of individual potential subjects as well as to the methods used to deliver the information. 
           After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed consent, 
preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed.       
           All medical research subjects should be given the option of being informed about the general outcome and 
results of the study. 
27.      When seeking informed consent for participation in a research study the physician must be particularly 
cautious if the potential subject is in a dependent relationship with the physician or may consent under 
duress. In such situations the informed consent must be sought by an appropriately qualified individual 
who is completely independent of this relationship. 
28.      For a potential research subject who is incapable of giving informed consent, the physician must seek 
informed consent from the legally authorised representative. These individuals must not be included in a 
research study that has no likelihood of benefit for them unless it is intended to promote the health of the 
group represented by the potential subject, the research cannot instead be performed with persons capable 
of providing informed consent, and the research entails only minimal risk and minimal burden. 
29.      When a potential research subject who is deemed incapable of giving informed consent is able to give 
assent to decisions about participation in research, the physician must seek that assent in addition to the 
consent of the legally authorised representative. The potential subject’s dissent should be respected. 
30.      Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving informed 
consent is a necessary characteristic of the research group. In such circumstances the physician must seek 
informed consent from the legally authorised representative. If no such representative is available and if 
the research cannot be delayed, the study may proceed without informed consent provided that the 

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specific reasons for involving subjects with a condition that renders them unable to give informed consent 
have been stated in the research protocol and the study has been approved by a research ethics committee. 
Consent to remain in the research must be obtained as soon as possible from the subject or a legally 
authorised representative. 
31.      The physician must fully inform the patient which aspects of their care are related to the research. The 
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must 
never adversely affect the patient-physician relationship. 
32.      For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its collection, 
storage and/or reuse. There may be exceptional situations where consent would be impossible or 
impracticable to obtain for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
Use of Placebo 
33.      The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the 
best proven intervention(s), except in the following circumstances: 
           Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
           Where for compelling and scientifically sound methodological reasons the use of any intervention less 
effective than the best proven one, the use of placebo, or no intervention is necessary to determine the 
efficacy or safety of an intervention  
           and the patients who receive any intervention less effective than the best proven one, placebo, or no 
intervention will not be subject to additional risks of serious or irreversible harm as a result of not 
receiving the best proven intervention.  
           Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34.      In advance of a clinical trial, sponsors, researchers and host country governments should make provisions 
for post-trial access for all participants who still need an intervention identified as beneficial in the trial. 
This information must also be disclosed to participants during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35.      Every research study involving human subjects must be registered in a publicly accessible database before 
recruitment of the first subject. 
36.      Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research. Researchers have a duty to make publicly 
available the results of their research on human subjects and are accountable for the completeness and 
accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. Negative 
and inconclusive as well as positive results must be published or otherwise made publicly available. 
Sources of funding, institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not be accepted for 
publication. 
Unproven Interventions in Clinical Practice 
37.      In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorised representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, made publicly available. 
 

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Appendix 3 
Investigator Signature Pages 
I have read the Clinical Investigation Plan including all appendices, and I agree to all of the 
terms as described. I will conduct the clinical investigation according to the procedures 
specified herein. 
 
Study code: CL1 
 
Site No.: 
 
Principal Investigator: 
 
 
 
Signature:  
Date: