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

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 1 of 67 
 
 
Version 4.0 | Version 2023-07-04 
CLINICAL INVESTIGATION PLAN 
AN OPEN-LABELLED STUDY TO EVALUATE CLINICAL PERFORMANCE OF 
THE GEDEA PESSARY IN ADULT WOMEN WITH VULVOVAGINAL 
CANDIDIASIS  
 
 
 
Study Product: 
Gedea Pessary, pHyph gen II 
Study Number: 
CL4 
Sponsor: 
Gedea Biotech AB 
Medicon Village 
SE-223 81 Lund, Sweden 
Clinical Investigation Plan 
(CIP) document ID: 
 
QRS-CL4-003 
CIV ID: 
CIV-22-01-038786 
CIP Version number: 
4.0 
CIP Version Date: 
2023-07-04 
Confidentiality Statement 
This CIP contains information that is confidential and proprietary to Gedea Biotech AB. 
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-CL4-003 
Study CL4 
Gedea Pessary 
Page 2 of 67 
 
 
Version 4.0 | Version 2023-07-04 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
Gedea Biotech AB, Sweden, is the Sponsor of the clinical investigation and is funding the 
investigation. All financial details are provided in the separate contract(s) between the 
Institution, the Investigator, and the Sponsor or designee. The Sponsor will compensate the 
Institution for their work in the study. However, the compensation will not be affected by the 
outcome of the study.  
The Sponsor or designee maintains appropriate insurance coverage for clinical investigations 
and will follow applicable local compensation regulations. All patients in the study can 
retrieve financial compensation in the case of harm as a consequence of study participation. 
The Investigators and key study administrative personnel are presented in the list below. A 
full contact list will be provided to all sites in the Investigator site file (ISF). 
Coordinating Investigator: 
NAME 
Danderyds sjukhus 
Kliniska vetenskaper, D1 Obstetrik o gynekologi 
SE-182 88 Stockholm, Sweden 
Telephone: TELEPHONE 
Email: NAME 
Sponsor: 
Gedea Biotech AB 
Medicon Village 
SE-223 81 Lund, Sweden 
Telephone: TELEPHONE 
Medical Expert: 
NAME 
Department of Obstetrics and Gynaecology 
Skåne University Hospital 
SE-221 85, Lund, Sweden 
Telephone: TELEPHONE 
Email: NAME 
Study Director: 
NAME Gedea Biotech AB 
Medicon Village 
SE-223 81 Lund, Sweden 
Telephone: TELEPHONE 
Email: NAME 
Contract Research Organisation 
(CRO)  
(biostatistics, medical writing, 
data management, safety, biobank 
and monitoring): 
Clinical Trial Consultants CTC AB 
Dag Hammarskjölds väg 10B, SE-752 37 Uppsala, Sweden 
Telephone: TELEPHONE 
 
Study Biostatistician: 
NAME 
Clinical Trial Consultants CTC AB 
Dag Hammarskjölds väg 10B, SE-752 37 Uppsala, Sweden 
Telephone: TELEPHONE 
Email: NAME 
Pharmacovigilance: 
CTC Pharmacovigilance Department 
Email: device_sae@ctc-ab.se 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 3 of 67 
 
 
Version 4.0 | Version 2023-07-04 
Electronic case report form 
(eCRF) and patient reported 
outcomes (ePRO) system 
provider: 
Viedoc Technologies AB 
Stationsgatan 23  
SE-753 40 Uppsala, Sweden 
Email: info_se@viedoc.com 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 4 of 67 
 
 
Version 4.0 | Version 2023-07-04 
APPROVAL PAGE 
 
 
Sponsor: 
 
 
_______________________________________ 
 
NAME, Gedea Biotech AB 
 
 
Date: 
 
 
 
Coordinating Investigator: 
 
 
_______________________________________ 
NAME  
 
 
 
 
 
Date: 
Danderyds sjukhus  
 
 
Biostatistician: 
 
 
_______________________________________ 
NAME 
 
Date: 
Clinical Trial Consultants CTC AB 
 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 5 of 67 
 
 
Version 4.0 | Version 2023-07-04 
SYNOPSIS 
Name of Sponsor: 
Gedea Biotech AB 
Name of product: 
Gedea Pessary (pHyph gen II) 
Name of active ingredient: 
Glucono-delta-lactone (GDL) and sodium gluconate (NaG). 
Title of study: 
An open-labelled study to evaluate clinical performance of the Gedea Pessary in adult women with 
vulvovaginal candidiasis 
Clinical investigation plan number: 
QRS-CL4-003 
Coordinating Investigator: 
NAME 
Classification of study: 
Clinical investigation 
Objectives: 
Primary objective: 
To investigate the clinical performance of acute treatment with Gedea Pessary in patients with 
vulvovaginal candidiasis (VVC). 
Primary endpoint: 
Clinical cure rate on Day 7-14, defined as the percentage of patients clinically cured at Day 7-14.   
Secondary objectives: 
To investigate the safety of acute treatment with Gedea Pessary and to further investigate the 
clinical performance of acute treatment with Gedea Pessary in patients with VVC. 
Secondary endpoints: 
1. 
Safety and tolerability, based on reported treatment-emergent adverse events (AEs) (safety 
endpoint). 
2. 
Proportion of patients having a continued clinical response to treatment at Day 25, defined 
as the proportion of patients clinically cured on Day 7-14 and thereafter responding “no” to 
the yes/no question, “Have the symptoms recurred?” 
3. 
Proportion of patients having a cure defined as clinical cure Day 7-14 according to primary 
endpoint and mycological cure (culture negative for growth of Candida species). 
4. 
Proportion of patients having a reduction in composite vulvovaginal signs and symptoms 
(CVVS) score on Day 7-14 compared to Day 0. 
5. 
Change in the CVVS score from Day 0 to Day 7-14. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 6 of 67 
 
 
Version 4.0 | Version 2023-07-04 
6. 
Proportion of patients having a reduction in the sum of the 3 vulvovaginal symptoms scores 
(itching, burning, and irritation) on Days 1-7, Day 11, Day 14 and Day 25, compared to 
Day 0. 
7. 
Change in the sum of the 3 vulvovaginal symptoms scores (itching, burning, and irritation) 
on Days 1-7, Day 11, Day 14 and Day 25, compared to Day 0. 
8. 
Proportion of patients having a mycological cure as assessed by vaginal culture on Day 7-
14 and Day 25. 
9. 
Proportion of patients having an absence of Candida hyphae in the wet smear on Day 7-14. 
10. Usability, measured by patient questionnaire, on Day 6. 
Exploratory endpoints:  
1. 
Correlation between vaginal microbiome as assessed by vaginal swab DNA-analysis on 
Days 0, 7, 14, and 25 and clinical cure. 
2. 
Correlation of presence of fungus as analysed by vaginal swab DNA-analysis on Days 0, 7, 
14 and 25 and presence of fungus as assessed by culture, and clinical cure. 
Methodology: 
This is an open-labelled study to evaluate the clinical performance and safety of treatment with 
Gedea Pessary in adult women with confirmed VVC.  
Number of patients planned: 
26 patients 
Diagnosis and main criteria for inclusion: 
The study population will consist of post-menarchal, pre-menopausal females, 18 years or older, 
seeking care for VVC symptoms. To be included in the study, patients should have a VVC 
diagnosis. Patients with known or apparent signs of other infectious causes of VVC and patients 
who were treated for VVC within the past 14 days, or are currently receiving anti-fungal therapy 
unrelated to VVC will be excluded form the study. 
Investigational products, dose and mode of administration: 
Test product: Gedea Pessary, a pessary containing 150 mg GDL and 184 mg NaG, administered 
vaginally with a CE-marked pessary applicator. The Gedea Pessary (commercial name pHyph) is a 
Class IIb medical device according to Medical device regulation (MDR) 2017/745.   
Study duration: 
Planned study time:  First patient in: Q1 2023. Last patient out: Q3 2023. 
Duration: Patients will be treated for 6 days (Day 0 to Day 5) and have 4 follow-ups (on Day 4, 
Day 7, Day 14 and Day 25). The total study duration will be 26 days (±3 days), including 
Screening. 
Statistical methods: 
Assuming a true proportion of 54% clinically cured in the treated group a sample size of 24 patients 
is needed to obtain 80% power to show that the one-sided 95% confidence interval (CI) for the 
clinical cure rate is above 30%. To compensate for patients with missing data a total of 26 patients 
will be included. 
The primary performance objective of the trial is to show that the clinical cure rate is above 30 %, 
i.e. to show that the one-sided 95 % CI for the observed cure rate is above 30 %. The primary 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 7 of 67 
 
 
Version 4.0 | Version 2023-07-04 
endpoint, clinical cure rate on Day 7-14, will be presented together with a one-sided 95% CI based 
on the Wilson score. 
The secondary endpoint safety and tolerability, based on reported treatment-emergent adverse 
events (AEs) will be presented descriptively. 
All secondary clinical performance endpoints will be presented with descriptive statistics. Binary 
secondary clinical performance endpoints will show the endpoint estimate together with a two-sided 
95% CI based on the Wilson score. Presentation of continuous secondary clinical performance 
endpoints will include the two-sided 95% CIs for the arithmetic mean. 
 
 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 8 of 67 
 
 
Version 4.0 | Version 2023-07-04 
TABLE OF CONTENTS 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .................................. 2 
APPROVAL PAGE ........................................................................................................................ 4 
SYNOPSIS ...................................................................................................................................... 5 
TABLE OF CONTENTS ............................................................................................................... 8 
LIST OF FIGURES ..................................................................................................................... 10 
LIST OF TABLES ....................................................................................................................... 11 
LIST OF APPENDICES .............................................................................................................. 11 
LIST OF ABBREVIATIONS ...................................................................................................... 12 
1 
STATEMENT OF COMPLIANCE ................................................................................ 14 
2 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................. 14 
3 
INTRODUCTION............................................................................................................. 15 
3.1 
Indication ........................................................................................................................... 15 
3.2 
Glucono-delta-lactone, mode of action ............................................................................. 16 
 
Biofilm ............................................................................................................................ 16 
 
Lactobacilli ..................................................................................................................... 17 
3.3 
Product description and previous experience .................................................................... 17 
 
Non-clinical data ............................................................................................................. 17 
 
Clinical data .................................................................................................................... 18 
4 
STUDY OBJECTIVES ..................................................................................................... 20 
4.1 
Primary objective .............................................................................................................. 20 
 
Primary endpoint ............................................................................................................. 20 
4.2 
Secondary objectives ......................................................................................................... 21 
 
Secondary endpoints ....................................................................................................... 21 
4.3 
Exploratory objectives ....................................................................................................... 21 
 
Exploratory endpoints ..................................................................................................... 21 
5 
STUDY DESIGN ............................................................................................................... 22 
5.1 
General outline .................................................................................................................. 22 
5.2 
Rationale for the study design ........................................................................................... 26 
5.3 
Risks and benefits .............................................................................................................. 27 
5.4 
Study visits and procedures ............................................................................................... 28 
 
Day 0; Screening and enrolment ..................................................................................... 28 
 
Day 0 to Day 5; Treatment administration ...................................................................... 29 
 
Day 7 (+2 days); Follow-up visit .................................................................................... 29 
 
Day 11 (±1 day); Follow-up at home .............................................................................. 30 
 
Day 14 (±2 days); Follow-up visit .................................................................................. 30 
 
Day 25 (±2 days); Follow-up visit .................................................................................. 31 
 
Early withdrawal visit ..................................................................................................... 32 
6 
SELECTION OF STUDY POPULATION ..................................................................... 32 
6.1 
Patient information and informed consent ........................................................................ 32 
6.2 
Recruitment ....................................................................................................................... 33 
6.3 
Inclusion criteria ................................................................................................................ 33 
6.4 
Exclusion criteria ............................................................................................................... 34 
6.5 
Restrictions ........................................................................................................................ 34 
6.6 
Withdrawal of patients and termination of the investigation ............................................ 34 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 9 of 67 
 
 
Version 4.0 | Version 2023-07-04 
 
Withdrawal from study and termination criteria ............................................................. 34 
 
Reasons for treatment discontinuation or withdrawal from the study ............................ 35 
 
Procedure for withdrawal of a patient ............................................................................. 35 
 
Procedure for discontinuation of treatment ..................................................................... 36 
 
Replacements .................................................................................................................. 36 
 
Sponsor termination of study .......................................................................................... 36 
7 
TREATMENTS ................................................................................................................ 36 
7.1 
Treatment groups ............................................................................................................... 36 
7.2 
Identity of the investigational product ............................................................................... 36 
 
Test product/Gedea Pessary ............................................................................................ 36 
 
Manufacturing, packaging and labelling of investigational product ............................... 37 
 
Stability program ............................................................................................................ 37 
 
Storage and handling of investigational products ........................................................... 38 
 
Doses and treatment regimens ........................................................................................ 38 
7.3 
Investigational product accountability .............................................................................. 38 
7.4 
Method of assigning patients to treatment groups ............................................................. 39 
7.5 
Additional products and material ...................................................................................... 39 
 
Additional material ......................................................................................................... 39 
 
Rescue medication .......................................................................................................... 39 
7.6 
Treatment compliance ....................................................................................................... 40 
8 
ASSESSMENTS ................................................................................................................ 40 
8.1 
Informed consent ............................................................................................................... 40 
8.2 
Demography ...................................................................................................................... 40 
8.3 
Eligibility criteria .............................................................................................................. 41 
8.4 
Prior and concomitant medications ................................................................................... 41 
8.5 
Medical and surgical history ............................................................................................. 41 
8.6 
Pregnancy test ................................................................................................................... 41 
8.7 
Menstruation...................................................................................................................... 41 
8.8 
Administration of investigational product ......................................................................... 41 
9 
CLINICAL PERFORMANCE ........................................................................................ 42 
9.1 
Clinical performance assessments ..................................................................................... 42 
 
Gynaecological examination ........................................................................................... 42 
 
Patient questionnaire ....................................................................................................... 42 
10 
SAFETY AND TOLERABILITY ASSESSMENTS ...................................................... 43 
10.1 
Clinical laboratory evaluation ........................................................................................... 43 
 
Vaginal swab samples ..................................................................................................... 43 
 
Vaginal pH ...................................................................................................................... 43 
10.2 
Untoward medical events and AEs ................................................................................... 44 
 
Adverse event ................................................................................................................. 44 
 
Adverse device effect ...................................................................................................... 44 
 
Serious Adverse Events .................................................................................................. 44 
 
Definitions of adverse event ratings................................................................................ 45 
 
Severity/intensity ......................................................................................................... 45 
 
Causality assessment/relatedness ................................................................................. 45 
 
Outcome ....................................................................................................................... 47 
 
Capturing and reporting of untoward medical events/AEs ............................................. 48 
 
Reporting of SAEs .......................................................................................................... 48 
 
Reporting to national competent authorities ................................................................ 49 
 
Reporting to Investigators ............................................................................................ 49 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 10 of 67 
 
 
Version 4.0 | Version 2023-07-04 
 
Follow-up of untoward medical events/AEs ................................................................... 49 
10.3 
Device deficiencies ........................................................................................................... 50 
10.4 
Pregnancy .......................................................................................................................... 50 
11 
DATA MANAGEMENT .................................................................................................. 51 
11.1 
The web-based case report form ....................................................................................... 51 
 
The entering of data into the electronic case report form ............................................... 51 
 
Electronic patient reported outcomes .............................................................................. 52 
 
The query process ........................................................................................................... 52 
 
Signing of data ................................................................................................................ 53 
 
Audit trail and database lock ........................................................................................... 53 
11.2 
Medical coding .................................................................................................................. 53 
12 
STATISTICAL METHODS AND PLANNED ANALYSIS ......................................... 53 
12.1 
Statistical analysis; data presentation ................................................................................ 53 
12.2 
Analysis data sets and populations .................................................................................... 53 
12.3 
Demographic, other baseline characteristics, prior and concomitant medications and 
compliance ........................................................................................................................ 54 
12.4 
Primary and secondary endpoints analysis ........................................................................ 54 
 
Estimand consideration ................................................................................................... 54 
 
Primary endpoint analysis ............................................................................................... 54 
 
Secondary endpoints analysis ......................................................................................... 55 
 
Adverse events ............................................................................................................. 55 
 
Performance endpoints ................................................................................................. 55 
12.5 
Exploratory endpoints analysis ......................................................................................... 56 
12.6 
Sample size determination................................................................................................. 56 
13 
STUDY MANAGEMENT ................................................................................................ 57 
13.1 
Clinical monitoring ........................................................................................................... 57 
13.2 
Training of staff ................................................................................................................. 58 
13.3 
Patient records and source data ......................................................................................... 58 
13.4 
Audits and inspections ...................................................................................................... 58 
13.5 
Changes to the plan and ICF ............................................................................................. 59 
13.6 
Deviations from the clinical investigation plan ................................................................. 59 
13.7 
Clinical investigation timelines ......................................................................................... 60 
13.8 
Declaration of end of investigation ................................................................................... 60 
13.9 
Patient protection procedures ............................................................................................ 60 
 
Procedures in case of medical emergency ...................................................................... 60 
 
Patient data protection ..................................................................................................... 60 
 
Patient confidentiality ..................................................................................................... 60 
13.10 
Insurance ........................................................................................................................... 61 
13.11 
Reporting and publication ................................................................................................. 61 
13.12 
Record retention ................................................................................................................ 61 
14 
REFERENCES .................................................................................................................. 62 
 
LIST OF FIGURES 
Figure 1 
Study flow chart ......................................................................................................... 24 
Figure 2 
Gedea Pessary and the Gedea Pessary blister package .............................................. 37 
Figure 3 
Vaginal tablet applicator ............................................................................................ 37 
 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 11 of 67 
 
 
Version 4.0 | Version 2023-07-04 
LIST OF TABLES 
Table 1 
 Schedule of assessments and procedures .................................................................. 25 
 
LIST OF APPENDICES 
Appendix 1 Patient Questionnaire 
Appendix 2 Principal Investigator Signature Page 
Appendix 3 List of Participating Sites and Principal Investigators 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 12 of 67 
 
 
Version 4.0 | Version 2023-07-04 
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 
CA 
Competent authority 
CI 
Confidence interval 
CIP 
Clinical investigation plan 
CIR 
Clinical investigation report 
COVID-19 
Coronavirus disease of 2019 
CRF 
Case report form 
CRO 
Contract research organisation 
CVVS 
Composite vulvovaginal signs and symptoms 
DPO 
Data Protection Officer 
eCRF 
Electronic case report form 
ePRO 
Electronic patient reported outcomes (system) 
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 
GMP 
Good manufacturing practice 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International conference on harmonisation 
ICPS 
International Programme on Chemical Safety 
IEC 
Independent ethics committee 
ISF 
Investigator site file 
ISO 
International Organization for Standardization 
KOH 
Potassium hydroxide 
MDR 
Medical device regulation 
MedDRA 
Medical dictionary for regulatory activities 
NaCl 
Sodium Chloride 
NaG 
Sodium gluconate 
OTC 
Over the counter 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 13 of 67 
 
 
Version 4.0 | Version 2023-07-04 
PPAS 
Per protocol analysis set 
PT 
Preferred term 
RA 
Regulatory authorities 
SaaS 
Software as a Service 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SOC 
System organ class 
SOP 
Standard operating procedure 
VVC 
Vulvovaginal candidiasis 
U-HCG 
Urinary human chorionic gonadotropin 
USADE 
Unanticipated serious adverse device effect 
WHO 
World Health Organization 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 14 of 67 
 
 
Version 4.0 | Version 2023-07-04 
1 
STATEMENT OF COMPLIANCE 
This clinical investigation will be conducted in accordance with this CIP which has been 
prepared in accordance with: 
 The International Conference on Harmonisation (ICH) Guideline for Good Clinical 
Practice (GCP) (ICH Harmonised Tripartite Guideline)/Note for Guidance on Good 
Clinical Practice: CPMP/ICH/135/95, January 1997 (where applicable to medical 
devices). 
 The principles of the European Standard EN International Organization for 
Standardization (ISO) 14155:2020 Clinical Investigation of Medical Devices for 
Human Patients – Good Clinical Practice. 
 The Medical device regulation (MDR) 2017/745. 
 MDCG 2020-10/1 Guidance on safety reporting in clinical investigations (May 2020) 
 The latest revision of the Ethical Principles for Medical Research Involving Human 
Subjects (World Medical Association Declaration of Helsinki).  
 The ICH E9 (R1) addendum: Statistical Principles for Clinical Trials.  
 Local laws and regulations/applicable regulatory requirements. 
2 
ETHICAL AND REGULATORY CONSIDERATIONS  
The Sponsor or designee will, prior to site initiation, obtain favourable opinion/approval to 
conduct the study from all regulatory agencies (RAs)/competent authorities (CAs) in 
accordance with any applicable country specific regulatory requirements. 
It is the responsibility of the Sponsor to submit the CIP, any protocol amendments, the patient 
information sheet and informed consent form (ICF), patient recruitment procedures, the 
Investigator’s Brochure (IB), information on payments and compensation available to 
patients, Investigator remuneration and other study‐specific documentation (as required) to 
the applicable independent ethics committee (IEC). 
Any additional requirements imposed by the IEC, RA or CA after their review shall be 
followed, as applicable.  
The IEC which reviewed and approved the study, as well as the name of the committee 
chairmen will be included in the Clinical investigation report (CIR). All applicable ethical and 
regulatory approvals must be available before a patient is exposed to any trial-related 
procedure, including screening for eligibility. 
The Coordinating Investigator is obliged to submit substantial amendments and other relevant 
updates to safety information to the IEC. The Sponsor is obliged to submit substantial 
amendments and other relevant documents to the RA. 
No substantial amendments to the CIP may be implemented prior to receipt of written 
approval from the IEC and/or RA, as applicable, unless the amendments are necessary to 
avoid immediate hazard for the patient. The Coordinating Investigator will maintain an 
accurate and complete record of all submissions made to the IEC. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 15 of 67 
 
 
Version 4.0 | Version 2023-07-04 
The Sponsor will compensate the study site for their work in the study. However, the 
compensation will not be affected by the outcome of the study.  
Patients will receive a small token of appreciation as compensation for study participation and 
they will be reimbursed for any reasonable travel cost as a result of participating in this study.  
All patients participating in the study can retrieve financial compensation in the case of harm 
(see Section 13.10). 
Each patient will be given full information about the study and will be asked to sign the ICF 
prior to initiation of any study-related activities (see Section 6.1). Patients will be free to 
withdraw from the study at any time (see Section 6.6.1).  
Each patient should be informed in writing that the study results will be stored and analysed 
in a computer, maintaining confidentiality in accordance with local data protection laws (see 
Sections 6.1 and 13.9). 
3 
INTRODUCTION 
3.1 
Indication 
Vaginal infection is a huge and largely underestimated problem, affecting 70% to 75% of 
women at some point in their life, and 5% to 8% of adult women have recurrent vulvovaginal 
candidiasis (VVC) with ≥ 4 episodes yearly.1,2  
The vaginal microbiome is a dynamic system, composed of a complex mixture of 
microorganisms in different ratios and quantities, which depend on lactic acid producing 
bacteria to maintain a weakly acidic environment.3 Changes to vaginal microflora increase the 
pH, thereby forming a favourable 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.4-8 Infections are also 
facilitated due to the mucosal effect of increased oestrogen levels and a weakened immune 
system during pregnancy.9 Recurrences are more common in pregnant women, and their 
therapeutic response is reduced compared to non-pregnant women.10, 11 Further, contraceptive 
pills, menstruation, and diabetes mellitus have been identified as predisposing factors for 
VVC.12, 13 Candida albicans is the most prevalent pathogen, which, according to 
epidemiological studies, is present in between 73% and 92% of vaginal isolations.14 Candida 
glabrata is the second most prevalent pathogen.14  
Many women diagnose themselves with VVC and purchase over the counter (OTC) anti-
mycotic treatments. However, many misdiagnose themselves and therefore receive 
unnecessary or inappropriate treatment.15 In a study of  95 symptomatic women who 
purchased OTC anti-mycotics for treatment of presumed VVC, only 34% of them were 
actually diagnosed with VVC.16 The most common other diagnosises were bacterial vaginosis 
(BV; 18.9%), mix of BV and VVC (18.9%), and normal (13.7%). 
Current treatment strategies for uncomplicated or acute VVC include anti-mycotic 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 after 27 to 
38 days of intravaginal imidazole treatment (clotrimazole, terconazole, butoconazole, or 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 16 of 67 
 
 
Version 4.0 | Version 2023-07-04 
miconazole) have been reported in a range of 64% to 87%, across different studies. None of 
these clinical cure rates were statistically significant.17, 18 Short-term clinical cure rates have 
been reported to be 85% 1 to 2 weeks after treatment,20 but also as low as 35% 7 days after 
treatment.19 Mycological cure rates have been reported to be higher compared to clinical cure 
rates in some studies and lower in others.19-22 
Severe VVC is characterised by extensive vulvar oedema, excoriations, and fissure formation. 
Short courses of treatment, which are normally effective in uncomplicated VVC, are often not 
sufficient.15 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.18, 22, 23  
Recurrent VVC is characterised by ≥ 4 yearly episodes, and treatment usually entails 
intensive initial therapy to induce clinical and mycological remission, followed by a 6-month 
systemic fluconazole maintenance therapy.15, 24, 25 While treatment guidelines for recurrent 
VVC are consistent, recommended treatments are not particularly effective in the long term 
17, 24, as 30% to 50% of patients experience recurrence after treatment discontinuation.15 
Oral anti-fungal therapies are not recommended during pregnancy due to the potential risk of 
foetal harm and spontaneous abortions.26-28 Therefore, treatment guidelines recommend that 
topical, rather than oral, anti-fungal therapy is used in pregnant women.17 
There are limited data regarding the anti-fungal 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.31-34 
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.33 
In summary, current treatment and prevention strategies for infections in the genital area are 
limited, and there is a need for novel OTC treatment alternatives which are safe during 
pregnancy and have low risk for resistance development. 
Given the high frequency of women misdiagnosing themselves with VVC, and self-treating 
with OTC treatments for VVC even though they in fact have a BV infection or mixed VVC 
and BV infection16, there is a need for products that are able to treat both VVC and BV. 
3.2 
Glucono-delta-lactone, mode of action 
 
Biofilm 
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 enhanced 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 utilised by yeasts and 
other eukaryotes in the pentose phosphate pathway. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 17 of 67 
 
 
Version 4.0 | Version 2023-07-04 
Biofilms are characterised by a transformation of planktonic cells to form hyphae, which can 
invade the mucous membrane and induce inflammation.39 The hyphal form, i.e. filamentous 
cells, can invade tissues and induce inflammation, mediated by Candidalysin, a cytotoxic 
peptide toxin that destroys the epithelial cells of the vagina.40 Thus, it is reasonable to assume 
that GDL functions as an indicator of a favourable environment for several pathogens, such as 
Candida, which favours planktonic cells over hyphae and results in reduced biofilm 
formation. 
We have shown in vitro that GDL can significantly reduce the biofilm formation in 
C.albicans and other Candida species.38 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 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 also remove mature 
biofilm (biofilm grown for 2 days before treatment). 
Though it has been reported that Candida containing biofilm cannot be found in human 
vaginal tissue biopsies 41, Harriot et al 42 have shown in in vivo and ex vivo murine models 
that C. albicans forms biofilms, and the general view is that the Candida biofilm formation on 
human vaginal mucosa is an important part of the pathogenic mechanism of VVC. 
 
Lactobacilli 
There are different reports and theories on how Lactobacilli interacts with Candida in the 
vagina. There is a hypothesis that Lactobacilli does not prevent the colonisation of Candida 
but may prevent their proliferation. This is supported by the finding that lactic acid producing 
bacteria may inhibit the yeast-to hyphae switch.43 As mentioned in Section 3.1, there is also a 
correlation between the use of antibiotics and the susceptibility to Candida infection, since 
antibiotics lead to the depletion of favourable vaginal bacteria. 
Different research groups have shown that L. crispatus and L. fermentum can affect the 
growth and yeast-to-hyphae transition of C. albicans, in addition to hydrogen peroxide and 
organic acids. In these studies, the anti-Candida effects have been excerted by compounds 
released from these strains of Lactobacilli.44, 45   
Preliminary unpublished data from the Gedea Biotech AB clinical investigation CL1, suggests 
that women who were treated with pHyph gen I and cured had an increase in the relative 
abundance of L. crispatus, contrary to women who were treated but not cured, where an 
increase in L. crispatus was not seen. Thus, a yeast-to hyphae switch induced by an increase 
in Lactobacilli is likely to be an important part of the mechanism of pHyph treating VVC. 
3.3 
Product description and previous experience 
 
Non-clinical data 
Glucono-delta-lactone is a normal intermediate in glucose metabolism through the pentose 
phosphate cycle in mammals. Studies in rats have shown that GDL gives similar weight 
increase as glucose on low-calorie diets.46 Furthermore, several studies on humans have been 
performed using oral doses of 3 g to 50 g of GDL and showed no signs of toxicity.47 There 
was no evidence of carcinogenicity, teratogenicity, or genotoxicity of GDL, nor of D-gluconic 
acid or the magnesium, potassium, calcium, or sodium salts thereof. In addition, both the US 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 18 of 67 
 
 
Version 4.0 | Version 2023-07-04 
Food & Drug Administration (FDA) and the World Health Organization (WHO) International 
Programme on Chemical Safety (ICPS) accepts GDL as a safe food additive.48, 49 
In this study, GDL and sodium gluconate (NaG) have been formulated as a more easily 
soluble and slow-release pessary, the Gedea Pessary (pHyph gen II) for increased dosing 
accuracy and patient compliance. 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 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 sensitisation (local lymph node assay, ISO 10993-10). The tests were 
performed on Gedea Pessary gen I, by Eurofins Medical Device Testing (Munich, Germany) 
in compliance with the principles of good laboratory practice (GLP). The cytotoxicity test, 
which was 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 was a 
prerequisite to continue with the in vivo irritation and sensitisation 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 sensitisation test showed no signs of 
sensitisation after treatment with Gedea Pessary. The biological evaluation test results for 
Gedea Pessary gen I are also applicable for the Gedea Pessary gen II (QRS-BC-008)55. Thus, 
it can be concluded that the product fulfilled the current biocompatibility requirements for 
medical devices. For further pre-clinical data, refer to the IB. 
 
Clinical data 
The Gedea Pessary (pHyph gen II) used in this clinical investigation has been tested in a 
randomised, double-blind, placebo-controlled investigation in adult women with BV, the CL3 
study. The objective of the investigation was to evaluate clinical performance, and safety of 
initial and preventive treatment with the Gedea Pessary, as compared to placebo, in women 
with BV. In the part 1 of the study, treatment for 6 consecutive days was given and the 
clinical cure rate on Day 7, defined as absence of all of the 3 Amsel criteria was evaluated 
(pH excluded). 115 patients treated with pHyph and 30 patients treated with placebo were 
included in the Full Analysis Set (FAS). There were no significant between-group differences 
in the percentage of women who were clinically cured; 50.4% in the pHyph group and 46.7% 
in the placebo group. In vitro studies performed, showed that the placebo was not inactive, it 
strongly promoted the growth of Lactobacillus Iners and this may explain the high placebo 
cure rate in the CL3 study58. 
During Part 1 of the CL3 study, 26 AEs were reported by 22 patients (19.1%) in the Gedea 
Pessary group and 5 AEs were reported by 4 patients (13.3%) in the placebo group. The most 
commonly reported AEs were Vulvovaginal candidiasis (Gedea Pessary: 5 AEs in 5 patients, 
4.3%; Placebo: 1 AE in 1 patient, 3.3%), Vulvovaginal burning sensation (Gedea Pessary: 3 
AEs in 3 patients, 2.6%) and Vulvovaginal pruritus (Gedea Pessary: 2 AEs in 2 patients, 
1.7%; Placebo: 1 AE in 1 patient, 3.3%).  
A total of 8 AEs (Vulvovaginal discomfort [2 events in 2 patients], Dysmenorrhoea, 
Vulvovaginal pruritus, and Vaginal discharge/Vulvovaginal burning sensation/Vulvovaginal 
erythema/Vulvovaginal swelling [reported at the same time in 1 patient]) in 4 patients (2.8%, 
N=145) (Gedea Pessary: 6 AEs in 3 patients, 2.6%; Placebo: 2 AEs in 1 patient, 3.3%) were 
judged as possibly related. One AE (Vulvovaginal pruritus) in 1 patient (0.9%) in the Gedea 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 19 of 67 
 
 
Version 4.0 | Version 2023-07-04 
Pessary group was judged as probably related to the study procedure. Most AEs (22 AEs) 
were of mild intensity, except for 9 AEs (Vulvovaginal candidiasis [2 events], Back pain, 
COVID-19, Urinary tract infection, and Vaginal discharge/Vulvovaginal burning sensation/ 
Vulvovaginal erythema/Vulvovaginal swelling [reported at the same time in 1 patient]) in 6 
patients (4.1%) that were assessed as moderate. No severe events were reported.  
A total of 10 device deficiencies were reported by 9 patients (6.2%; 8 patients in the Gedea 
Pessary group and 1 patient in the placebo group) during Part 1 of the study. The reported 
device deficiencies were considering malfunction (tablet falling out and/or that the tablet did 
not melt completely) of the device (9 device deficiencies) or use error (1 device deficiency). 
The part II of the CL3 study has not yet been reported. 72 patients were randomised to once 
weekly treatment with either Gedea Pessary or placebo during four months or until a BV 
recurrence was confirmed. There were no SAEs and no local vaginal AEs in the Gedea 
Pessary arm. 
The GDL-and-NaG-containing investigational device, Gedea Pessary pHyph gen I (300 mg 
GDL, 367.5 mg NaG, administered every second day on Days 0, 2, 4 and 6), has been tested 
in two open-label clinical investigations in adult women with VVC (CL1 study 50) or BV 
(CL2 study 50).  
In both studies, the primary objective was to investigate the clinical performance, tolerability 
and safety of the Gedea Pessary pHyph gen I. In the first study, CL1, 22 patients with 
confirmed VVC were evaluated for clinical cure rate on Day 7. Clinical cure rate, 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, was 41% after 4 administrations with 
the Gedea Pessary. No serious adverse events (SAEs) occurred and few adverse events (AEs) 
were reported.50 The most common AEs were headache, dysmenorrhoea and nasopharyngitis 
and most were of mild intensity and not assessed as related to the product or procedure. One 
patient experienced non-application site rash the day after the first administration. The 
Investigator assessed the reaction as severe, however not related to the product or the 
procedure, nevertheless the patient´s study participation was ended.  
In the CL2 study, 24 patients with confirmed BV were evaluated.50 The clinical cure rate on 
Day 7, defined as absence of all of the 3 Amsel criteria, was 82% after 4 administrations with 
the Gedea Pessary. Also, in this study, no SAEs occurred, and few AEs were reported, which 
were mainly mild in intensity and not assessed as related to the product or procedure. The 
most commonly reported AEs were headache and dysmenorrhoea. Single events of headache, 
dysmenorrhoea (2 events reported by 2 patients), urinary tract infection, vaginal disorder 
(reported term: “pain and itching in the vagina”) and vaginal haemorrhage (reported 
term: “really bad smelly blood fluid from vagina”) were judged as possibly related to the 
product and/or the procedure.  
In both studies, the usability of the pHyph gen I was assessed as good, however, about a third 
of patients reported malfunctions of the Gedea Pessary considering the tablet falling out 
and/or that the tablet did not melt completely. This malfunction was more commonly reported 
in the CL1 study and may have been caused by the limited amount of vaginal discharge in 
VVC patients.  
The new formulation to be used in the present study (pHyph gen II; 150 mg GDL, 184 mg 
NaG) is considered to counteract these malfunctions and thereby increase the device efficacy. 
In addition, the instructions for use have been updated with information that the patients 
should moist the tablets (by shortly holding the tablet over tap water) before use, to promote 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 20 of 67 
 
 
Version 4.0 | Version 2023-07-04 
the dissolution. Also, the Gedea Pessary pHyph gen II has been reformulated to be more 
easily soluble for daily dosing. In the CL3 study, there were, as mentioned above, only 9 
reports of tablet falling out and/or that the tablet did not melt completely out of 152 patients 
included.  
Based on published studies on current treatments for VVC, all vaginal and local anti-mycotics 
are generally well tolerated.17 Local irritation is the most frequent AE reported in conjunction 
with topical azole therapy, and headache is the most frequently reported AE of oral 
imidazoles.52, 18 Nausea and diarrhoea has been reported as treatment-emergent AEs in a study 
with oral fluconazole, both at a rate of 1.9%.19 
Collectively, pre-clinical data indicate that GDL and NaG are safe and may be effective 
topical treatments for VVC, and a modified formulation of the GDL-and-NaG-containing 
slow-release pessary (pHyph gen II) for daily dosing is to be further investigated in this 
clinical investigation. 
4 
STUDY OBJECTIVES 
The objectives and clinical endpoints are stated in this section. Note, however, that as the ICH 
E9 (R1) addendum has been consulted in the design and analysis of this study, i.e. an 
estimand approach has been applied, the final definition of the endpoints to be used in the 
statistical analysis are stated in Section 12.4.  
4.1 
Primary objective 
To investigate the clinical performance of acute treatment with Gedea Pessary in patients with 
VVC. 
 
Primary endpoint  
The primary endpoint is the clinical cure rate on Day 7-14, which is defined as the percentage 
of patients clinically cured at Day 7 to Day 14.   
Clinical cure is defined as the absence of signs and symptoms of VVC in terms of having a 
CVVS score ≤ 3 53 
Each of the following 6 vulvovaginal signs and symptoms will be individually scored using 
the scoring scale below. 
 Vulvovaginal signs: erythema, oedema and excoriation 
 Vulvovaginal symptoms: itching, burning and irritation 
Scoring scale: each score should be objectively defined: 
0 = none (absent) 
1 = mild (slight) 
2 = moderate (definitely present) 
3 = severe (marked, intense) 
The CVVS score is the sum of the 6 individual scores. If any of the 6 individual signs and 
symptoms are missing, then the CVVS score will be considered missing. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 21 of 67 
 
 
Version 4.0 | Version 2023-07-04 
4.2 
Secondary objectives 
To investigate the safety of acute treatment with Gedea Pessary and to further investigate the 
clinical performance of acute treatment with Gedea Pessary in patients with VVC. 
 
Secondary endpoints  
1. Safety and tolerability, based on reported treatment-emergent AEs (safety endpoint). 
2. Proportion of patients having a continued clinical response to treatment at Day 25, 
defined as the proportion of patients clinically cured on Day 7-14 and thereafter 
responding “no” to the yes/no question, “Have the symptoms recurred?” 
3. Proportion of patients having a cure defined as clinical cure Day 7-14 according to 
primary endpoint and mycological cure (culture negative for growth of Candida 
species). 
4. Proportion of patients having a reduction in CVVS score on Day 7-14 compared to 
Day 0. 
5. Change in the CVVS score from Day 0 to Day 7-14. 
6. Proportion of patients having a reduction in the sum of the 3 vulvovaginal symptoms 
scores (itching, burning, and irritation) on Days 1-7, Day 11, Day 14 and Day 25, 
compared to Day 0. 
7. Change in the sum of the 3 vulvovaginal symptoms scores (itching, burning, and 
irritation) on Days 1-7, Day 11, Day 14 and Day 25, compared to Day 0. 
8. Proportion of patients having a mycological cure as assessed by vaginal culture on 
Day 7-14 and Day 25. 
9. Proportion of patients having an absence of Candida hyphae in the wet smear on 
Day 7-14. 
10. Usability, measured by patient questionnaire, on Day 6. 
4.3 
Exploratory objectives 
 
Exploratory endpoints  
1. Correlation between vaginal microbiome as assessed by vaginal swab DNA-analysis 
on Days 0, 7, 14, and 25 and clinical cure. 
2. Correlation of presence of fungus as analysed by vaginal swab DNA-analysis on 
Days 0, 7, 14 and 25 and presence of fungus as assessed by culture, and clinical cure. 
 
 
 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 22 of 67 
 
 
Version 4.0 | Version 2023-07-04 
5 STUDY DESIGN 
5.1 General outline 
This is a multi-centre study to evaluate the clinical performance and safety of treatment with 
Gedea Pessary in adult women with confirmed VVC.  
The study population will consist of post-menarchal, pre-menopausal females, 18 years or 
older, seeking care for VVC symptoms.  
A total of 26 patients are planned to be included in the study. 
On Day 0 (Screening, Visit 1), eligible patients will undergo a gynaecological examination, 
including collection of CVVS data, and vaginal samples. Patients will be provided with 
6 doses of Gedea Pessary that will be self-administered as a daily treatment (Days 0 to 5). 
Patients will visit the clinic on Day 7 (+2 days, Visit 2) for gynaecological examinations, 
including collection of CVVS data for the assessment of clinical cure and reporting of AEs 
and concomitant medications. On Day 14 (±2 days, Visit 3), patients that did not have a 
clinical and mycological cure Day 7 will re-visit the clinic for additional gynaecological 
examinations, including collection of CVVS data for the assessment of clinical cure. Rescue 
treatment will be offered during visits 2 and 3, if necessary. Patients will have a final 
telephone follow-up on Day 25 (±3 days, Visit 4), for for reporting of AEs, concomitant 
medications and potential menstruation onset. 
Vaginal sampling for culture and sequencing, as well as vaginal pH measurements will be 
performed at the clinic on Day 0, Day 7, and Day 14. On Day 25, patients will self-perform 
vaginal swabs at home for sequencing and vaginal culture.  
Patient questionnaires for assessing VVC symptoms, will be used during the treatment period 
(Days 0 to 5), 1 day after the treatment (Day 6) and on Days 11 and 25. Usability will be 
assessed on Day 7, also via the patient questionnaire. The patient questionnaire will be based 
on an electronic patient reported outcomes (ePRO) system, i.e. a mobile application 
(ViedocMe™). The questionnaire is provided in Appendix 1. 
An overview of the study design is provided in  
 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 23 of 67 
 
 
Version 4.0 | Version 2023-07-04 
Figure 1. For details on the specific assessments to be performed at each study visit and 
contact see Table 1 and Section 5.4. 
 
 
 
 
 
 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 24 of 67 
 
 
Version 4.0 | Version 2023-07-04 
Figure 1 
Study flow chart  
 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 25 of 67 
 
 
Version 4.0 | Version 2023-07-04 
Table 1 
Schedule of assessments and procedures  
Evaluations 
Day 0 
Day 0-5 
Day 6 
Day 7  
(+2 days) 
Day 11 
(±1 day) 
Day 14a 
(±2 days) 
Day 25 
(±3 days) 
 
Screening 
Treatment 
Follow-up 
Follow-up 
Follow-up 
Follow-up 
Follow-up 
 
Visit 1 
 
At home 
Visit 2 
At home 
Visit 3 
Visit 4 (Telephone) 
Informed consent 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
Pregnancy test (urinary) 
X 
 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
Prior and concomitant medications 
X 
 
 
X 
 
X 
X 
Menstruation (date of end/onset) 
X 
 
 
X 
 
X 
X 
Gynaecological examination incl. CVVS 
X 
 
 
X 
 
X 
 
Vulvovaginal symptoms (via patient 
questionnaire or telephone) 
 
X 
X 
 
X 
 
X 
Fungal microscopy assessment 
X 
 
 
X 
 
X 
 
Vaginal swab for cultureb  
X 
 
 
X 
 
X 
X 
Vaginal swab for sequencingb 
X 
 
 
X 
 
X 
X 
Treatment dispensing 
X 
 
 
 
 
 
 
Treatment with Gedea Pessaryc 
 
X (Daily) 
 
 
 
 
 
Vaginal pH (pH strip test) 
X 
 
 
X 
 
 
 
Patient questionnaire/Usability 
 
 
X 
 
 
 
 
AEs 
 
 
 
X 
 
X 
X 
Device deficiencies 
 
 
 
X 
 
 
 
Product accountabilityd 
 
 
 
X 
 
 
 
Rescue treatment 
 
 
 
Xe 
 
Xe 
Xf 
a Only for patients with no clinical and mycological cure Day 7. 
b Self-swab on Day 25(presence of Candida + sequencing analysis of the vaginal microbiome). Taken in duplicates Day 0 and 7. 
c Treatment to be self-administered by the patient at home, at night before going to bed. 
d Patients should be asked to return all used and not used treatment packages. 
e Offered if the VVC symptom score on that day is equal to or higher than the score at the inclusion visit (Day 0). 
f If symptoms recur on Day 25, or symptoms persist, rescue medication could be offered according to standard clinical practice.

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 26 of 67 
 
 
Version 4.0 | Version 2023-07-04 
5.2 Rationale for the study design 
As described in Section 3.1, 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 further investigate the clinical 
performance and safety of the Gedea Pessary containing GDL and NaG, now formulated for 
daily dosing (pHyph gen II), 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 (Section 3.2). Data also indicate that GDL is 
tolerable and does not pose any special risk to humans (Section 3.3.1). 
Due to the widespread clinical problem of VVC and the issues involving current therapies 
(see Section 3.1) trials involving patients are justified. The clinical performance of Gedea 
Pessary, pHyph gen I, has been evaluated in 2 open-label clinical investigations (see 
Section 3.3.2). These studies provided evidence of a good safety/tolerability profile of the 
Gedea Pessary. The clinical cure rate for VVC was 41%. The rather low clinical cure rate may 
be due to that the pessaries did not dissolve properly and in some cases fell out from the 
vagina too early. This theory is based on observations that no or lower pH decrease was 
reported in patients that were not cured, suggesting that the device did not perform as 
intended. Also, the number of incidences of pessaries falling out were 3 times higher in 
patients that were not cured compared to patients that were cured. 
In this study, the Gedea Pessary (pHyph gen II) formulated for increased dosing accuracy and 
patient compliance, will be further investigated in this open-labelled study, similar to the 
previous CL1 study. This is done to evaluate the performance of the new formulation in VVC 
patients and  to evaluate the potential clinical cure. The reduction of vulvovaginal symptoms 
day by day during Day 0 to Day 7 will also be investigated. How soon a relief of the 
symptoms may be achieved is an essential feature of a VVC-treatment and also important to 
know concerning the timing of offering rescue treatment in a possible future controlled study. 
The diagnosis of VVC in the study is based on the FDA Guidance for Industry. The FDA 
recommendation is that the patients should have 1) 2 or more of the following signs and 
symptoms: itching, burning, irritation, edema, erythyma, or excoriation; 2) Potassium 
hydroxide (KOH) or saline preparation from the inflamed vaginal mucosa or secretions 
demonstrating yeast forms (hyphae or pseudohyphae) or budding yeasts, and 3) vaginal 
pH ≤ 4.5. However, in this study, pH ≤ 4.5 will not be an inclusion criterion. The low risk 
profile of the Gedea Pessary allows this less stringent inclusion criteria and the VVC 
diagnosis will be confirmed post inclusion, by both vaginal culture and microbiome analysis. 
The VVC diagnosis will be validated by culture and microbiome analysis. The vaginal 
microbiome will be analysed to better understand the relation between vaginal dysbiosis and 
VVC. 
To fulfil the primary endpoint (clinical cure), signs and symptoms of VVC must be absent and 
this is defined in terms of having a CVVS score ≤ 3. This is consistent with the current FDA 
guidelines and the CVVS score is an established method to define VVC signs and symptoms 
and clinical cure. 53 
The safety endpoints were selected to assure a sufficient method to assess the safety of the 
Gedea Pessary. The usability endpoint was selected to ensure the Gedea Pessary is easy to use 
for the patients.  

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 27 of 67 
 
 
Version 4.0 | Version 2023-07-04 
The dose of 150 mg GDL and 184 mg NaG administered daily for 6 days was chosen based 
on clinical data from previous studies (see Section 3.3.2). Also, pre-clinical measurements of 
pH in an in vitro dissolution test have shown a pH decrease duration of approximately 
24 hours for the pHyph gen II (see the IB).  
5.3 Risks and benefits 
The investigational device, Gedea Pessary pHyph gen I 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 sensitisation (local lymph node assay, ISO 10993-10). The in vitro 
cytotoxicity test classified the test item as slight to moderate cytotoxic (scale 1 to 2 on 
a 3-grade scale); the in vivo irritation test as well as the in vivo sensitisation test showed no 
signs of irritation, necrosis, or sensitisation 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 and are unlikely to cause any major 
inconvenience to patients.  
In a previous study with the Gedea Pessary pHyph gen II, there were no SAEs reported.Only 
single reported events of vulvovaginal discomfort, dysmenorrhoea, vulvovaginal pruritus, and 
vaginal discharge/vulvovaginal burning sensation/vulvovaginal erythema/vulvovaginal 
swelling [reported at the same time in 1 patient],  could not be ruled out as caused by the 
Gedea Pessary or the study procedure (see Section 3.3.2). A few patients experienced that the 
pessary fell out or did not melt completely. This type of device deficiency was more common 
with the previous formulation Gedea Pessary pHyph gen I, especially in the CL1 VVC study. 
In the present study, this type of device deficiency will be closely monitored to confirm that 
the reformulation has reduced the risk also in VVC. 
It is anticipated that patients participating in this study may be cured from their VVC, 
however, there is a risk that they will have no clinical benefit from treatment with the 
investigational device. This may cause patients to experience symptoms of VVC including 
vaginal itching, burning or soreness, pain during sexual intercourse, pain or discomfort when 
urinating, or abnormal vaginal discharge longer than necessary. However, rescue treatment 
according to standard clinical practice, will be offered to the patient at Visit 2 and Visit 3 (i.e. 
Day 7 and 14) to patients experiencing VVC symptoms of the same or higher intensity 
compared to Day 0. Rescue treatment will also be offered to patients with recurrence, or 
persisting symptoms, on Day 25. Thus, any risk associated with long-term untreated VVC 
will be avoided. For details on rescue treatment see in Section 7.5.2.  
All residual risks have been classified as low after risk control measures. Risks that were 
classified as “High risk level” before risk control are listed in Appendix 1 of the IB. 
Patients included in the study must refrain from using other intravaginal products to mitigate 
any risk of interactions with concomitant vaginally administered products. The investigational 
device acts locally on the vaginal mucosa and will most likely not affect any concomitant 
systemic treatment. No possible interactions with concomitant medical treatments are 
expected.  

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 28 of 67 
 
 
Version 4.0 | Version 2023-07-04 
Taken together, as the anticipated levels of discomfort are transient and mild, and that risks 
associated with long-term untreated VVC are avoidable, the use of the investigational product 
Gedea Pessary appears to offer clinical benefits at a reasonable risk level. 
The Sponsor Gedea Biotech AB realises that extraordinary measures may need to be 
implemented and the management of the investigation may need to be adjusted due to 
unexpected risks, including the outbreak and pandemic spread of the coronavirus disease 
of 2019 (COVID-19). For example, participants safety, participants being in 
self-isolation/quarantine, limited access to public places (including clinics and hospitals) due 
to the risk of spreading infections, and healthcare professionals being committed to critical 
tasks, may affect the conduct of the study.  
The study has been designed in a way so that many assessments are performed at home by the 
patients and follow-up visits are conducted over the phone. There are only a few extra visits to 
the clinic planned for the patients outside of their routine clinical care.  
Patients with VVC are not considered a risk group for infection with serious COVID-19 
illness. The increased risk, for patients participating in this investigation, of contracting 
COVID-19 is considered low.  
All patients’ visits to the clinics/hospital will occur in facilities which are not used for patients 
with COVID-19. Recommended procedures to prevent COVID-19 infection, as recommended 
by the local public health agencies in the countries where the study will be executed, will be 
followed. 
Taken all the above into consideration, Gedea Biotech AB considers that the benefits of 
initiating the study outweighs the risks related to COVID-19.  
During the investigation, the site initiation visits may be performed remotely and the 
possibility to use remote monitoring will be implemented. Deviations to the CIP that are due 
to the COVID-19 will be tracked separately and described in the CIR. 
5.4 Study visits and procedures 
All study visits and procedures are described in the following subsections and summarised in 
Table 1. 
 
Day 0; Screening and enrolment 
Patients seeking treatment for symptoms relating to VVC may be informed about the study 
and, if agree to participate, sign the ICF. After the ICF is signed, patients will undergo a 
gynaecological examinations, where the Investigator or an authorised designee will assess the 
presence of vulvovaginal signs (erythema, oedema, or excoriation) and symptoms (itching, 
burning, or irritation) and score each sign and symptom, as described in Section 9.1.  
Vaginal samples will be examined under a microscope for yeast forms (hyphae or 
pseudohyphae) or budding yeast. Two vaginal secretion samples will also be collected by a 
vaginal swab. One sample will be cultured to verify the presence of Candida and the other 
(taken in duplicates) will be used for sequencing analysis of the vaginal microbiome prior to 
treatment (Section 10.1.1). If the Investigator assesses that the patient has VVC, based on the 
gynaecological examination and the fungal microscopy, the patient will receive the 
investigational product to be self-inserted vaginally at home during 6 consecutive days 
(Days 0 to 5). In addition, the Investigator will measure the vaginal pH, as described in 
Section 10.1.2.  

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 29 of 67 
 
 
Version 4.0 | Version 2023-07-04 
The Investigator or delegee will ask the patient about onset and end of last menstruation. The 
patient should not be enrolled, or the enrolment should be postponed, if menstruation is 
foreseen to occur at the time of the Day 7 visit.  
Procedures to be performed: 
 Informed consent 
 Demography 
 Eligibility criteria 
 Pregnancy test (urinary) 
 Recording of  
o Medical and surgical history 
o Prior and concomitant medications 
o Onset and end of last menstruation 
 Gynaecological examination by Investigator or authorised designee, evaluating 
vulvovaginal signs (erythema, oedema, and excoriation) and symptoms (itching, 
burning, and irritation) according to a scoring scale (0-3). 
 Fungal microscopy assessment (KOH or saline preparation) 
 Vaginal swab for: 
o Culture 
o Sequencing 
 Vaginal pH 
 Treatment dispensing for self-administration by patients at home. 
 
Day 0 to Day 5; Treatment administration 
During Days 0 to 5, patients will self-administer the investigational product, at night before 
going to bed.  
Patients will be reminded about the administration and will also receive questions about VVC 
symptoms (itching, burning, or irritation) via the mobile application (ViedocMe™) (see 
Section 9.1.2).  
Procedures to be performed: 
 Daily self-administration of treatment (Gedea Pessary) by patients. 
 Patient questionnaire (via mobile application)  
o Vulvovaginal symptoms (itching, burning, and irritation), evaluated by patients 
according to a scoring scale (0-3).  
Note that VVC symptoms will also be assessed on Day 6, although no treatment is 
administered. Additionally, the patient will complete the questionnaire regarding Usability 
(via mobile application) at Day 6.  
 
Day 7 (+2 days); Follow-up visit 
Patients will visit the clinic on Day 7 to have gynaecological examination performed. The 
Investigator or an authorised designee will assess the presence of vulvovaginal signs 
(erythema, oedema, and excoriation) and symptoms (itching, burning, and irritation) and score 
each sign and symptom on a scale of 0 to 3 (see Section 9.1.2). 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 30 of 67 
 
 
Version 4.0 | Version 2023-07-04 
Vaginal samples will be examined under a microscope for yeast forms (hyphae or 
pseudohyphae) or budding yeast. Vaginal secretion samples collected by swabs will be used 
for culture and for sequencing analysis of the vaginal microbiome (this sample will be taken 
in duplicates). If the patient is menstruating at this timepoint, the visit should be postponed 
until the menstruation is over, even though the visit will happen outside the visit window. 
Procedures to be performed: 
 Gynaecological examination by Investigator or authorised designee, evaluating 
vulvovaginal signs (erythema, oedema, and excoriation) and symptoms (itching, 
burning, and irritation) according to the scoring scale (0 to 3). 
 Fungal saline microscopy assessment 
 Vaginal swab for 
o Culture 
o Sequencing 
 Vaginal self-swab for:  
o Sequencing  
 Vaginal pH 
 Recording of 
o Concomitant medications 
o AEs 
o Potential menstruation onset 
 Product accountability – patients should be asked to return all used and not used 
treatment packages 
Rescue treatment, according to standard clinical practice, will be offered if the intensity of the 
VVC symptoms is the same or higher compared to the inclusion visit (Visit 1, Day 0). See 
details in Section 7.5.2.  
An assessment of mycological cure will be done as soon as the results from the laboratory are 
received. A mycological cure is defined as no presence of Candida species. If the patient has 
both a clinical and mycological cure at Day 7, the Day 14 visit should be cancelled. 
 
Day 11 (±1 day); Follow-up at home 
On Day 11, patients will be reminded to complete the patient questionnaire (via mobile 
application) for self-assessment of VVC symptoms (itching, burning, or irritation) according 
to a scoring scale (0-3) (see Section 9.1.2). 
 
Day 14 (±2 days); Follow-up visit 
Patients with clinically and mycologically cured VVC at Day 7, or patients initiating rescue 
treatment Day 7 (even if they are clinically cured according to the CIP), will not perform the 
Day 14-visit. For these patients, this visit will be omitted.  
Patients without clinically and mycologically cured VVC at Day 7 will visit the clinic on 
Day 14 to have gynaecological examination performed. The Investigator or an authorised 
designee will assess the presence of vulvovaginal signs (erythema, oedema, and excoriation) 
and symptoms (itching, burning, and irritation) and score each sign and symptom on a scale of 
0 to 3 (see Section 9.1.2). 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 31 of 67 
 
 
Version 4.0 | Version 2023-07-04 
Vaginal samples will be examined under a microscope for yeast forms (hyphae or 
pseudohyphae) or budding yeast. Vaginal secretion samples collected by swabs will be used 
for culture and for sequencing analysis of the vaginal microbiome. If the patient is 
menstruating at this timepoint, the visit should be postponed until menstruation is over. 
The Investigator or delegee will ask the patient about potential menstruation onset. 
Procedures to be performed: 
 Gynaecological examination by Investigator or authorised designee, evaluating 
vulvovaginal signs (erythema, oedema, and excoriation) and symptoms (itching, 
burning, and irritation) according to the scoring scale (0 to 3). 
 Fungal microscopy assessment (KOH or saline preparation) 
 Vaginal swab for 
o Culture 
o Sequencing 
 Recording of: 
o Concomitant medications 
o AEs 
o Potential menstruation onset 
 
Rescue treatment, according to standard clinical practice, will be offered if the intensity of 
VVC symptom is the same or higher compared to the inclusion visit (Visit 1, Day 0). See 
details in Section 7.5.2.  
 
Day 25 (±2 days); Follow-up visit 
All patients will be contacted by the investigational site staff by telephone and asked about 
concomitant medications, AEs and potential menstruation onset. In addition, patients will be 
asked about symptom recurrence; “Have the symptoms recurred – yes/no?”. If the answer is 
“yes”, then the patient will be managed according to standard clinical practice. The site will 
decide if the patient should return to the site and if rescue medication should be prescribed 
(see Section 7.5.2). 
Patients will also be reminded to complete the patient questionnaire for self-assessment of 
vulvovaginal symptoms, and to collect vaginal samples by self-swab. If the patient is 
menstruating at this time point, the patient should take the sample on the first day after 
menstruation. The self-swab samples will be sent by post to the laboratory for culture and 
sequencing of vaginal microbiome.  
Procedures to be performed: 
 Patient questionnaire (via mobile application) 
o Vulvovaginal symptoms of VVC (itching, burning, or irritation), evaluated by 
patients according to a scoring scale (0-3). 
 Vaginal self-swab for  
o Culture 
o Sequencing 
 Recording of 
o Concomitant medications 
o AEs 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 32 of 67 
 
 
Version 4.0 | Version 2023-07-04 
o Potential menstruation onset 
 
Early withdrawal visit 
If a patient is prematurely withdrawn from the study for any reason, the patient must be 
followed-up for at least safety purposes and if the patient is withdrawn prior to the Day 14 
visit (if this visit is applicable), the patient should be asked to visit the site for follow-up 
assessments (see Section 6.6.3 for withdrawal procedures).  
If a withdrawal occurs during a study visit, the electronic case report form (eCRF) for that 
specific visit shall be completed as far as possible.  
The following assessments should be performed to the extent possible on the day for early 
withdrawal: 
 Reason for withdrawal. 
 Vaginal swab (self-swab as applicable) for 
o Culture 
o Sequencing  
 Recording of 
o Concomitant medications 
o Vulvovaginal signs (if a visit is performed) 
o AEs 
o Potential menstruation onset 
 Product accountability – if not already performed on previous visit, patients should be 
asked to return all used and not used treatment packages.  
 Patient questionnaire (via mobile application) 
o Vulvovaginal symptoms (itching, burning, and irritation), evaluated by patients 
according to a scoring scale (0-3). 
o Usability (if not already obtained). 
6 SELECTION OF STUDY POPULATION 
6.1 Patient information and informed consent 
The recruitment of patients will start only after the approval of the CIP including the patient 
information sheet and ICF by the RA/CA and the IEC, as applicable (see Section 2).  
The Investigator must always use IEC-approved patient information sheet that must not be 
changed without prior Sponsor and IEC approvals. No study procedures will be performed 
unless the patient has provided written informed consent to study participation.  
It is the responsibility of the Investigator, or any authorised designee, to give each patient 
adequate verbal and written information about the nature of the investigation, its purpose, 
expected duration, the benefits and risks involved in the study participation. This information 
will emphasise 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. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 33 of 67 
 
 
Version 4.0 | Version 2023-07-04 
Each patient should be informed in writing that the data from the study will be stored and 
analysed, maintaining confidentiality in accordance with local data protection laws. 
Before any clinical investigation-related procedures are undertaken, the ICF must 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. 
The ICF will incorporate (or be accompanied by a separate document incorporating) 
information on the processing of the patient data within the scope of this study which 
complies with relevant data protection and privacy legislation. If any data are transferred to 
European Economic Area countries outside the countries where the study is executed, the data 
will not identify any persons taking part in the clinical investigation in accordance with the 
EU General Data Protection Regulation (GDPR). 
A copy of the patient information sheet, including the signed ICF, will be provided to the 
patient. The date of informed consent must be recorded in the source documentation and in 
the eCRF. The patient information sheet and the signed ICF should be filed by the 
Investigator for possible future audits and/or inspections. 
If any new information becomes available that may influence the patient’s decision to 
participate in the study, the Investigator will contact and inform all currently enrolled patients 
and obtain additional informed consent, as applicable (see Section 13.5).  
6.2 Recruitment 
Post-menarchal, pre-menopausal females, 18 years or older, seeking care for VVC symptoms 
(itching, burning, or irritation) should be considered. Patients with confirmed VVC, may be 
informed verbally and in writing about the study and asked about their willingness to 
participate (clinical routine samples and gynaecological examination may be used for 
confirmation of the VVC diagnosis). 
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.  
After signing of the ICF, the screening procedures may start and available clinical routine 
samples may be used for confirmation of VVC diagnosis).  
Patients who have signed the ICF shall be listed on a Screening and enrolment log together 
with an assigned Screening number. Patients not fulfilling all inclusion criteria as described in 
Section 6.3, or fulfilling any of the exclusion criteria listed in Section 6.4, shall be considered 
Screening failures. Screening failure reasons shall be stated in the Screening enrolment log, 
and recorded in the eCRF. 
The patient should not be enrolled, or the enrolment should be postponed, if menstruation is 
foreseen to occur at the time of the Day 7 visit.  
6.3 Inclusion criteria 
1. 
Having decisional capacity and providing written informed consent. 
2. 
Adult, post-menarchal, pre-menopausal women, aged 18 years or older 
3. 
Diagnosis of VVC, defined as: 
o Having a white or creamy vaginal discharge  

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 34 of 67 
 
 
Version 4.0 | Version 2023-07-04 
o At least 2 of the following signs and symptoms of VVC that are characterised 
as at least moderatea: itching, burning, irritation, oedema, erythema, or 
excoriation. 
o KOH or saline preparation from the inflamed vaginal mucosa or secretions 
revealing yeast forms (hyphae or pseudohyphae) or budding yeasts. 
4. 
Negative urine pregnancy test at Screening. 
5. 
Refrain from using any intravaginal products (i.e. contraceptive creams, gels, foams, 
sponges, lubricants, or tampons, etc.) until Day 14. 
6. 
Refrain from sexual intercourse or use a condom until Day 7. 
7. 
Signed informed consent and willing and able to comply with all study requirements. 
6.4 Exclusion criteria 
1. 
Patients with known or apparent signs of other infectious causes of vaginal infection 
(BV, Trichomonas vaginalis, Neisseria gonorrhoeae, Chlamydia trachomatis, Herpes 
simplex, or human papillomavirus) at Screening. 
2. 
Patients who are pregnant or breastfeeding. 
3. 
Patients who were treated for VVC within 14 days prior to Screening. 
4. 
Patients who are currently receiving anti-fungal therapy unrelated to VVC or has taken 
anti-fungal therapy within 14 days prior to Screening. 
5. 
Patients who have received an investigational drug in a clinical investigation within 
30 days prior to Screening. 
6. 
Known/previous allergy or hypersensitivity to any product constituent or fluconazole. 
7. 
Any medical condition that in the Investigator’s judgements would make the patient 
unsuitable for inclusion. 
8. 
More than 3 previous VVC infections during the last 12 months. 
6.5 Restrictions 
During the study, the following medications are not allowed and should be avoided: 
1. 
Anti-fungal medication related to VVC. 
2. 
Other treatments for VVC (e.g. probiotics like Candicur and Multigyn). 
Also see further information on rescue medication in Section 7.5.2 and prior and concomitant 
medications in Section 8.4. 
6.6 Withdrawal of patients and termination of the investigation 
 
Withdrawal from study and termination criteria 
Patients shall be informed by the Investigator and through the ICF about their rights to 
withdraw their participation in the study at any time and for whatever reason without affecting 
 
a scoring scale: 
0 = none (absent) 
1 = mild (slight) 
2 = moderate (definitely present) 
3 = severe (marked, intense) 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 35 of 67 
 
 
Version 4.0 | Version 2023-07-04 
their right to an appropriate follow-up investigation. If possible, the reason for withdrawal 
should be documented. 
The Investigator may, at his or her discretion, withdraw a patient from the study and/or 
discontinue study treatment and assessments at any time. The specific reasons for 
discontinuing a patient from the treatment or the study shall be documented in the eCRF. 
 
Reasons for treatment discontinuation or withdrawal from the study  
Reasons for a patient to discontinue treatment or withdraw from study 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 from treatment if judged that an 
AE poses an unacceptable risk or consequence to the patient. 
 Medical reasons 
The Investigator may withdraw patients from the study 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 for study withdrawal  
Other reasons include but are not limited to failure of the patient to comply with study 
procedures or requirements. 
 
Procedure for withdrawal of a patient 
If a patient does not return for a scheduled follow-up visit, every effort should be made to 
contact the patient, to collect answers on the patient questionnaire and information on 
concomitant medications, vulvovaginal signs and AEs, if any (see Section 5.4.7 for more 
details). If possible, the reason for withdrawal should be sought and recorded in the eCRF.  
If the withdrawal from treatment is due to lack of clinical performance or for safety reasons of 
the investigational product, the patient will if possible continue to be followed-up in the study.  
If a withdrawal from the study occurs during a study visit, the eCRF for that specific visit 
shall be completed as far as possible. 
Any AE should be followed-up until the AE is resolved or the Investigator decides that the 
AE is stable and needs no further follow-up.  
If a patient is not prematurely withdrawn from the study, the last day for follow-up will be 
Day 25 (Visit 4).  

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 36 of 67 
 
 
Version 4.0 | Version 2023-07-04 
AEs ongoing at the last day for follow-up shall be assessed as chronic or stable. Wherever 
possible, other assessments should be carried out according to the CIP at the time of 
withdrawal. 
 
Procedure for discontinuation of treatment 
If a patient permanently discontinues treatment, the date and reason for discontinuation (if 
known) will be documented in the eCRF.  
After discontinuation of treatment in a patient, the patient will continue in the study and 
should be followed-up as described above (Section 6.6.3). 
 
Replacements 
Re-screening is allowed.  
Patients that are withdrawn or discontinued during the study will not be replaced or re-entered 
into the study. 
 
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, 
the Investigator will be informed of additional procedures to be followed to ensure that 
adequate consideration is given to the protection of the patient’s interest. Breaking of the 
treatment code (unblinding) will be performed and the Investigator will be informed.  
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, including give information 
regarding treatment received. The Sponsor should promptly inform the study site, and the 
RA/CA 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. 
7 TREATMENTS 
7.1 Treatment groups 
Patients in this study will receive the test product Gedea Pessary  
In the study, 26 patients will be treated with Gedea Pessary to be self-administered daily for 
6 days (Day 0 to Day 5).   
7.2 Identity of the investigational product 
 
Test product/Gedea Pessary 
The test product, Gedea Pessary (commercial name pHyph), is a Class IIb medical device 
according to MDR 2017/745, containing 150 mg GDL and 184 mg NaG.  
Gedea Pessary is a white, convex, bullet-shaped pessary, approximately 17 mm in length, to 
be administered vaginally with a CE-marked pessary applicator (Schägner GmbH, 
Steinmauern, Germany) (Figure 2 and  Figure 3).  

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 37 of 67 
 
 
Version 4.0 | Version 2023-07-04 
 
Figure 2 
Gedea Pessary and the Gedea Pessary blister package  
   
Figure 3 
Vaginal tablet applicator  
 
 
 
 
Manufacturing, packaging and labelling of investigational product 
Gedea Biotech AB is the responsible manufacturer of the investigational products (Gedea 
Pessary). Gedea Biotech AB has subcontracted production, packing, labelling and release 
testing of the clinical investigation material for use in the clinical investigation to Galenica 
AB (Malmö, Sweden). Batch release is performed by Gedea Biotech AB Quality Assurance 
Director. 
The investigational products will be packed in blister packs containing 6 pessaries packed 
together with 6 pessary applicators in a cardboard box (Figure 2 and Figure 3). The cardboard 
box will be labelled with “Gedea Pessary pHyph”, batch number, study number, package 
number, manufacturing date and expiry date. The label used in the study will be written in the 
local language. 
Labels will be prepared in accordance with good manufacturing practice (GMP), the Medical 
Devices Directive 93/42/EEC and local regulatory guidelines.  
 
Stability program 
The stability of Gedea Pessary pHyph pessaries has been evaluated and confirmed in a 
technical stability study at the conditions 25°C (up to 9 months, as of May 2021) and 40°C 
(up to 6 months) and in a clinical stability study, confirming stability up to 6 months at the 
conditions 25°C and 40°C. The stability program is planned up to 36 months, and extension 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 38 of 67 
 
 
Version 4.0 | Version 2023-07-04 
of shelf life will be done accordingly. For further information, refer to the Investigator’s 
Brochure (IB). 
 
Storage and handling of investigational products 
The investigational products Gedea Pessary will be stored at room temperature (15°C--25°C) 
and protected from direct sunlight or freezing. The investigational products must not be used 
outside of the study. For further information, refer to the IB.  
It is the responsibility of the Investigator to ensure that the investigational product is stored in 
its original packaging in a secure location with access only by authorised personnel, separate 
from other medications. The temperature should be noted daily (working days only unless 
automatic temperature readings are available).  
 
Doses and treatment regimens 
Each patient will self-administer a total of 6 doses of Gedea Pessary in the study. The pessary 
is slow-release formulated, administering 150 mg GDL and 184 mg NaG, over 24 hours.  
The pessary will be self-administered vaginally by the patient at night, before going to bed. 
Instructions for use will be distributed at the first visit, advising patients on how to use the 
product together with the applicator. The patients will also be trained by site personnel in how 
to use the product, no previous experience of use is needed.  
Briefly, patients will be instructed to wash their hands and vaginal area prior to use; place a 
tablet into the applicator and insert as far into the vagina 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.  
7.3 Investigational product accountability 
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 quantity at storage and deliveries to and from storage. 
Shipping records of investigational product deliveries from the manufacturer shall be kept at 
study sites, including at least the following information 
 Investigational product name and quantity received 
 Delivery date 
 Batch number 
 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 dispensed 
 Patient (patient number) receiving the investigational product 
 Number of units remaining in stock 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 39 of 67 
 
 
Version 4.0 | Version 2023-07-04 
Patients will be asked to return all used and not used treatment packages. 
Any non-functioning investigational products or applicators shall be documented. All 
returned, 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. 
7.4 Method of assigning patients to treatment groups 
Not applicable. 
7.5 Additional products and material 
 
Additional material  
The Sponsor will provide the study sites with study specific kits containing vaginal swabs for 
culture and sequencing of the vaginal microbiome. The kits will be developed specifically for 
the study and include all material needed as well as instructions and pre-paid envelopes where 
applicable. 
Study sites will provide pH-test strips and urine dipstick pregnancy tests (urinary human 
chorionic gonadotropin [U-HCG]). pH-test strips and urine dipsticks used as per clinical 
routine at the site may be used. 
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 
 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 
 Number of units remaining in stock 
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. 
 
Rescue medication 
On Days 7 and 14, patients having VVC symptoms of the same or higher intensity compared 
to the inclusion visit (Day 0), will be offered rescue treatment, if considered necessary. For 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 40 of 67 
 
 
Version 4.0 | Version 2023-07-04 
details on VVC symptom score see Section 9.1.2  Rescue treatment will be according to 
standard clinical routines, as described below. 
Patients will receive a prescription of fluconazole (50-150 mg as a single dose, orally) or 
Clotrimazole pessary (500 mg as a single dose, intra-vaginally) and if necessary, topical 
treatment with 1% clotrimazole or 1% clotrimazole/1% hydrocortisone. Rescue medication 
will not be provided by the Sponsor, however the Sponsor will reimburse the cost. 
In addition, patients with recurrence or persistent symptoms on Day 25 (i.e. symptoms 
recurred on Day 25) may also be offered rescue treatment, according to the standard clinical 
routines mentioned above. The site will decide whether a visit to the clinic is needed and if 
rescue medication should be prescribed. 
Patients taking rescue medications prior to the visit where clinical cure is assessed (Day 7 or 
Day 14), will be considered in the statistical analysis as described in Section 12. In general, 
these patients should stay in the study and continue to be followed-up.  
The use of any rescue medication will be recorded in the eCRF.  
7.6 Treatment compliance 
Patients will be asked about investigational product administration via the mobile application 
on each treatment day (Day 0 to Day 5).  
Vaginal pH assessments on Days 0 and 7 will be used as a measure of investigational product 
in vivo duration. If the vaginal pH on Day 7 is lower than the pH on Day 0, that would 
indicate appropriate release duration. It will be measured by site personnel on Day 0 and Day 
7.  
No other measurements of treatment compliance will be made. 
 
8 ASSESSMENTS 
The assessments performed during the study are described in the subsections below. 
For details on clinical performance assessments (gynaecological examination and patient 
questionnaire), see Section 9. For details on safety assessments (clinical laboratory 
assessments, AEs and device deficiencies), see Section 10. 
8.1 Informed consent 
The procedures used for screening and obtaining informed consent at Day 0 are described in 
Section 6.1. 
8.2 Demography 
Demographic information will be collected at Screening (Day 0) and will include initials, sex, 
birth date and ethnic origin (Caucasian, Asian or Pacific Islander, African descent, 
Mixed/multi-racial, or other).  
Full information about the patients’ Social Security Number or similar and name is to remain 
confidential in the records of the respective Investigator. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 41 of 67 
 
 
Version 4.0 | Version 2023-07-04 
8.3 Eligibility criteria 
Eligibility criteria should be checked during Screening (Day 0) and verified before 
enrollment. The criteria are specified in Sections 6.3 and 6.4. 
8.4 Prior and concomitant medications 
Information about any concomitant medication, including OTC medications and vitamins 
used by patients within 14 days prior to inclusion and during the study, shall be collected at 
all site visits (Day 0 and Day 14) for all patients and also at the telephone contacts (Day 7 and 
Day 25). The generic name or trade name, dosage and reason for use shall be recorded in the 
eCRF for all medications. 
NOTE:  
VVC-treatment or any anti-fungal therapy unrelated to VVC within 14 days prior to inclusion, 
is not allowed (see Section 6.4). 
During the study, anti-fungal therapy and other treatments related to VVC should be avoided 
(unless rescue treatment at Day 14) (see Section 6.5).  
See further information on rescue medication in Section 7.5.2. 
8.5 Medical and surgical history 
Medical and surgical history will be collected during the Screening visit (Day 0). It should be 
obtained by interview and include descriptions of all relevant medical conditions and 
procedures within 14 days prior to Screening, as judged by the Investigator. 
The number of previous VVC infections during the last 12 months prior to inclusion, should 
be noted, according to exclusion criterion #8 (see Section 6.4).  
Relevant pre-treatment events (pre-treatment AEs) occurring between the signing of ICF and 
first administration of the investigational product will be registered in the medical history log 
of the eCRF.  
8.6 Pregnancy test  
All study patients will perform a pregnancy test (urine dipstick) at Screening (Day 0).   
Pregnancy is an exclusion criterion (see Section 6.4). If pregnancy is confirmed in a patient 
during the study, the patient will be withdrawn, and the pregnancy will be followed (see 
Section 10.4). 
8.7 Menstruation 
The Investigator or delegee will ask about onset and end of last menstruation on the Day 0 
visit, and ask for possible menstruation onset on Day 7, Day 14 the Day 25. Intermittent 
bleeding should also be possible to register in the eCRF as AE. 
8.8 Administration of investigational product 
For details on the administration procedures, see Section 7.2.5. 
For restrictions during the treatment period, see Section 6.5. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 42 of 67 
 
 
Version 4.0 | Version 2023-07-04 
9 CLINICAL PERFORMANCE 
9.1 Clinical performance assessments 
Assessments described in Section 9.1.1 will be used to diagnose VVC.  
A CVVS score will be used for assessment of the primary endpoint, clinical cure on Day 7-14 
(see Section 4.1.1). 
Further, the CVVS score will also be used for assessment of the secondary endpoints 2, 3 and 
6 (see Section 4.2.1). 
Assessments described in Section 9.1.2, patient questionnaire, will be used to assess the 
secondary endpoints 4 and 10 (see Section 4.2.1). 
 
Gynaecological examination 
Patients will undergo a gynaecological examination by the Investigator or an authorised 
designee at the site visits (on Day 0, Day 7 and Day 14), in order to assess: 
 Vulvovaginal symptoms (assessed by the patient): Vulvovaginal symptoms 
(itching, burning, and irritation) will be assessed by patients themselves according to a 
scoring scale (0-3) as per the patient questionnaire, on Days 0 to 6, Day 11 and Day 25 
(see Section 9.1.2).  
 VVC diagnosis (assessed by the Investigator or designee): The diagnosis is based 
on CVVS score and microscopic analysis of a KOH or saline preparation, during the 
site visits (Day 0, Day 7 and Day 14). The assessments will be recorded in the eCRF. 
The diagnosis criteria are the following. 
o Having a white or creamy vaginal discharge  
o At least 2 of the following signs and symptoms of VVC that are characterised 
as at least moderatea: itching, burning, irritation, oedema, erythema, or 
excoriation. 
o KOH or saline preparation from the inflamed vaginal mucosa or secretions 
revealing yeast forms (hyphae or pseudohyphae) or budding yeasts. 
For definition of clinical cure Section 4.1.1. 
 
Patient questionnaire 
The patient questionnaire can be found in Appendix 1. 
The patient questionnaire is relating to VVC symptoms (itching, burning, and irritation) and 
pessary administration. Questionnaire should be filled in via the mobile application 
ViedocMe™ (see Section 11.1.2) on Days 0 to 6, Day 11 and Day 25. 
Questions about usability should be filled in by all patients on Day 6. 
 
a scoring scale: 
0 = none (absent) 
1 = mild (slight) 
2 = moderate (definitely present) 
3 = severe (marked, intense) 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 43 of 67 
 
 
Version 4.0 | Version 2023-07-04 
10 SAFETY AND TOLERABILITY ASSESSMENTS 
Assessments described in Section 10.1, will be used to assess the secondary endpoints 7, 8, 
and 9 (see Section 4.2.1) and the two exploratory endpoint (see Section 4.3.1). 
Assessments described in Section 10.2, AEs will be used to assess the secondary 
endpoint 1 (see Section 4.2.1). 
10.1 Clinical laboratory evaluation 
 
Vaginal swab samples 
Vaginal samples will be collected via a vaginal swab by the Investigator or delegee on site 
visits (Day 0, Day 7 and Day 14) or by patients themselves at home, on Day 25. For the 
testing made at home, labelled swabs will be given to the women who then will do the testing 
as per provided instructions. The swabs for vaginal culture will need to be sent for analysis to 
ensure receipt by the lab within 48 hours. Swabs for sequencing of the vaginal microbiome 
can be stored in ambient temperature for a month. These samples will be gathered and stored 
in < -70°C until analysis at the end of the study. 
The collected samples will be used for the following analyses. 
 Microscopic analysis; presence of hyphae: KOH or saline preparations for fungus, 
using samples collected on Day 0, Day 7 and Day 14. Briefly, vaginal samples will be 
covered with 10% to 20% KOH or 0.9% isotonic NaCl solution and inspected under a 
microscope. Presence of hyphae indicates Candida and will serve as an immediate, 
preliminary VVC diagnosis. 
 Candida culture: Samples collected on Days 0, 7, 14 and 25, will be sent to 
laboratory for culture and confirmation of the VVC diagnosis/mycological cure. 
 Sequencing of the vaginal microbiome: Vaginal swabs for sequencing of the vaginal 
microbiome will be collected on Days 0, 7, 14, and 25. On Days 0 and 7, the swabs 
will be taken in duplicates. 
The effects of the investigational product on the vaginal microbiome will be assessed. 
Collected samples will be sent to a central laboratory for assessment of bacterial and 
fungus species, through DNA sequencing. 
Samples sent to the central laboratories will be coded with no possibility to identify the 
patients, and all samples will be destroyed directly after the analysis has been completed.  
Samples that are analysed at the investigational site will be destroyed directly after analysis. 
No samples will be kept for future research. 
 
Vaginal pH 
Patients’ vaginal pH will be assessed on Day 0 and on Day 7 by the Investigator or delegee 
using a pH-test strip.  
Vaginal pH will be used for assessments of investigational product in vivo duration. If the 
vaginal pH on Day 7 is lower than the pH on Day 0, that would indicate appropriate release 
duration. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 44 of 67 
 
 
Version 4.0 | Version 2023-07-04 
10.2 Untoward medical events and AEs 
 
Adverse event 
An AE is any untoward medical occurrence, unintended disease or injury, or any untoward 
clinical signs including abnormal laboratory findings in patients, users or other persons, in the 
context of a clinical investigation, whether or not related to the investigational device. 
Note:  
a. This definition includes events that are anticipated as well as unanticipated events.  
b.  This definition includes events occurring in the context of a clinical investigation-related to 
the investigational device, the comparator or the procedures involved. 
 
Adverse device effect 
An adverse device effect (ADE) is an AE related to the use of an investigational medical 
device. 
NOTE 1 This includes any AE resulting from insufficiencies or inadequacies in the 
instructions for use, the deployment, the implantation, the installation, the 
operation, or any malfunction of the investigational medical device. 
NOTE 2 This includes any event that is a result of a use error or intentional abnormal use of 
the investigational medical device. 
The following events are not considered untoward medical events/AEs: 
 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. 
 Conditions or diseases known when the patient signs the ICF, are not considered 
untoward medical events AEs. These will be registered in the medical history eCRF 
page. 
 
Serious Adverse Events 
A SAE is an AE that led to any of the following: 
a) Death, 
b) Serious deterioration in the health of the subject that resulted in any of the following: 
 Life-threatening illness or injury 
 Permanent impairment of a body structure or a body function 
 Hospitalisation or prolongation of patient hospitalisation 
 Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function 
 Chronic disease 
c) Foetal distress, foetal death or a congenital physical or mental impairment or birth 
defect. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 45 of 67 
 
 
Version 4.0 | Version 2023-07-04 
NOTE: Planned hospitalisation for a pre-existing condition, or a procedure required by the 
current CIP, without serious deterioration in health during the course of the study, 
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. 
An 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.  
SAEs related to procedures imposed by the CIP but not with the use of the device should not 
be considered Serious Adverse Device Effects. 
 
The classification of an untoward medical event as USADE or ASADE will be done 
retrospectively. The event will initially be captured as an SAE. 
 
Definitions of adverse event ratings 
 Severity/intensity 
Untoward medical events/AEs will be rated according to their severity/intensity. The 
following rating will be done by the Investigator: 
Mild: 
Transient symptoms, no interference with daily activities of the participant. 
Moderate: Clear symptomatology that moderately affects the daily activities of the 
participant. 
Severe: 
Symptoms that clearly affects or hinders daily activities of the participant. 
 Causality assessment/relatedness 
The relationship between the use of the medical devicea (including the medical - surgical 
procedure) and the occurrence of each AE shall be assessed and categorised.b During 
causality assessment activity, clinical judgement shall be used and the relevant documents, 
such as the IB, the CIP or the Risk Analysis Report shall be consulted, as all the foreseeable 
SAEs and the potential risks are listed and assessed there. The presence of confounding 
factors, such as concomitant medication/treatment, the natural history of the underlying 
disease, other concurrent illness or risk factors shall also be considered. The above 
considerations apply also to the SAEs occurring in the comparison group. 
 
a Intended as both medical device investigated in the investigation and comparator. 
b Procedure related events refers to the procedure related to the initial application of the investigational 
medical device only and therefore not to any other procedures or treatments applied later throughout 
the clinical investigation, for instance to treat AEs. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 46 of 67 
 
 
Version 4.0 | Version 2023-07-04 
For the purpose of harmonising reports, each SAE will be classified according to 4 different 
levels of causality. The Sponsor and the Investigators will use the following definitions to 
assess the relationship of the SAE to the investigationala medical device or procedures: 
Not related: 
Relationship to the device, comparator or procedures can be excluded 
when: 
 the event has no temporal relationship with the use of the 
investigational device, or the procedures related to application of 
the investigational device; 
 the SAE 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 SAE; 
 the event involves a body-site or an organ that cannot be affected by 
the device or procedure; 
 the SAE 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 diagnosis, when applicable; 
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 SAE. 
Possible: 
The relationship with the use of the investigational device or comparator or 
the relationship with study procedures 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 assessed or no information 
has been obtained should also be classified as possible. 
Probable: 
The relationship with the use of the investigational device or comparator or 
the relationship with study procedures seems relevant and/or the event 
cannot reasonably be explained by another cause. 
Causal 
relationship: 
The SAE is associated with the investigational device or comparator 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; 
 
a Investigational device: any device object of the clinical investigation, including the comparators.   

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 47 of 67 
 
 
Version 4.0 | Version 2023-07-04 
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 patient 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. 
 
The Sponsor and the Investigators will distinguish between the SAEs related to the 
investigational device and those related to the procedures (any procedure specific to the 
clinical investigation). An AE can be related both to the procedures and the investigational 
device. Complications of procedures are considered not related if the said procedures would 
have been applied to the patients also in the absence of investigational device use/application. 
In some particular cases the event may be not adequately assessed because information is 
insufficient or contradictory and/or the data cannot be verified or supplemented. The Sponsor 
and the Investigators will make the maximum effort to define and categorise the event and 
avoid these situations. Where the Sponsor remains uncertain about classifying the serious 
event, it should not exclude the relatedness and classify the event as “possible”. 
Particular attention shall be given to the causality evaluation of USADE. The occurrence of an 
USADE could suggest that the clinical investigation places patients at increased risk of harm 
than was to be expected beforehand. 
 Outcome 
The outcome or the result of the untoward medical event/AE for a participant will be rated by 
the Investigator as; 
 
 
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. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 48 of 67 
 
 
Version 4.0 | Version 2023-07-04 
Recovered/ 
resolved: 
Fully recovered spontaneously or after medical or surgical intervention, i.e. 
the status is the same as the pre-study status. 
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. 
 
Capturing and reporting of untoward medical events/AEs 
Patients will be asked about AEs or events related to the investigational device and/or 
procedure at all site visits and telephone contacts.  
Questions to be asked: 
 Have you experienced any health problems since the last visit/telephone contact? 
 Has there been any event related to the investigational device or procedure? 
AEs can also be obtained from: 
 Signs and symptoms from patient examinations. 
 Laboratory values. 
 Spontaneous reports by patients or their relatives. 
All AEs and ADEs, will be captured in the forms for AEs or device events in the eCRF. In 
case of a serious event, SAE, SADE or USADE will be recorded in the respective form as 
applicable. 
All events fulfilling the definition of an 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.  
Relevant pre-treatment events (pre-treatment AEs) occurring between the signing of ICF and 
first dose will be registered in the medical history log of the e-CRF.  
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. 
 
Reporting of SAEs 
The Investigator will report any SAE or device deficiency that might have led to a SAE (see 
below) to the Sponsor authorised representative immediately but not later than within 
24 hours after awareness that the event has occurred by completing the SAE eCRF pages. 
If the eCRF is unavailable, an initial paper SAE report form may be used and sent to Sponsor 
authorised representative (device_sae@ctc-ab.se), however the SAE must be registered in the 
eCRF as soon as the eCRF is functioning. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 49 of 67 
 
 
Version 4.0 | Version 2023-07-04 
Applicator device deficiencies that caused a SAE or might have led to a SAE have to be 
reported by the Sponsor to the manufacturer of the CE-marked applicator. All other further 
reportable events according to MDR 2017/745 have to be reported by the Sponsor/authorised 
representative to the National Competent Authority where the event occurred using a 
summary SAE tabulation (Summary Reporting Form, MDCG 2020-10/1). 
The following events are considered reportable: 
a) Any SAE that has a causal relationship with the investigational device, the 
comparator or the investigation procedure or where such causal relationship is 
reasonably possible; 
b) Any device deficiency that might have led to a SAE if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less 
fortunate; 
c) Any new findings in relation to any event referred in points a) and b). 
In case of SADEs and device deficiencies that could have led to an SAE, the Sponsor shall 
determine whether the risk analysis needs to be updated and assess whether corrective or 
preventive action is required. 
 Reporting to national competent authorities 
The reporting of events to the national competent authorities must follow these reporting 
timelines: 
 All reportable events as described in section 10.2.6 which that indicate an imminent 
risk of death, serious injury, or serious illness and that requires prompt remedial action 
for other patients/subjects, users or other persons or a new finding to it: immediately, 
but not later than 2 calendar days after awareness by the Sponsor of a new 
reportable event or of new information in relation with an already reported event. 
This includes events that are of significant and unexpected nature such that they 
become alarming as a potential public health hazard. It also includes the possibility of 
multiple deaths occurring at short intervals. 
 Any other reportable events as described in 10.2.6 or a new finding/update to it must be 
reported immediately, but not later than 7 calendar days following the date of 
awareness by Gedea Biotech AB of the new reportable event or of new information in 
relation with an already reported event. 
 Reporting to Investigators 
The Sponsor is responsible for informing in writing all Principal Investigators. This reporting 
is applicable for all the events outlined in section 10.2.6.1 above and will be made on ongoing 
basis. 
 
Follow-up of untoward medical events/AEs 
Any AE that is ongoing when the patient withdraws 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.  

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 50 of 67 
 
 
Version 4.0 | Version 2023-07-04 
The last day for follow-up will be Day 25.  
AEs ongoing at the last visit shall be assessed as chronic or stable. 
10.3 Device deficiencies 
The below is applicable both for the Gedea Pessary and the applicator. 
Patients will be asked about events related to the investigational device and/or procedure at 
the Day 7 visit. 
A device deficiency will, in this study, be defined as an inadequacy of an investigational 
medical device related to its identity, quality, durability, reliability, safety or performance, 
including malfunction, use errors or inadequacy in information supplied by the manufacturer. 
Inadequacy of device safety refers to properties of the device that could have or have led to an 
AE. 
All device deficiencies shall be documented in the form for device events in the eCRF. The 
information recorded will include a description of the device deficiency as well as information 
about whether there was any injury to the subject or user as a result of the deficiency. If an 
injury occurred, an AE or SAE should also be recorded in the eCRF.  
If no SAE occurred as a result of the device deficiency, the Investigator shall assess whether 
or not the device deficiency could have led to an SAE if: 
a) suitable action had not been taken 
b) treatment/intervention had not occurred 
c) circumstances had been less fortunate 
The Sponsor will also review all device deficiencies during the investigation and determine 
and document in writing whether they could have led to an SAE.  
If the Investigator or the Sponsor judges that the device deficiency could have led to an SAE, 
the device deficiency will be subject to similar safety reporting procedures as for SAEs, 
described in applicable sections above. 
If necessary, the device deficiencies seen will be categorised at the database lock meeting. 
 
10.4 Pregnancy 
Patients must be instructed to immediately inform the Investigator if any pregnancy should 
occur from the time of signing the ICF and during the study period. Any confirmed pregnancy 
in a study patient 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 authorised 
representative (device_sae@ctc-ab.se).  
Patients becoming pregnant will be withdrawn from the study and followed until delivery and 
additional information on the infant will be collected until the infant is 1 month old. The 
outcome of the pregnancy must be reported on a Pregnancy Report Form.  

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 51 of 67 
 
 
Version 4.0 | Version 2023-07-04 
AEs in connection with the pregnancy, in the foetus, 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, foetus and infant fulfilling any criteria for seriousness. Procedures and timelines 
for AE/SAE reporting applies to reporting of AEs/SAEs in the pregnant patient, the foetus and 
the infant. 
11 DATA MANAGEMENT 
Data management refers to the activities defined to achieve safe routines to efficiently enter 
patient information into a database, avoiding errors. 
Customised data management system will be developed for this study using Viedoc™ 
software, owned, developed and maintained by Viedoc Technologies AB. Information entered 
into the data entry system will be by patient study identification number; names will not be 
linked with patient data in the database. Study sites will maintain records in secure areas 
linking the patient name with the identification number assigned for the study. Study sites will 
have full access to their own data and be able to view these data remotely. Study staff will not 
be able to view patient data associated with other sites. The software is designed to be 
compliant with Title 21 Code of Federal Regulations Part 11. 
Clinical Trial Consultants will provide the data management services for this study. The data 
management routines include procedures for handling of eCRF, database set-up and 
management, data entry, data verification and validation (quality control of the database), and 
documentation of the performed activities, including information of discrepancies in the 
process. Further details of the data management services and processes will be described in 
the Data management plan. The eCRF/data entry screens, and the database/programs will be 
designed in accordance with the CIP and  Clinical Trial Consultants standard operating 
procedure (SOP) system. 
11.1 The web-based case report form 
Clinical data (including AEs and concomitant medications) will be entered into the 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. 
Authorised study site personnel designated by the Investigator will complete data collection. 
Appropriate training and security measures will be completed with the Investigator and all 
authorised 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 entering of data into the electronic case report form 
The eCRF is essentially considered a data entry form and should not constitute the original (or 
source) medical records unless otherwise specified. Source documents are further described in 
Section 13.3. 
All data must be entered in English. The eCRFs should always reflect the latest observations 
on the patients participating in the study. Therefore, the eCRFs should be completed as soon 
as possible during or after the patient’s visit.  

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 52 of 67 
 
 
Version 4.0 | Version 2023-07-04 
To avoid inter-observer variability, every effort should be made to ensure that the same 
individual who made the initial baseline determinations completes all corresponding 
follow-up evaluations. 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. 
 
Electronic patient reported outcomes 
The patients themselves will record data using an ePRO system, a mobile application, 
ViedocMe™, linked to the eCRF system Viedoc™. ViedocMe™ is provided as a Software as 
a Service (SaaS) application. The ePRO includes password protection and internal quality 
checks. Text reminders will be sent to the patient through the ePRO. All data registered in the 
ePRO is stored together with the eCRF data. 
The data from the ePRO system are stored exactly the same way as the rest of the patient data 
in the eCRF Viedoc™, with the same security and control. Only authorised personnel with 
provided access to the system will be able to review the data.  
The data entered in the ePRO system will be sent encrypted into the eCRF. No data are ever 
stored locally on the patient’s device.  
Each patient will receive a unique user name and PIN code for their ePRO account. Once 
generated, the site personnel will not be able to see the PIN code. The patient’s telephone 
number and email address connected to their user account will also always be encrypted. 
Email address and telephone number are not possible to extract from the ePRO once entered 
and the site personnel cannot see these. Only the participating patient can change this 
information within their own user account. The telephone number and email will not be 
possible to link to the patient data. 
The data entered by the patient in the ePRO system cannot be changed without the patient’s 
consent.  
 
 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 authorised designee. The Monitor cannot enter data in the eCRFs.  
Once 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. This will be audit trailed by the electronic data capture 
application meaning that the name of study personnel, time, and date are logged. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 53 of 67 
 
 
Version 4.0 | Version 2023-07-04 
 
Signing of data 
The eCRF 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.  
 
Audit trail and database lock 
All changes in the eCRF 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, including all queries are solved, 
medical coding approved and SAE reconciliation performed, the database will be locked to 
prevent any further changes in the clinical study data. 
11.2 Medical coding 
Before database lock, medications will be coded according to the WHO anatomical 
therapeutic chemical (ATC) classification system (ATC-index). 
Medical history and AEs will be coded using the medical dictionary for regulatory activities 
(MedDRA). 
12 STATISTICAL METHODS AND PLANNED ANALYSIS 
The principal features of the statistical analysis of the data are described in this section. More 
details of the planned statistical analysis will be provided in a separate statistical analysis plan 
(SAP) that will be finalised prior to database lock. Any deviations from the planned statistical 
analysis will be documented in the CIR. 
The statistical planning, analysis and reporting work will follow CTC’s SOP system. All 
analyses described below will be performed using SAS (Version 9.4 or higher, SAS Institute 
Inc., Cary, NC, USA)54.  
12.1 Statistical analysis; data presentation 
Continuous data will be summarised using descriptive statistics, where the following 
parameters will be reported: number of evaluable and missing observations, mean and 
standard deviation, median, quartiles, and extreme values (minimum and maximum). 
Categorical data will be presented as absolute and relative frequencies. 
All tests will be two-sided and performed at the 5% significance level unless stated otherwise. 
Baseline will be the last non-missing value prior to treatment if not stated otherwise. 
12.2 Analysis data sets and populations 
The full analysis set (FAS) is defined as all patients who received at least 1 treatment dose. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 54 of 67 
 
 
Version 4.0 | Version 2023-07-04 
The per protocol analysis Set (PPAS) is a subset of the FAS and consists of patients who 
sufficiently complied with the CIP. Criteria for inclusion in the PPAS will be specified in the 
SAP. 
All clinical performance analyses will be performed on both the FAS and the PPAS. The 
analyses performed on the FAS are to be considered as main and the analyses performed on 
the PPAS as supportive. 
The safety analyses will be performed on the FAS.  
12.3 Demographic, other baseline characteristics, prior and concomitant 
medications and compliance 
The disposition of patients, demographic data and relevant baseline characteristics (including 
medical and surgical history and menstruation data), as well as prior and concomitant 
medication will be presented descriptively. 
Medical history will be coded according to MedDRA and will be presented by system organ 
class (SOC) and preferred term (PT) as part of the baseline data. 
Prior and concomitant medications will be coded using WHO ATC-index and summarised by 
ATC Class.  
Treatment compliance data will be presented descriptively. For details on compliance 
assessment see Section 7.6 
12.4  Primary and secondary endpoints analysis 
 
Estimand consideration 
The study estimands will be defined based on the 5 attributes listed in the ICH E9 (R1) 
guideline: 
*The treatment. See Sections 7.1 and 7.2 above. 
*The population. See study inclusion and exclusion criteria in Sections 6.3 and 6.4, and the 
description of the main analysis set populations that will be used in Section 12.2. 
*The endpoint. The final endpoints are defined in Sections 12.4.2 and 12.4.3. When the 
composite strategy has been used to account for the identified intercurrent events, the 
intercurrent events have been incorporated into the final endpoint definition, see further 
information below in Sections 12.4.2 and 12.4.3. 
*Other intercurrent events. In this study, the strategy for addressing intercurrent events has 
been chosen to be built into one of the other attributes, namely the endpoint attribute, i.e. the 
composite strategy has been applied to the identified intercurrent events.  
*Population-level summary of the endpoint. This is described in Section 12.4.2.  
 
Primary endpoint analysis  
In the estimand setting, the primary endpoint will, in addition to the definition stated in 
Section 4.1.1, take the following identified intercurrent events into account: 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 55 of 67 
 
 
Version 4.0 | Version 2023-07-04 
1. Concomitant anti-fungal therapy or other treatments related to VVC due to lack of 
clinical performance prior to CVVS evaluation used for the primary endpoint 
definition. 
2. Treatment discontinuation due to lack of clinical performance. 
3. Rescue medication prior to the CVVS evaluation used for the primary endpoint 
definition. 
Applying the composite strategy to account for these intercurrent events, these have been 
incorporated in the endpoint definition. Thus, to be defined as clinically cured on Day 7-14, 
the patient needs to have the last available CVVS score equal to or below 3 at Day 7-14, and 
that none of the above stated intercurrent events have occurred. If the CVVS score is above 3, 
or any of the intercurrent events has occurred, the patient is defined as not clinically cured on 
Day 7-14. 
Patients with missing CVVS score at Day 7-14 and no intercurrent events will be considered 
as missing in the analysis. 
The primary endpoint clinical cure rate on Day 7-14, as defined in the section will be 
calculated and presented together with a one-sided 95 % CI based on the Wilson score.  
The primary performance objective of the trial is to show that the clinical cure rate is above 
30 %, i.e. to show that the lower limit of the one-sided 95 % CI for the observed cure rate is 
above 30 %. 
Hypotheses for the primary clinical performance endpoint 
Null hypothesis: Clinical cure rate is less than or equal to 30 %.  
Alternative hypothesis (one-sided): Clinical cure rate is above 30 %.  
 
Sensitivity analyses to evaluate the effect of missing data for any of the 6 individual 
vulvovaginal signs and symptoms scores included in the CVVS score will be performed. 
Details on the sensitivity analyses will be described in the SAP. 
 
Secondary endpoints analysis 
 Adverse events 
An overview of all AEs, including SAEs, intensity, relationship to the investigational product, 
and deaths, will be presented by SOC and PT according to MedDRA. 
Incidence of AEs and SAEs will be presented by SOC and PT. AEs will also be presented by 
intensity and relationship to IMP. 
For all summaries of AEs, the number and percentage of patients, as well as the number of 
events will be presented. 
 Performance endpoints 
All secondary clinical performance endpoins will be presented with descriptive statistics. The 
following binary secondary clinical performance endpoints will show the endpoint estimate 
together with a two-sided 95% CI based on the Wilson score.   
 Proportion of patients having a continued clinical response to treatment at Day 25, 
defined as the proportion of patients clinically cured on Day 7-14 (taking into account 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 56 of 67 
 
 
Version 4.0 | Version 2023-07-04 
the intercurrent events and applying the composite strategy as described in Section 
12.4.2) and thereafter responding “no” to the yes/no question, “Have the symptoms 
recurred?” and no rescue medication has been given up to day 25 
 Proportion of patients having a cure defined as clinical cure Day 7-14 according to 
primary endpoint (taking into account the intercurrent events and applying the 
composite strategy as described in Section 12.4.2) and mycological cure at Day 7-14 
(culture negative for growth of Candida species). 
 Proportion of patients having a reduction in CVVS score on Day 7-14 compared to 
Day 0.  
 Proportion of patients having a reduction in the sum of the 3 vulvovaginal symptoms 
scores (itching, burning, and irritation) on Days 1 to 7, Day 11, Day 14 and Day 25, 
compared to Day 0. 
 Proportion of patients having a mycological cure as assessed by vaginal culture on 
Day 7-14 and Day 25. 
 Proportion of patients having an absence of Candida hyphae in the wet smear on 
Day 7-14. 
Presentation of the continuous secondary clinical performance endpoints below will include 
the two-sided 95% CIs for the arithmetic mean. 
 The change in CVVS score from Day 0 to Day 7-14 (last available assessment).. 
 Change in the sum of the 3 vulvovaginal symptoms scores (itching, burning, and 
irritation) to each post baseline assessment. 
Usability will be measured on Day 7, by a patient questionnaire (see Appendix 1). The 
questionnaire contains 4 specific yes/no (i.e. binary) variables, and the question, “How do you 
generally regard the treatment?”, rated on a 1-10 integer scale. These endpoints will be 
presented descriptively, treating the question as a continuous variable.  
12.5 Exploratory endpoints analysis 
The analysis of the two exploratory endpoints (see Section 4.3.1) will be described in the 
SAP. 
12.6 Sample size determination 
Assuming a true proportion of 54% clinically cured in the treated group a sample size of 24 
patients is needed to obtain 80% power to show that the one-sided 95% CI for the clinical 
cure rate is above 30%. To compensate for patients with missing data a total of 26 patients 
will be included.  
In the previous Gedea VVC study, a clinical cure rate of 41% was seen.50 By using a new 
formulation, pHyph gen II, in the CL4 study, a higher cure rate is expected. The data from 
CL1 indicates that for a large number of patients, the pessary did not stay in the vagina and/or 
did not resolve properly.50 Taken these problems into account when changing the formulation, 
it is estimated that a cure rate of 54% can be achieved. Other treatments have shown a clinical 
cure rate of between 50 and 87% but a somewhat lower cure rate for pHyph gen II is 
acceptabel due to its dual high clinical cure for BV, high safety profile, and for the OTC 
market the medical device is intended for.17,18,56, 57 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 57 of 67 
 
 
Version 4.0 | Version 2023-07-04 
 
13 STUDY MANAGEMENT 
The Sponsor Gedea Biotech AB has delegated the following tasks to CTC, whose SOP 
system will be followed. 
 Study management, including examining and assessment of investigational sites, 
institutions and medicl device storage facilities (including all data and documents 
related to the investigation) and monitoring (further described in the below sections). 
 Setting up and maintaining the Trial master file. 
 Medical writing, including preparation of the CIR.  
 Device vigilance and handling of safety events in accordance with local requirements 
(see Section 10.2). 
 Data management, including cleaning of the database (eCRF) and data validation 
(see Section 11). 
 Biostatistics, including programming, preparation of listings, tables and figures and 
quality check of statistical analysis (see Section 12). 
13.1 Clinical monitoring 
Before the initiation of the investigation, the study Monitor will: 
 Determine the adequacy of the facilities. 
 Discuss with the Investigator and site personnel (as applicable) their responsibilities 
with regard to MDR, ISO14155, CIP adherence and local regulations. 
At an initiation meeting, the Monitor will review the investigation procedures with the 
Investigator and the Investigator’s staff and document this in compliance with the ISO 
14155 Guidelines. 
During the investigation, the Monitor will have regular contacts with the investigational 
site, including site visits to: 
 Provide information and support to the Investigator and staff. 
 Confirm that facilities remain acceptable. 
 Confirm that the study team is adhering to the CIP.  
 Confirm that data are being accurately recorded in the eCRF. 
 Ensure that accountability checks for the investigational products are being performed. 
 Conduct source data verification, which will require direct access to all original 
records for each patient (e.g. Medical records). 
The Monitor will be available (by phone and email) between visits whenever the Investigator 
or other personnel at the site needs information, advice or help. The frequency of the 
monitoring visits per site will be determined through a risk-based approach depending on 
recruitment rate, observed data quality and overall site performance. Initiation visits and 
monitoring visits may be performed remotely. 
All documentation and correspondence pertaining to the study (raw data, letters etc.) should 
be kept in accordance with ISO 14155. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 58 of 67 
 
 
Version 4.0 | Version 2023-07-04 
13.2 Training of staff 
A delegation log will be completed for each investigational site team member to indicate 
which activities the Investigator has authorised 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 before start of any study-related work in 
the study. The Investigator will also ensure that new information of relevance to the 
performance of this clinical investigation is forwarded to the staff involved. All training 
completed in the study will be documented in a training log.  
13.3 Patient records and source data 
Source documents are all documents used by the Investigator or hospital that relate to the 
patient’s medical history, that verifies the existence of the patient, the inclusion and exclusion 
criteria, and all records covering the patient’s participation in the study. They include 
laboratory notes, memoranda, material dispensing records, patient files, etc. The origin of 
source data in the investigation will be further specified in a separate document (Origin of 
source data form). 
The Investigator is responsible for maintaining source documents. These will be made 
available for inspection by the Monitor at each monitoring visit. The Investigator must submit 
a completed eCRF for each patient who signed the ICF. All supportive documentation 
submitted with the eCRF, such as laboratory or hospital records, should be clearly identified 
with the study ID and Patient Number. Any personal information, including the patient’s 
name, should be removed or rendered illegible to preserve individual confidentiality. 
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 
the patient.  
 All visits during the investigation period 
 All AEs/ADEs, SAEs/SADEs and device deficiences 
 Treatments and medications 
 The Investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data recorded in the eCRFs. 
13.4 Audits and inspections 
The purpose of an audit or inspection is to systematically and independently examine all 
study-related activities to document that they were conducted, recorded, analysed and 
accurately reported according to the CIP and the background regulatory demands. 
Audits or inspections may therefore be performed by authorised representatives of the 
Sponsor, by CTC or by a RA/CA at the investigational site during or after the investigation. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 59 of 67 
 
 
Version 4.0 | Version 2023-07-04 
These visits may include source data verification and confidentiality documents are therefore 
created. This implies that auditors/inspectors will have the right to inspect the investigational 
sites at any time during and/or after completion of the investigation and will have direct 
access to source documents, including patients’ medical records. By participating in this 
study, the Investigator agrees to this requirement. 
The Investigator should contact the Monitor immediately if they are contacted by a RA/CA 
about an inspection at their study site. 
13.5 Changes to the plan and ICF 
During the study, study procedures will not be changed without the mutual agreement of the 
Investigators and the Sponsor. Changes to the CIP and/or the ICF must be approved by the 
Sponsor, IEC and if applicable, the regulatory authority before implementation. In case of 
acute safety risks, changes may be implemented without prior approval. In this case any 
implemented change must be properly documented by the Investigator and the Sponsor must 
be immediately notified. 
If an amendment to the CIP substantially alters the study design, or increases the potential risk 
to the patients, the Investigator will be responsible to contact and inform all currently enrolled 
patients about this new information and obtain additional written informed consent This 
information must also be provided to new patients prior to their entry into the study. 
13.6 Deviations from the clinical investigation plan 
Deviations from the CIP should not occur. Investigators ascertain they will apply due 
diligence to avoid deviations to CIP. Under no circumstances should the Investigator contact 
Sponsor or Sponsors delegate to request approval of a protocol deviation, as no authorised 
deviations are permitted. If the Investigator feels a deviation would improve the conduct of 
the study this must be considered in an amendment to the CIP and unless such an amendment 
is agreed upon Sponsor and approved by the RA/CA and/or IEC (as applicable) it cannot be 
implemented. All significant deviations to the CIP will be recorded and reported in the CIR.  
However, the Investigator is expected to take any immediate action required for the safety of 
any patient included in this investigation, e.g. in case of an emergency, even if this action 
represents a deviation from the CIP. In such cases, Sponsor or Sponsors delegate should be 
notified of this action as soon as possible. Any deviation will be logged, including 
documentation of the reason and date for the deviation. If repeated violations or deviations 
occur, a corrective and preventive action procedure will be implemented, and the involved 
Investigator(s) may be disqualified for study participation.  
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 RA 
and/or IEC as applicable according to local laws and regulations, as soon as possible after the 
Sponsor has become aware of them. 
Deviations from the CIP that are due to the COVID-19 pandemic spread will be tracked 
separately and described in the CIR. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 60 of 67 
 
 
Version 4.0 | Version 2023-07-04 
13.7 Clinical investigation timelines 
The recruitment period is planned to proceed until 26 patients have been enrolled, where the 
intended first patient’s first visit is in Q1 2023 and the intended last patient’s last visit in 
Q4 2023. 
13.8 Declaration of end of investigation 
The end of the clinical investigation is defined as the last patient’s last visit. 
The RA/CA and the IEC will be informed that the clinical investigation has ended within 
90 days of the end of the investigation. If the investigation has to be terminated early, this 
period will be reduced to 15 days and the reasons will be clearly explained. 
13.9 Patient protection procedures 
 
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. 
 
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 authorised 
representatives of the investigational site, Sponsor, RA/CA 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. 
In case of any data breach, Gedea Biotech’s Data Protection Officer (DPO) should be 
contacted and informed of the data breach. An investigation (root cause analysis) of the data 
breach must be performed to establish the extent and impact of the breach and corrective 
action(s)/corrective action(s) will be initiated. The DPO will report the breach to the 
authorities. 
 
 
Patient confidentiality 
The patients have the right to request access to their personal data and the right to request 
rectification of any data that is not correct and/or complete. The Sponsor or designee 
personnel whose responsibilities require access to personal data agree to keep the identity of 
each patient confidential.  
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 ICF 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 patients to give their consent not only to the participation in the study, but also to the 
processing of personal data.  

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 61 of 67 
 
 
Version 4.0 | Version 2023-07-04 
13.10 Insurance 
The Sponsor has arranged the appropriate product liability and clinical study insurance to 
cover the requirements of this clinical investigation (Chubb European Group SE). 
13.11 Reporting and publication 
A final CIR should be completed, even if the investigation is prematurely terminated. The 
report will be prepared by the Sponsor according to the MDR and ISO 14155-guidelines. The 
CIR will be completed within one year of the end of the clinical investigation or within three 
months of the early termination or temporary halt and will be submitted to the CAs in the 
countries where the study has been executed. The submission will be made according to local 
submission procedures.  
All publications and presentations must be based upon the CIR. 
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 
Sponsor has the right to use the results for registration, internal presentation and for 
promotion. 
The study and a summary of the study results will be made publicly available at 
www.ClinicalTrials.gov.  
13.12 Record retention 
The Investigator will retain copies of the records for at least 10 years after the investigational 
device has been placed on the market or longer if mandated by local requirements or specified 
in the clinical trial agreement. 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 patients’ medical records, signed CIP, copies of paper forms (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 the same as above-mentioned for records. Archiving of 
data are performed according to industry standards such as in PDF/A format. 
In addition, if the Investigator is no longer able to fulfil the role of Investigator (e.g. if he/she 
retires), a new Investigator will be appointed in consultation with the Sponsor. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 62 of 67 
 
 
Version 4.0 | Version 2023-07-04 
14 REFERENCES 
1. Allsworth JE, Peipert JF. Prevalence of bacterial vaginosis: 2001-2004 National Health and 
Nutrition Examination Survey data. Obstetrics and gynecology. 2007;109(1):114-120. 
2. Bilardi J, Walker S, McNair R, et al. Women's Management of Recurrent Bacterial Vaginosis 
and Experiences of Clinical Care: A Qualitative Study. PloS one. 2016;11(3):e0151794. 
3. Bradford LL, Ravel J. The vaginal mycobiome: A contemporary perspective on fungi in 
women's health and diseases. Virulence. 2017;8(3):342-351. 
4. 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. 1999;180 
(1 Pt 1):14-17. 
5. Glover DD, Larsen B. Relationship of fungal vaginitis therapy to prior antibiotic exposure. 
Infectious diseases in obstetrics and gynecology. 2003;11(3):157-160. 
6. 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. 
7. Bluestein D, Rutledge C, Lumsden L. Predicting the occurrence of antibiotic-induced 
candidal vaginitis (AICV). Family practice research journal. 1991;11(3):319-326. 
8. 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. 
9. 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. 
10. Dennerstein GJ, Ellis DH. Oestrogen, glycogen and vaginal candidiasis. Aust N Z J Obstet 
Gynaecol. 2001;41(3):326-328. 
11. Tarry W, Fisher M, Shen S, Mawhinney M. Candida albicans: the estrogen target for vaginal 
colonization. J Surg Res. 2005;129(2):278-282. 
12. 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. 
13. 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. 
14. Makanjuola, O., F. Bongomin, and S.A. Fayemiwo, An Update on the Roles of Non-albicans 
Candida Species in Vulvovaginitis. J Fungi (Basel), 2018; 4 (4). 
15. Workowski KA, Bolan GA, Centers for Disease C, Prevention. Sexually transmitted diseases 
treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1-137. 
16. 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. 
17. Mendling W, Brasch J, Cornely OA, et al. Guideline: vulvovaginal candidosis (AWMF 
015/072), S2k (excluding chronic mucocutaneous candidosis). Mycoses. 2015;58 
Suppl. 1:1-15. 
18. Martin Lopez JE. Candidiasis (vulvovaginal). BMJ clinical evidence. 2015; 2015:0815. 
19. 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. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 63 of 67 
 
 
Version 4.0 | Version 2023-07-04 
20. Sobel et al. Single oral dose fluconazole compared with conventional clotrimazole topical 
therapy of Candida vaginitis, Am J Obstet Gynecol. 1995, Apr;172 (4 Pt 1):1263-8 
21. Stein et al. Placebo-Controlled Trial of Itraconazole for Treatment of Acute Vaginal 
Candidiasis, Antimicrobial agents and Chemotherapy 1993;37(1):89-92. 
22. Osser. Treatment of candida vaginitis, Acta Obstet Gynecol Scand. 1991:70:73-78 
23. 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. 
24. Matheson A, Mazza D. Recurrent vulvovaginal candidiasis: A review of guideline 
recommendations. Aust N Z J Obstet Gynaecol. 2017;57(2):139-145. 
25. 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. 
26. Alsaad, A.M., Y.C. Kaplan, and G. Koren, Exposure to fluconazole and risk of congenital 
malformations in the offspring: A systematic review and meta-analysis. Reprod Toxicol, 
2015. 52: p. 78-82. 
27. Howley, M.M., et al., Fluconazole use and birth defects in the National Birth Defects 
Prevention Study. Am J Obstet Gynecol, 2016. 214(5): p. 657 e1-9. 
28. Molgaard-Nielsen, D., et al., Association Between Use of Oral Fluconazole During 
Pregnancy and Risk of Spontaneous Abortion and Stillbirth. JAMA, 2016. 315(1): p. 58-67. 
29. Donders G, Bellen G, Donders F, et al. Improvement of abnormal vaginal flora in Ugandan 
women by self-testing and short use of intravaginal antimicrobials. Eur J Clin Microbiol 
Infect Dis. 2017;36(4):731-738. Dequalinium for bacterial vaginosis. Drug Ther Bull. 
2017;55(5):54-57. 
30. Cerca N, Martins S, Cerca F, et al. Comparative assessment of antibiotic susceptibility of 
coagulase-negative staphylococci in biofilm versus planktonic culture as assessed by bacterial 
enumeration or rapid XTT colorimetry. J Antimicrob Chemother. 2005;56(2):331-336. 
31. 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. 
32. 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. 
33. 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. 
34. 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. 
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. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 64 of 67 
 
 
Version 4.0 | Version 2023-07-04 
38. Ishchuk OP, Sterner O, Ellervik U, Manner S. Simple Carbohydrate Derivatives Diminish the 
Formation of Biofilm of the Pathogenic Yeast Candida albicans. Antibiotics (Basel). 2019 
Dec 30;9(1):10. 
39. Sudbery PE. Growth of Candida albicans hyphae. Nature reviews Microbiology. 
2011;9(10):737-748. 
40. Moyes DL, Wilson D, Richardson JP, et al. Candidalysin is a fungal peptide toxin critical for 
mucosal infection. Nature. 2016;532(7597):64-68. 
41. Swidsinski A, Guschin A, Tang Q, et al. Vulvovaginal candidiasis: histologic lesions are 
primarily polymicrobial and invasive and do not contain biofilms. Am J Obstet Gynecol 
2019;220:91 
42. Harriott MM, Lilly EA, Rodriguez TE, Fidel PL, Noverr MC. Candida albicans forms 
biofilms on the vaginal mucosa. Microbiology (Reading). 2010 Dec;156(Pt 12):3635-3644. 
43. Noverr MC, Huffnagle GB. Regulation of Candida albicans morphogenesis by fatty acid 
metabolites. Infect Immun. 2004 Nov;72(11):6206-10. 
44. Jang SJ, Lee K, Kwon B, You HJ, Ko G. Vaginal lactobacilli inhibit growth and hyphae 
formation of Candida albicans. Sci Rep. 2019 May 31;9(1):8121. doi: 10.1038/s41598-
019-44579-4. 
45. Wang S, Wang Q, Yang E, Yan L, Li T, Zhuang H. Antimicrobial Compounds Produced by 
Vaginal Lactobacillus crispatus Are Able to Strongly Inhibit Candida albicans Growth, 
Hyphal Formation and Regulate Virulence-related Gene Expressions. Front Microbiol. 2017 
Apr 4;8:564 
46. 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. 
47. Prescott FJ, Shaw JK, Bilello JP, Cragwall GO. Gluconic Acid and Its Derivatives. Industrial 
& Engineering Chemistry. 1953;45(2):338-342. 
48. International Programme on Chemical Safety (IPCS). Glucono-Delta-Lactone and the 
Calcium, Magnesium, Potassium, and Sodium Salts of Gluconic Acid. 1999. 
49. U.S. Food and Drug Administration. 21CFR184.1318. 
50. Gedea Biotech AB. An open-label study to evaluate clinical performance of Gedea Pessary in 
adult women with vulvovaginal candidiasis (VVC). Clinical investigation report. Version 1.0 
(final), 2020-09-25. 
51. Gedea Biotech AB. An open-label study to evaluate clinical performance of Gedea pessary in 
adult women with bacterial vaginosis. Clinical investigation report. Version 1.0 (final), 
2020-05-12. 
52. Zhou, X., et al., The efficacy and safety of clotrimazole vaginal tablet vs. oral fluconazole in 
treating severe vulvovaginal candidiasis. Mycoses, 2016. 59(7): p. 419-28. 
53. Sobel JD, Wiesenfeld HC, Martens M, Danna P, Hooton TM, Rompalo A, Sperling M, 
Livengood C 3rd, Horowitz B, Von Thron J, Edwards L, Panzer H, Chu TC. Maintenance 
fluconazole therapy for recurrent vulvovaginal candidiasis. N Engl J Med. 2004 Aug 
26;351(9):876-83. 
54. SAS Institute Inc. Base SAS® 9.4 Procedures Guide: Statistical Procedures, Second Edition. 
Cary, NC: SAS Institute Inc.; 2013. 
55. QRS-BC-008 Eurofins medical device consulting statement No. 021-0055 regarding the 
applicability of biocompatibility tests performed with pHyph gen I to the evaluation of pHyph 
gen II 
56. Nyirjey P, Schwebke JR, Angulo, DA, Harriot IA, Nkechi EA, Sobel JD.  Phase 2 
randomized study of oral ibrexafungerp vs fluconazole in vulvovaginal candidiasis. Clinical 
Infectious Diseases, 2021;, ciab841 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 65 of 67 
 
 
Version 4.0 | Version 2023-07-04 
57. Schwebke JR, Sobel R, Gersten JK, Sussman SA et al. Ibrexafungerp Versus Placebo for 
Vulvovaginal Candidiasis Treatment: A Phase 3, Randomized, Controlled Superiority Trial 
(VANISH 303). Clinical Infectious Diseases, 2021;, ciab750 
58. Gedea Biotech AB. QRS-CL3-021 Report on growth of vaginal bacterial strains and effect of 
pre-biotic compounds. 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 66 of 67 
 
 
Version 4.0 | Version 2023-07-04 
Appendix 1 
Patient Questionnaire 
Questions will be asked directly in the electronic patient reported outcomes (ePRO) system 
mobile application ViedocMe™. 
Section 1. Vaginal candidiasis symptoms and pessary administration 
Pessary administration: 
At Days 0 to 5, the patient should confirm that they have administered the pessary: 
Question on treatment days:  
Have you applied the pessary? 
 
Yes 
 
No 
If no, please provide reason: (free text). 
Scoring of vulvovaginal candidiasis symptoms: 
The vulvovaginal candidiasis (VVC) symptoms will be rated by all patients on Days 0 to 6 , Day 11 
and Day 25.  
The VVC symptoms will be rated according to 0-3 scale, as shown below. 
 
0 = none 
(absent) 
1 = mild 
(slight) 
2 = moderate 
(definitely present) 
3 = severe 
(marked, intense) 
Irritation 
 
 
 
 
Itching 
 
 
 
 
Burning  
 
 
 
 
 
Section 2. Usability 
All patient should reply to the following questions on Day 6. 
Questions – Day 6 
1. Is the vaginal pessary easy to use?  
 
Yes 
 
No 
If no, provide reason: 
(free text). 
2. Did all pessaries remain in the vagina during treatment? 
 
Yes 
 
No 
 (if No)  2a. During how many dose administrations did you experience that the pessary did not 
remain in the vagina?  
o Once 
o 2-3 
o 4-5 
o All  

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 67 of 67 
 
 
Version 4.0 | Version 2023-07-04 
 2b. When the pessary does not remain, how would you describe what most frequently is 
happening? 
o Just small pieces are falling out 
o Large pieces are falling out 
 
 
Please specify after how long time they generally falls out. 
 
Within 12 hours 
 
Between 12-24 hours after administration 
 
More than 24 hours after administration 
o The whole pessary is falling out 
 
 
 Please specify after how long time it falls out. 
 
Within 12 hours 
 
Between 12-24 hours after administration 
 
More thatn 24 hours after administration 
3. How do you generally regard the treatment?  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Not satisfied 
Very satisfied  
 
Section 3. Reminders 
Patients will receive the following reminders and questions via the mobile application:  
 
Administration 
Reminder about administration of the investigational product on Days 0 to 5 and VVC symptom 
scoring on Days 0 to 6, Day 11 and Day 25.  
The investigational product is to be self-administered at night before going to bed. 
Please score your vulvovaginal symptoms. 
 
 
 
 
Sampling reminder and questions at Day 25 
1. Have both vaginal swab samples been taken?  
 
Yes 
 
No 
 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 68 of 67 
 
 
Version 4.0 | Version 2023-07-04 
Appendix 2 
Principal Investigator Signature Page 
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: CL4 
 
Site/Institution: 
 
Principal Investigator: 
 
 
Signature: 
 
Date: 
 
 
 
Printed name: 
 
 
 
 
 
 

Clinical Investigation Plan QRS-CL4-003 
Study CL4 
Gedea Pessary 
Page 69 of 67 
 
 
Version 4.0 | Version 2023-07-04 
Appendix 3 
List of Participating Sites and Principal Investigators  
 
Name of Institution 
/Site 
Site address 
Principal Investigator 
Contact details, 
Principal Investigator 
Danderyds sjukhus  
Kliniska vetenskaper 
Obstretrik och 
gynekologi 
SE-182 88 Stockholm, 
Sweden 
NAME 
Phone:                                
TELEPHONE             
E- mail: NAME 
Karolinska 
Universitetssjukhuset 
Huddinge 
Kvinnoforskingsenheten 
B79 
SE-141 86 Stockholm, 
Sweden 
NAME 
Phone:                                
TELEPHONE             
E- mail: NAME 
Carlanderska sjukhuset, 
Forskningsenheten 
Carlandersparken 1,   
SE-405 45 Gäteborg, 
Sweden 
NAME 
Phone:                                
TELEPHONE 
E- mail: NAME 
Clinical Trial 
Consultants AB 
Dag Hammarskjölds väg 
10B, SE-752 37 Uppsala, 
Sweden 
NAME                       
Phone:                                
TELEPHONE          
E- mail: NAME