A Two-arm, Parallel-design, Clinical Investigation to Determine the Effectiveness and Safety of a Water-based Personal Lubricant With a Sensory Action and Silicone-based Personal Lubricant With a Sensory Action for the Relief of Intimate Discomfort Associated With Vaginal Dryness
Phase: NA
Conditions: Dyspareunia, Vaginal Dryness
Sponsor: Reckitt Benckiser Healthcare (UK) Limited

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 1 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
RECKITT 
CLINICAL INVESTIGATION TITLE 
A two-arm, parallel-design, clinical investigation to determine the effectiveness and safety of a 
water-based personal lubricant with a sensory action and silicone-based personal lubricant with a 
sensory action for the relief of intimate discomfort associated with vaginal dryness. 
Short Investigation Title 
Effectiveness and safety of a water-based and a silicone-based personal lubricants with sensory 
action. 
Reckitt Investigation 
Number: 
5025003 
Vendor Investigation 
Number: 
22.0225-99 
Phase of Investigation: 
Pivotal 
CIP Version and Date: 
V3.0 27-Oct-2022 
Previous Versions / Date(s): V2.0 28-Sep-2022 
 
Unique identification 
number EUDAMED: 
CIV-22-08-040346 
Confidentiality Statement: 
The information contained in this document is privileged and 
confidential. Do not copy, circulate or otherwise distribute 
without written authority from Reckitt. 
 
 
 
 
 
 
 
 
 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 2 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
 
KEY CONTACTS  
Name and title 
Address 
Phone  
e-mail 
Sponsor: 
Reckitt Benckiser 
Health Limited  
 
  
  
  
 
  
  
Sponsor’s Medical 
Expert: 
 
  
  
  
  
  
 
 
 
Principal 
Investigator(s): 
 
 
  
 
 
 
 
 
 
Vendor: 
 
 
  
 
 
 
 
 
 
Vendor Head of 
Project 
Management: 
 
 
  
 
 
 
 
 
 
Vendor Project 
Manager:  
 
 
  
 
 
 
 
 
 
Vendor Statistician: 
 
 
  
 
 
 
 
 
 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 3 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
 
 
 
 
 
 
 
 
 
 
 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 6 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
TABLE OF CONTENTS 
KEY CONTACTS ................................................................................................................... 2 
SIGNATURE PAGE ............................................................................................................... 4 
TABLE OF CONTENTS ......................................................................................................... 6 
LIST OF ABBREVIATIONS .................................................................................................. 10 
CLINICAL INVESTIGATION SYNOPSIS .............................................................................. 12 
1 
BACKGROUND AND RATIONALE .................................................................... 26 
1.1 
Background for the Investigation and Rationale .............................................26 
1.2 
Investigational Product ...................................................................................29 
1.3 
Treatment Rationale ......................................................................................29 
1.4 
Investigation Population and Indication ..........................................................30 
1.5 
Non-Clinical Evidence ....................................................................................31 
1.6 
Clinical Evidence to Date ...............................................................................31 
 
 
 
 
 
 
1.6.4 
Summary of adverse events from literature ....................................................33 
1.7 
Benefits / Risks Assessment ..........................................................................33 
1.7.1 
Covid-19 ........................................................................................................34 
1.8 
Ethical Conduct of the Investigation ...............................................................35 
2 
INVESTIGATION OBJECTIVES AND ENDPOINTS .......................................... 35 
2.1 
Investigation Objectives and Endpoints..........................................................35 
2.2 
Success Criteria .............................................................................................38 
3 
INVESTIGATION DESIGN AND RATIONALE FOR DESIGN ............................ 38 
3.1 
Investigation Design.......................................................................................38 
3.2 
Rationale for Investigation Design ..................................................................40 
3.3 
Determination of Sample Size ........................................................................41 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................ 42 
4.1 
Investigation Population .................................................................................42 
4.2 
Inclusion Criteria ............................................................................................42 
4.2.1 
Universal Inclusion Criteria ............................................................................42 
4.2.2 
Pre-menopausal Inclusion Criteria .................................................................43 
4.2.3 
Post-menopausal Inclusion Criteria ................................................................43 
4.3 
Exclusion Criteria ...........................................................................................44 
4.3.1 
Universal Exclusion Criteria ...........................................................................44 
4.3.2 
Pre-menopausal Exclusion Criteria ................................................................46 
4.3.3 
Post-menopausal Exclusion Criteria ..............................................................46 
4.3.4 
Tolerance Subset - Exclusion Criteria for Enrolling into Treatment Phase ......46 
4.4 
Investigation Restrictions ...............................................................................46 
4.4.1 
Dietary and Lifestyle Restrictions ...................................................................46 
4.4.2 
General Restrictions ......................................................................................48 
4.5 
Discontinuation / Withdrawal and Replacement of Subjects ...........................49 
5 
INVESTIGATION TREATMENT ......................................................................... 49 
5.1 
Medical Device ..............................................................................................49 
5.2 
Non-Investigational Products .........................................................................50 
5.3 
Concomitant Therapies ..................................................................................51 
5.4 
Packaging and Labelling and Supply / Resupply ............................................51 
5.5 
Storage Conditions ........................................................................................51 
5.6 
Masking .........................................................................................................51 
5.7 
Emergency Unblinding Procedures ................................................................51 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 7 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
5.8 
Accountability of Medical Device ....................................................................52 
5.9 
Return and Destruction ..................................................................................52 
6 
INVESTIGATION PROCEDURES BY VARIABLE ............................................. 52 
6.1 
Informed Consent ..........................................................................................52 
6.2 
Male Partners ................................................................................................53 
6.3 
Randomisation ...............................................................................................53 
6.4 
Administration of Medical Device ...................................................................54 
6.4.1 
Tolerance Phase ............................................................................................54 
6.4.2 
Treatment Phase ...........................................................................................54 
6.5 
Demographics ................................................................................................55 
6.6 
Medical History and Prior Therapies ..............................................................55 
6.7 
Physical Examination .....................................................................................56 
6.8 
Pregnancy Test ..............................................................................................56 
6.9 
Verbal Rating Scale (VRS) of Dyspareunia and Vaginal Dryness ..................56 
6.10 
Lubricant Use History .....................................................................................57 
6.11 
Tolerance Phase Variables ............................................................................57 
6.11.1 
Vaginal Epithelial Tolerability (VET) Assessment ...........................................57 
6.11.2 
Global Assessment of Vulvovaginal Tolerance ..............................................57 
6.11.3 
Overall Vulvovaginal Tolerance Rating Statement .........................................58 
6.11.4 
Oral Mucosal Tolerance .................................................................................58 
6.11.5 
Global Assessment of Oral Mucosal Tolerance ..............................................58 
6.11.6 
Overall Oral Mucosal Tolerance Rating Statement ........................................58 
 
 
 
 
6.11.9 
Subject Perceived Questionnaire (SPQ) – Tolerance Phase ..........................59 
6.12 
Treatment Phase Variables ............................................................................60 
6.12.1 
Female Sexual Function Index (FSFI) ............................................................60 
6.12.2 
Subject Diary .................................................................................................60 
6.12.3 
Subject Perceived Questionnaire (SPQ) – Treatment Phase .........................60 
6.12.4 
Global Evaluation of Product Effectiveness, Tolerability and Usability ...........60 
6.12.5 
Patients Global Impression of Change (PGIC) ...............................................61 
 
 
6.13 
Adverse Events ..............................................................................................61 
7 
INVESTIGATION PROCEDURES BY VISIT ...................................................... 62 
7.1 
Investigation Flow Chart / Table of Investigation Procedures and Assessments
 ......................................................................................................................62 
7.2 
Visit 1 – Screening Visit .................................................................................66 
7.3 
Tolerance Phase ............................................................................................66 
7.3.1 
Wash-Out Period ...........................................................................................66 
7.3.2 
Visit 2 .............................................................................................................67 
7.3.3 
Visit 3 .............................................................................................................68 
7.4 
Treatment Phase ...........................................................................................68 
7.4.1 
Run-In Phase .................................................................................................68 
7.4.2 
Visit 2 – Baseline ...........................................................................................68 
7.4.3 
Visit 3 (End of Investigation) ..........................................................................69 
7.5 
Unscheduled Visits ........................................................................................70 
8 
SAFETY REPORTING ....................................................................................... 70 
8.1 
Adverse Event Definitions ..............................................................................70 
8.2 
Assessment of Adverse Events......................................................................72 
8.3 
Reporting of Adverse Events .........................................................................75 
8.4 
Follow-up of Adverse Events .........................................................................75 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 8 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
8.5 
Misuse and Medical Device administration Errors ..........................................76 
8.6 
Pregnancy .....................................................................................................76 
9 
STATISTICAL CONSIDERATIONS ................................................................... 77 
9.1 
Statistical Analysis Plan .................................................................................77 
9.2 
Interim Analysis .............................................................................................77 
9.3 
Analysis Datasets ..........................................................................................77 
9.4 
Subject Disposition and Characteristics .........................................................77 
9.5 
Statistical Analyses ........................................................................................78 
9.5.1 
Primary Endpoint(s) .......................................................................................78 
9.5.2 
Secondary Endpoints .....................................................................................80 
9.5.3 
Exploratory Endpoints ....................................................................................82 
9.6 
Description Statistics and Listings ..................................................................82 
9.7 
Adverse Events ..............................................................................................83 
9.8 
Handling of Missing Data and Drop-outs ........................................................83 
10 
DATA HANDLING AND RECORD KEEPING .................................................... 83 
10.1 
Case Report Forms........................................................................................83 
10.2 
Specification of Source Documents ...............................................................84 
10.3 
Data Management .........................................................................................84 
10.4 
Reporting of CIP Deviations ...........................................................................85 
10.5 
Retention of Essential Documentation ...........................................................85 
11 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 85 
11.1 
Monitoring ......................................................................................................85 
11.2 
Audits and Inspections ...................................................................................86 
11.3 
Sponsor Policy on Fraud in Clinical Studies ...................................................86 
12 
ETHICAL AND REGULATORY ASPECTS ........................................................ 86 
12.1 
Ethics Review and Regulatory Authority Approval .........................................86 
12.2 
Early / Premature Termination of the Investigation .........................................86 
13 
COMPENSATION, INDEMNITY AND INSURANCE .......................................... 87 
13.1 
Clinical Investigation Agreement ....................................................................87 
13.2 
Insurance .......................................................................................................87 
14 
REPORTING, PUBLICATION AND PRESENTATION ....................................... 87 
15 
REFERENCES .................................................................................................. 88 
16 
APPENDICES .................................................................................................... 91 
16.1 
Appendix 1:  Female Sexual Function Index (FSFI) .......................................91 
 
List of Tables Contained in the Body of the Protocol 
Table 2-1 Investigation Objectives and Endpoints ................................................................35 
Table 3-1 IPs and Comparators Tested in Each Phase/Tolerance Assessment ...................41 
Table 4-1 Dietary and Lifestyle Restrictions ..........................................................................46 
Table 4-2 General Restrictions .............................................................................................48 
Table 5-1 Investigational Product – Quantitative Composition of Each Component per variant
 .............................................................................................................................................50 
Table 7-1 Schedule of Assessments – Tolerance Phase ......................................................62 
Table 9-1 Female Sexual Function Index Domain Scores and Full-Scale Score ...................78 
 
List of Figures Contained in the Body of the Protocol 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 9 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Figure 3-1 Investigation Design Schematic – Tolerance Phase ............................................39 
Figure 3-2 Investigation Design Schematic – Treatment Phase ............................................40 
 
 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 12 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
CLINICAL INVESTIGATION SYNOPSIS  
Investigation Title: 
A two-arm, parallel-design, clinical investigation to determine the 
effectiveness and safety of a water-based personal lubricant with a 
sensory action and silicone-based personal lubricant with a sensory 
action for the relief of intimate discomfort associated with vaginal 
dryness. 
Reckitt Investigation 
Number: 
5025003 
Background and 
Rationale: 
 
 
 
 
 
 
 
 
 
 
 
 
 To comply with the MDR, two 
personal lubricants, 
, will be investigated. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 13 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Objectives:  
The primary objective of this investigation is to demonstrate the 
effectiveness of two personal lubricants when used as intended during 
vaginal intercourse in women who experience intimate discomfort 
associated with vaginal dryness. 
The secondary objectives of this investigation, are as follows: 
 To assess subject’s perception of two personal lubricants when 
used during vaginal intercourse in women who experience intimate 
discomfort associated with vaginal dryness. 
 To assess subject’s global evaluation of two personal lubricants 
when used during vaginal intercourse in women who experience 
intimate discomfort associated with vaginal dryness. 
 To assess male partners’ perception of two personal lubricants 
when used during vaginal intercourse. 
 To assess the effects of two personal lubricants on the impression 
of change in the sexual intimacy between female subjects and their 
male partners. 
 To assess vulvovaginal tolerance of two personal lubricants in 
women who experience intimate discomfort associated with 
vaginal dryness. 
 To assess oral mucosal tolerance of two personal lubricants in 
women who experience intimate discomfort associated with 
vaginal dryness. 
 To assess the safety and establish the safety profile of two 
personal lubricants in women who experience intimate discomfort 
associated with vaginal dryness. 
 To assess the safety and establish the safety profile of two 
personal lubricants in males. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 14 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Primary Endpoint: 
The primary endpoint of this investigation is the change from baseline 
in total Female Sexual Function Index (FSFI) score at 4 weeks. An 
increase of at least 4 (≥4) points in the FSFI score from baseline to 4-
weeks post-lubricant use is considered a clinically important change.  

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 15 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Secondary Endpoints: The secondary endpoints of this clinical investigation, are as follows: 
 Number and percentage of subjects who achieve at least 4-point 
(≥4) increase in total FSFI between baseline and 4 weeks. 
 Number and percentage of subjects who transition from sexual 
dysfunction (≤26.55 total FSFI score) to sexual function (>26.55 
total FSFI score) between baseline and 4 weeks. 
 Change from baseline in individual domain scores (Pain, 
Lubrication, Desire, Arousal, Satisfaction, Orgasm) at 4 weeks. 
 The subjects’ perception of two personal lubricants determined 
through Subject Perceived Questionnaire (SPQ) after first product 
use (within 24 hours of intercourse) and at 4 weeks. 
 Subject Global Evaluation of product effectiveness, tolerability, 
and device usability (included in the SPQ) at 4 weeks. 
 The male partners’ perception of two personal lubricants 
determined through Subject Perceived Questionnaire (SPQ) after 
first product use (within 24 hours of intercourse) and at 4 weeks. 
 Number and percentage of female subjects recording ≥2 
improvement in sexual intimacy on the Patient Global Impression 
of Chang (PGIC) at 4 weeks.  
 Number and percentage of male partners recording ≥2 
improvement in sexual intimacy on the PGIC at 4 weeks. 
 An assessment of the Vaginal Epithelial Tolerability (VET) of the 
two personal lubricants at baseline, 2 and 24 hours post single 
application as assessed by gynaecologist examination. 
 Subject Perception of Vulvovaginal Tolerance of the two personal 
lubricants will be determined through Subject Perceived Questions 
at 24 hours post single application. 
 Global Assessment of Vulvovaginal Tolerance for each subject at 
24 hours post single application as determined by the 
gynaecologist. 
 Overall Vulvovaginal Tolerance Rating Statement for each 
personal lubricant as determined by the gynaecologist. 
 An assessment of the Oral Mucosal Tolerance of the personal 
lubricants at baseline, 30 minutes, 2 and 24 hours post single 
application to the upper and lower inner lip as assessed by 
dermatologist. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 16 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
 Subject Perception of Oral Mucosal Tolerance of the two personal 
lubricants will be determined through Subject Perceived Questions 
at 24 hours post single application. 
 Global Assessment of Oral Mucosal Tolerance for each subject at 
24 hours post single application as determined by the 
dermatologist. 
 Overall Oral Mucosal Tolerance Rating Statement for each 
personal lubricant as determined by the dermatologist. 
 Overall proportion of subjects with Adverse Events/Adverse 
Device Effects (AEs/ADEs) i.e. the occurrence of one of more 
AE/ADE per subject. 
 Overall proportion of males with Adverse Events/Adverse Device 
Effects (AE/ADEs) i.e. the occurrence of one of more AE/ADE per 
male partner. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Success Criteria:  
Observation of a statistically significant and clinically important 
change from baseline in total FSFI score at 4 weeks. A pre-specified 
minimum clinically important difference (MCID) is at least 4 (≥4) points 
from baseline to 4 weeks. 
Design: 
This is a two-arm, parallel-design clinical investigation determining the 
effectiveness and safety of two personal lubricants. 
This clinical investigation consists of two phases, a Tolerance Phase 
and a Treatment Phase, whereby a subset of subjects and their male 
partners will enter both the Tolerance Phase followed by the 
Treatment Phase. The remaining subjects and their partners will enter 
the Treatment Phase only. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 17 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Subjects: 
In this synopsis, female participant is referred to as the subject. 
Information on the activities undertaken by the male partner is 
specifically noted.  
The investigation population will include an approximate 1:1 ratio of 
pre-menopausal to post-menopausal, with a difference of up to 40:60 
(up to a maximum of 60% in either sub-population) being allowed. 33 
subjects will be randomised to each treatment group. A subset of 22 
subjects will be selected in a 1:1 treatment allocation ratio to 
participate in the Tolerance Phase of the investigation. 
Summary of Inclusion and Exclusion Criteria: 
Only subjects to whom all the following conditions apply will be 
included: 
Universal Inclusion Criteria: 
1. Subject and their male partner have provided written informed 
consent.  
2. Subject is female and both subject and their male partner are aged 
at least 18 years. Maximum age of female subject is 65 years. 
3. Female subject and their male partner in a mutually monogamous 
heterosexual relationship (≥ 3 months) who are sexually active, 
defined as having sexual intercourse at least once a week. (Note: 
The number of sexual intercourses may comprise twice in one 
week to account for a menstrual period break.) 
4. Female subject that agrees to have a gynaecological pelvic 
examination to ensure no significant disease findings and have 
intact skin and mucous in the test region (vaginal and vulvar / 
intimate area) except skin dryness as visually assessed by the 
gynaecologist at all the relevant time points. 
5. Female subject that agrees to an oral exam by a dermatologist to 
ensure no significant disease findings and have intact skin and 
mucous in the test region (oral cavity - including lips, inside lining 
of the lips, cheeks (buccal mucosa), teeth, gums, tongue, the floor 
of the mouth, roof of the mouth (hard palate) and area behind 
wisdom teeth (retromolar trigone). 
6. Subjects reporting mild to moderate vaginal dryness and 
dyspareunia during sex (when not using lubricant) in the past 3 
months as confirmed by a score of 1 or 2 for vaginal dryness and 
1 or 2 for dyspareunia on the Verbal Rating Scale (VRS) of 
dyspareunia and vaginal dryness. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 18 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Pre-menopausal Inclusion Criteria: 
1. Female subject of childbearing potential who is willing to use a 
highly effective method of contraception throughout the clinical 
investigation. A female is considered to be of childbearing potential 
following menarche and until becoming post-menopausal unless 
permanently sterile by methods including hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy. A highly effective 
method of contraception is defined as a method that can achieve 
a failure rate of less than 1% per year when used consistently and 
correctly. Such methods include combined (oestrogen and 
progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal and transdermal), 
progestogen-only 
hormonal 
contraception 
associated 
with 
inhibition of ovulation (oral, injectable and implantable), 
intrauterine device (IUD), intrauterine hormone-releasing system 
(IUS), bilateral tubal occlusion, vasectomised partner (who has 
received medical assessment of the surgical success). 
Post-menopausal Inclusion Criteria: 
1. Female subject in post-menopausal phase defined as having 
amenorrhea (absence of menstruation) for at least 12 consecutive 
months without an alternative medical cause. 
2. Female subject with premature menopause – due to surgical 
menopause or physiological menopause within the last 12 
consecutive months of the screening visit (diagnosis to be 
confirmed as irreversible in subjects’ medical history) or after 
having received chemotherapy. 
Subjects to whom any of the following conditions apply must be 
excluded: 
Universal Exclusion Criteria: 
1. Female subject or their partner who has previously experienced 
an irritant or allergic reaction to any personal lubricant, vaginal 
moisturiser or female hygiene product or known to have any 
contact allergy or allergy/ hypersensitivity to the test product 
ingredients. 
2. Female subject with history of mucosal intolerance to warming 
agents. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 19 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
3. Female subject with continuous or intermittent oral allergy 
syndrome or burning mouth syndrome, or history of thereof (self-
reported). 
4. Female subject with urinary, vaginal infection (fungal, bacterial) or 
sexually transmitted infection at screening visit, which in the 
opinion of the investigator would affect the study outcomes or the 
safety of the subject. 
5. Female subject that has any condition of the oral cavity, including 
oral infection, active oral herpes simplex virus, active canker sores 
or oral ulcers and erosions as determined by the investigator. 
6. Female subject who has had a positive cervical screening 
examination for human papillomavirus (HPV) within the 3 years of 
the screening visit (medical history/self-reported). 
7. Female subject presenting with signs of internal irritation, active 
psoriasis, lichen sclerosis, eczema or other active skin disorder 
upon clinical examination. 
8. Male partner of female subjects has broken skin or wounds in the 
intimate area (self-reported). 
9. Female subject with a history of skin disorder, which in the opinion 
of the investigator will affect study outcome. 
10. Female subject presenting clinically abnormal findings other than 
irritation e.g. lumps, open sores or blister type wounds during the 
physical examination (including the gynaecological examination) 
that in the opinion of the investigator will affect study outcome. 
11. Female subject that has had a suspicion of malignancy or history 
of malignancy within the past 2 years (self-reported). 
12. Female subject with autoimmune conditions or any medical 
conditions which in the opinion of the investigator could 
compromise the immune function. 
13. Female subject who has had surgical cervical excision or vaginal 
and/or vulvar procedures, including laser and cosmetic procedures 
to the vulva or vagina in the previous year. 
14. Female subject that has any tooth ache or other dental/oral malady 
(self- reported). 
15. Female subject with ongoing dental/orthodontic procedures or any 
medical/surgical interventions involving the oral cavity (self-
reported). 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 20 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
16. Female subject currently being treated with systemic medications 
or medicines (e.g. glucocorticosteroids, antibiotics, local oestrogen 
and other intravaginal products) that are acting locally in the 
vaginal area which may influence the clinical study outcomes. 
17. Female subject who has started, stopped, or changed hormonal 
treatments (for contraception, vaginal dryness, or any other 
condition) during the previous 3 months prior to screening or those 
intending or expecting a change in treatment during the 
investigation. 
18. Female subject who has used any kind of topical histamine and/or 
topical hormonal based product in the form of an intravaginal 
cream or moisturiser for local treatment of vaginal dryness in the 
past 3 months. 
19. Female subject taking steroid preparations, immunosuppressants 
or any other medication which in the opinion of the investigator 
may affect the test results:  
a. Anti-inflammatory or antihistamine within 1 week prior to the 
screening visit. 
b. Cough suppressants or corticosteroids within 4 weeks prior to 
screening visit. 
c. Retinoids or immune suppressants within 6 months prior to 
screening visits. 
20. Female subject who has had any change to medication or 
treatment regimen for the treatment of diabetes mellitus during the 
previous 3 months prior to screening. 
21. Female subject using non-medicated, over the counter product, 
herbal/natural remedies on the vulva, vaginal opening and inside 
the vagina and is unwilling to stop at least 7 days prior to screening 
and throughout the duration of clinical investigation. 
22. Female subject showing vaginal prolapse and/or other medical 
conditions that could interfere with the investigation conduct and 
participation. 
23. Female subject using vaginal douches and is unwilling to stop its 
use at least 2 weeks prior to screening and throughout the duration 
of the clinical investigation. 
24. Female subject or their male partner that, in the opinion of the 
investigator, will be unable to comply fully with the study 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 21 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
requirements or unable to tolerate the procedures described in the 
CIP. 
25. Female subject has participated in another investigation where a 
medicinal, medical device clinical investigation or any form of 
studies involved testing on female intimate area within 3 months 
prior to screening. 
26. Female subject or their male partner has received an 
investigational product or participated in another trial involving a 
marketed or investigational drug in the 30 days (or for 
investigational agents with a long half-life, a washout of 5 half-
lives) prior to screening. Or if the investigator believes that any 
previous participation in an investigational study would be to the 
detriment of the safety of the participant or the conduct of the 
study. 
27. Female subject or their male partner who is an employee at the 
site or a partner or first-degree relative of the Investigator. 
28. Female subject or their male partner fails to satisfy the investigator 
of fitness to participate for any other reason. 
Pre-menopausal Exclusion Criteria: 
1. Female subject who is pregnant (as confirmed by a positive 
pregnancy test), breast-feeding or trying to conceive. 
Post-Menopausal Exclusion Criteria: 
1. Female subject that has had previous episodes of vaginal bleeding 
of unknown origin within the last 6 months of the screening visit. 
Tolerance Subset - Exclusion criteria for Enrolling into Treatment 
Phase 
Subjects participating in the Tolerance Phase who have any of the 
following conditions must not continue to the Treatment Phase. 
1. Any observed severe irritancy reactions at any time point. 
2. Any reaction failing to adequately resolve or needing further 
treatment, that in the opinion of the investigator represents an 
unacceptable risk to proceed with the investigation. 
3. Any adverse events considered related to the investigational 
product that are serious and/or severe in nature that in the opinion 
of the investigator represent an unacceptable risk to proceed with 
the investigation. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 22 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Product(s) to be 
Evaluated and 
Treatment Regimen: 
The following investigational products (IP) will be evaluated in this 
investigation: 
 IP A: 
 
 IP B: 
 
The following comparator will be used in the Tolerance Phase: 
 Comparator A: non-sensate water-based lubricant 
 Comparator B: non-sensate silicone-based lubricant 
According to the randomisation schedule, each subject will test one 
IP and the respective comparator in the Tolerance Phase and will test 
one IP in the Treatment Phase.  
Tolerance Phase 
Subjects assigned to complete the Tolerance Phase are expected to 
apply a single application to assess tolerability: 
 Approximately 3 g amount of IP to the vagina and intimate area for 
vulvovaginal tolerance. 
 A pea-sized application of IPs and comparators to the inner linings 
of the upper and lower lips of the subject’s mouth for oral mucosal 
tolerance. 
Treatment Phase   
Approximately 3 g amount of IP will be considered as single 
application. Subjects will be expected to apply the IP when engaging 
in sexual intercourse, at least once a week over a 4-week period. This 
is to be able to assess key dimensions of sexual function of subjects. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 23 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Methodology: 
Visit 1 – Screening Visit: All subjects and male partners will attend 
a screening visit to assess eligibility. Eligible subjects and their male 
partners will either enter the Tolerance Phase or directly into the 
Treatment Phase. 
Tolerance Phase 
The Tolerance Phase consists of a 7-day wash-out period followed by 
two further visits.  
7-day wash-out period: Subjects will not be permitted to use any 
personal lubricants or other remedies for vaginal dryness and will be 
asked to refrain from engaging in vaginal sex or any other vaginal 
penetrative sexual activity e.g. digital stimulation or use of sex toys. 
Subjects will also be prohibited from using any new oral products that 
are irregular to their normal dental hygiene routine or eating any new 
foods outside their normal diet. 
Visit 2: At the clinical site, subjects will be provided with a snack and 
drink, ahead of an oral water rinse. After the oral water rinse the 
subjects will participate in an additional 30-minute oral wash-out 
period which they will be asked to refrain from using any oral products 
or consuming any foods/drinks. If necessary, subjects may have 
water, and this will be recorded. Oral examination will be carried out 
by the dermatologist at baseline, 30 minutes, and 2 hours after a 
single application of the allocated IP and the respective comparator. 
Gynaecological assessments, including VET, 
 
 
will be carried out by the 
gynaecologist at baseline, 2 hours post application of the allocated IP. 
After which subjects can leave the clinical site.  
Visit 3: 24 hours post application, subjects will return to the clinical 
site. The continued eligibility will be reconfirmed and above clinical 
assessments (oral examination, VET,
 
 and the completion of a SPQ - Tolerance 
Phase will be performed. The gynaecologist will complete a Global 
Assessment of Vulvovaginal Tolerance for each subject and provide 
an Overall Tolerance Rating Statement for each IP upon completion 
of the Tolerance Phase. The dermatologist will complete a Global 
Assessment of Oral Mucosal Tolerance for each subject and provide 
an Overall Tolerance Rating Statement for each IP and comparator 
upon completion of the Tolerance Phase. After which subjects will 
move into the Treatment Phase of the investigation. 
Treatment Phase 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 24 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
The Treatment Phase consists of a 4-week run-in phase, followed by 
two further visits. 
Run-In Phase: During this run-in phase, subjects will be asked to 
refrain from using any personal lubricants or remedies for vaginal 
dryness during sexual activity. Subjects will be asked to consent to 
engaging in vaginal penetrative sex at least once per week during this 
4-week period. Subjects will be asked to record into their diary the 
number and frequency of coital acts during this period, including when 
subjects were unable to have sexual intercourse without the use of a 
lubricant and/or for menstrual bleeding (pre-menopausal women). 
Visit 2*: Subjects will return to the clinical site, where continued 
eligibility will be reconfirmed. After which subjects will be asked to 
complete the FSFI as baseline assessment. 
 
 
Subjects will then be provided with their allocated IP to use at 
least once a week for vaginal penetrative sexual intercourse over a 4-
week period. Subjects will also be issued a diary to record the 
investigation compliance e.g. number and frequency of vaginal 
penetrative sex occasions, IP use etc. The SPQ – Treatment Phase 
will be provided to subjects. An SPQ – Treatment Phase should be 
completed by the subject and the male partner after first use of the 
product within 24 hours of penetrative intercourse.  
Visit 3**: Subjects and male partners will return to the clinical site, 
where continued eligibility will be reconfirmed. For subjects, the 
following 
clinical 
assessments 
will 
be 
performed: 
Gynaecological/Pelvic examination (if necessary, in the opinion of the 
Investigator), 
 completion of FSFI, completion of 
SPQ – Treatment Phase, completion of Global Evaluation of Product 
Effectiveness, Tolerability and Usability and completion of PGIC. For 
male partners, they will complete the SPQ – Treatment Phase and 
PGIC. There after couple’s involvement in the investigation will be 
complete. 
Adverse events and concomitant medication will be recorded 
throughout the investigation. 
* Visit 4 for subjects undergone the Tolerance Phase 
** Visit 5 for subjects undergone the Tolerance Phase 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 25 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Statistical Evaluation: For the primary endpoint, within each of the treatment groups, the total 
FSFI score at 4 weeks will be compared to baseline using a paired t-
test. Two separate null hypotheses that there is no difference 
compared to baseline (one per treatment group) will be tested. For the 
determination of the statistical significance of each comparison, an 
adjustment for multiple testing will be made according to the 
Bonferroni-Holm method to ensure the Family Wise Error is controlled 
at 5%. The mean change from baseline in total FSFI will be presented 
with Bonferroni-corrected 97.5% confidence intervals to account for 
the 2 treatment comparisons. If the within-subject differences are not 
normally distributed, a Wilcoxon signed rank test will be used to 
compare change from baseline. In this case, Hodges-Lehmann 97.5% 
confidence intervals will be calculated. 
The number and percentage of subjects (including a 95% confidence 
interval) achieving at least 4-point improvement in total FSFI at 4 
weeks will be presented by treatment group and overall. This will 
indicate the percentage of subjects who achieved the pre-defined 
MCID. Similarly, the number and percentage of subjects who move 
from the sexual dysfunction (total FSFI ≤26.55) to sexual function 
(total FSFI >26.55) classification between baseline and 4 weeks will 
be presented by treatment group and overall.  
The secondary endpoints of the individual FSFI domain scores at 4 
weeks will be compared to baseline using either a paired t-test or 
Wilcoxon signed rank test. 
AEs/ADEs from both the Tolerance Phase and Treatment Phase will 
be summarised together. Summaries will include incidence, severity 
and relationship to device and study procedures of treatment 
emergent adverse events and adverse device effects. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 26 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
1 
BACKGROUND AND RATIONALE 
1.1 
Background for the Investigation and Rationale 
Healthy female genital tissue structure, function and integrity is maintained through the actions of 
a series of hormones collectively known as oestrogens; with their actions being mediated through 
oestrogen receptors present in the epithelial, endothelial and smooth muscle cells of the genital 
tissues. Oestrogens maintain the thickness of vaginal epithelium while promoting collagen and 
elastin synthesis i.e. structural supports, in vaginal connective tissue (collagen ensures tissue 
elasticity, pliability, thickness and tone of the vaginal area). Furthermore, in a healthy and well 
oestrogenised vaginal environment, the normal vaginal flora hydrolyses glycogen from sloughed 
epithelial cells, converting it into glucose which in turn is metabolised to lactic acid thereby creating 
a mildly acidic vaginal environment which in turn discourages the growth of pathogenic 
microorganisms (Goldstein I and Alexander JL. 2005). 
As oestrogen levels start to decline, key physiological changes that occur in the vagina/vulva area 
include thinning of the vaginal epithelium, an increase in vaginal pH (from mildly acidic to neutral 
and alkaline) and a decrease of approximately 30% of type I & Type II collagen in the vaginal tissue 
during the first few years following menopause (Brincat et al., 1985; Affinito et al., 1999; Sodeberg 
et al., 2009) This results in a gradual relaxation of the connective tissue support structure which 
leads into a general decline in the structure and tone of the genital area (Affinito et al., 
1999).Thinning of the epithelial layer leads to increased friability and lowered elasticity of vaginal 
tissues. 
As the physiological changes gradually occur in the genital structure and function, vaginal and vulva 
atrophy increases. Atrophy of the vaginal epithelia, vascular muscular and connective tissue 
causes the vaginal vault to become pale or colourless with resulting loss of multiple folds or rugae 
that are present in a rich oestrogen environment. Associated atrophy of the lamina propria blood 
vessels reduce blood flow to the tissues. This in turn results in a decrease in natural lubrication 
resulting in vaginal dryness with the severity of dryness increasing over time from menopause. The 
endocervical glandular tissue also produces less mucin, which further contributes to vaginal 
dryness (Goldstein I and Alexander JL. 2005). 
Vaginal dryness or decreased vaginal lubrication is a symptom generally associated with 
menopause / post menopause and publications on vaginal dryness tend to focus on women in the 
menopause / postmenopausal phase (Palacios S, 2014; Panay N and Fenton A, 2014). Vaginal 
dryness, however, may occur in all ages. Approximately 15% of pre-menopausal and up to 57% of 
post-menopausal women experience symptoms of urogenital atrophy of which vaginal dryness is 
a symptom (Goldstein I and Alexander JL. 2005). Vaginal dryness in premenopausal women can 
be permanent or transient due to several reasons e.g. prolonged periods of low oestrogens such 
as post pregnancy and breast feeding (Davies et al., 2004), low dose combined oral contraceptive 
and or progestogen-only methods (Basson et al., 2005), smoking (Kalogeraki et al., 1996), vaginal 
nulliparity, medications to decrease oestrogen levels, some health conditions (Leiblum et al., 1983) 
and other potential contact and irritant factors to the vaginal mucosa resembling symptoms of 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 27 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
atrophic vaginitis (Bachmann G and Nevadunsky NS, 2000). Vaginal dryness may also occur after 
surgery to the uterus or ovaries (Nappi et al., 2012), during some metabolic disorders, stress, 
obesity (by increasing vaginal infections and worsening vaginal discharge aggravates symptoms 
of Vaginal/Vulva Atrophy (VVA)), diabetes (Pastore et al., 2004) and following cancer therapy 
(Couzi et al., 1995). 
The gradual decline in oestrogen production is accompanied by common menopausal vasomotor 
symptoms including hot flushes, menstrual irregularities, night sweats, insomnia, headaches, 
anxiety, dizziness, depression, irritability, gastrointestinal upset and urinary difficulties which 
eventually resolve with time (Bachmann G and Nevadunsky NS, 2000; Greendale GA and Judd 
HL, 1993). Urogenital symptoms which include a decrease in vaginal lubrication, however, 
increases in prevalence and therefore, unlikely to improve overtime without treatment and if 
treatment discontinues the symptoms return (Dennerstein et al., 2000). 
The symptoms of VVA can and do have a significant negative impact on interpersonal relationships, 
quality of life (QoL), daily activities such as walking or exercising which creates genital discomfort 
(Nappi et al., 2014). Studies have reported the marked effect it has on sexual activity and QoL 
which is discussed below. 
Physiologically, the female sexual response cycle is initiated by neurotransmitter-medicated 
vascular and non-vascular smooth muscle relaxation which results in an increased pelvic blood 
flow, vaginal lubrication and both clitoral and labial engorgement. These events are orchestrated 
through a combination of neuromuscular and vasocongestive mechanisms. Any physiologic 
impairment that interferes with this cycle will affect sexual arousal, vaginal lubrication, genital 
sensation and the ability to achieve orgasm (Berman et al., 2000). Oestrogen plays a key role in 
maintaining a balanced vaginal environment throughout the productive years, however, as the 
levels of oestrogen declines the resulting VVA increases together with the associated decrease in 
vaginal lubrication i.e. increase in vaginal dryness and dyspareunia. Continued vaginal dryness 
often leads to difficulties with sexual arousal, pruritus, dysuria, burning, purulent and malodorous 
discharge in addition to other sexual and non - sexual complaints (Sarrel PM, 1987; Macoy et al., 
1985) which can therefore lead to loss of sexual desire or emotional and interpersonal difficulties 
(Shearer et al., 1977; Easley EB, 1978). 
Unlike many other menopausal symptoms, vaginal dryness increases over time and with age. Over 
72% of women in their seventh decade may report inadequate vaginal moisture with up to two 
thirds of postmenopausal women associating their complaint of dyspareunia with vaginal dryness 
(Sarrel PM, 1987). As highlighted, symptoms of VVA can and do have a significant negative impact 
on sexual function. The Real Women’s Views of Treatment Options for Menopausal Vaginal 
Changes (REVIVE) survey conducted in 3046 postmenopausal women in the United States (US) 
highlighted the most common VVA symptoms to be dryness (55%), dyspareunia (44%) and 
irritation (37%) which affected enjoyment of sex in over half (59%) of the participants (Kingsberg et 
al., 2013). Other studies have highlighted that vaginal dryness affects their sexual activity and QoL 
(Stenberg et al., 1996). The results of these and other similar studies reinforces the fact that many 
women perceive vaginal dryness and discomfort as having a substantial negative impact on their 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 28 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
lives and in particular with respect to their sexual intimacy, their ability to have a loving relationship 
and an overall QoL (Simon et al., 2013). 
As a woman travels through pre-menopause, menopause and post-menopausal phases in her life, 
it is accompanied by physiological and emotional changes, sometimes accompanied by health 
issues which together, will have an impact on her QoL. Vaginal dryness is a key factor that has a 
significant impact on QoL as it can affect normal everyday activities and can have a major impact 
on sexual activity, to the point that it can lead to increasing hostility and dissatisfaction, decreasing 
frequency of sexual encounters, pain with coitus and increased symptoms of poor vaginal health. 
Sexual activity is a healthy prescription for postmenopausal women (Easley EB, 1978) as it has 
been shown to encourage vaginal elasticity and pliability with lubrication. Studies have shown that 
women with VVA have no coital discomfort as long as they are engaging in regular intercourse; 
abstinence from coital activity has been associated with progressive shrinkage of the vagina 
(Leiblum et al. 1983; Notelovitz M, 1978). It is necessary, therefore, to address vaginal dryness in 
order to create a balanced vaginal microenvironment that can support a better QoL. 
Treatment options for VVA consist of prescription e.g. systemic hormone replacement therapy 
(HRT), vaginal oestrogen products and over-the-counter non-hormone lubricants and moisturisers 
with the choice of therapy dependent of the severity of the symptoms, effectiveness and safety of 
the therapy for the individual patient and patient preference. Many women decline the use of 
hormone based estrogenic products for several reasons including side effects associated with 
oestrogens therapy e.g. breast tenderness, resumption of menstrual cycle or personal preferences 
(Semmens et al., 1985). Hormone therapy is also contraindicated under several conditions e.g. 
women with a history of cancer or thromboembolism. Many women choose not to use hormone-
based products due to the safety concerns raised in the aftermath of the women’s health initiative 
(Rossouw et al., 2002). The concerns led the Food and Drug Administration (FDA) to make 
changes in the labelling of hormone therapy defining clearly that its use in the treatment of moderate 
to severe vasomotor symptoms is the primary indication. This relabelling reduces the treatment 
options available especially for several groups of women i.e. older women with VVA who no longer 
complain of vasomotor symptoms, for women who prefer oral over vaginal treatment and women 
who want to avoid the use of oestrogen due to side effects or contraindications. 
The Endocrine Society Clinical Practice Guideline suggests that personal lubricants are 
recommended for those who produce insufficient vaginal secretions to allow for comfortable sexual 
activity (Steunkel CA et al., 2015). Additionally, the American Society of Clinical Oncology, Inc. 
(ASCO) and Cancer Care Ontario (CCO) also recommend lubricants for all sexual activity or touch 
as part of first-line treatment for mild to moderate symptoms of VVA (Carter et al., 2018). 
 
 
 
 
 
 
 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 29 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
 To comply with the MDR, two personal lubricants, 
, will be investigated. 
1.2 
Investigational Product 
The investigational products (IPs), 
, are personal vaginal lubricants 
 
 The IPs come in contact with vaginal 
and vulval skin / mucosa each time it is used. The lubricants are for short-term use and contact is 
unlikely to exceed 24 hours. The IP can be applied up to 4 times per day.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
A comparator, in the form of a non-sensate water-based lubricant and a non-sensate silicone-based 
lubricant, will be included as part of the oral assessment in the Tolerance Phase for comparison 
with 
, respectively. 
The lubricants to be used in this clinical investigation have been manufactured to Good 
Manufacturing Practice (GMP) requirements as per International Organisation for Standardisation 
(ISO) 13485 Medical device – Quality management system – Requirement for regulatory purposes. 
1.3 
Treatment Rationale 
The proposed clinical investigation is a parallel-design investigation to determine the effectiveness 
and safety of one water-based personal lubricant and one silicone-based personal lubricant for the 
relief of intimate discomfort associated with vaginal dryness. 
 
 
The clinical investigation will include two phases: the Tolerance Phase, followed by the Treatment 
Phase (use-as-intended phase).  

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 32 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
1.6.2 
Acute tolerance study on 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
1.6.3 
Post-marketing adverse event surveillance data 
 
 
 
 
 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 33 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
 
 
 
 
 
 
1.6.4 
Summary of adverse events from literature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.7 
Benefits / Risks Assessment 
This investigation has been designed to evaluate the effectiveness and safety of two personal 
vaginal lubricants: 
 Subjects in this investigation are females who 
experience intimate discomfort associated with vaginal dryness during sexual intercourse. Such 
investigational population are expected to experience a level of relief from intimate discomfort 
during sexual intercourse with the use of their allocated IP.  
Additionally, each subject will undergo a physical examination, including a gynaecological 
examination as part of enrolment into the investigation to confirm that the subject is sexually healthy 
as defined in this investigation. The examination is a standard gynaecological examination, 
however due to the indication of vaginal dryness, the examination may be unpleasant or painful 
depending on the severity of the subject’s symptoms. Slight bleeding due to injury to the skin may 
occur when inserting the speculum. Subjects with underlying conditions identified though the 
physical examination will be referred as appropriate. 
 
 
 
 
  

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 34 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Only those subjects who meet the eligibility criteria set out in this investigation, and as assessed 
by the Investigator as being suitable to enter into the investigation will be enrolled. Subjects of 
childbearing potential will be required to be on a highly effective form of contraception before being 
enrolled into the investigation, additionally subjects will be screened for sexually transmitted 
infection (STI), however in the event that the subject become pregnant or contracts an STI they will 
have access to the clinical site where appropriate follow-up measures will be taken.  
 
subjects who experience any untoward medical occurrence during the investigation have access 
to the Investigator/clinical site where appropriate measures will be taken. Additionally, the 
Investigator (in consultation with the gynaecologist) will determine if a subject remains eligible to 
move into the Treatment Phase of the investigation after the completion of the Tolerance Phase, 
as per the inclusion/exclusion criteria and provided that the subject has not experienced any 
untoward medical occurrence.  
 
 Female subjects or their partner who has previously 
experienced an irritant or allergic reaction to any personal lubricant, vaginal moisturiser or female 
hygiene product or known to have any hypersensitivity to the test product ingredients will be 
excluded from the study, and the subjects will be instructed to stop use and seek medical attention 
in any instance of irritation. Subjects and their male partners will also be excluded if they report 
broken skin or wounds in the intimate area. The investigation includes safety measures expected 
of a personal lubricant study and therefore, the overall benefit-risk profile for the use of the IPs as 
defined in this CIP is considered acceptable. 
1.7.1 
Covid-19 
For subjects, all mandated hygiene measures and social distancing requirements will be followed 
in line with government guidelines and all relevant local guidelines which will be monitored 
throughout the course of the clinical investigation and any changes will be implemented as the 
clinical investigation progresses. Procedures required to be followed by subjects will be 
documented in the site file. 
If required per local regulation, subjects will be provided with additional information about COVID-
19 and any additional requirements in relation to their participation. This information will be provided 
to subjects in written and verbal format and they will be asked to sign that they have understood 
this additional information before proceeding with their involvement in the clinical investigation. 
Subjects will be reminded that they can discontinue participation and withdraw their informed 
consent at any time. 
The risk-benefit analysis for this investigation has been performed to consider the potential impact 
of COVID-19 on the safety and wellbeing of subjects and on the potential for the clinical investigation 
to be conducted appropriately. Risk assessments will be revisited throughout the course of the 
clinical investigation and input from the Investigator(s) will be used to identify the current local risk 
to the clinical investigation and those at the site. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 38 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2 
Success Criteria  
Observation of a statistically significant and clinically important change from baseline in total FSFI 
score at 4 weeks. A pre-specified minimum clinically important difference (MCID) is +4 points from 
baseline to 4 weeks. The MCID of +4 points is based on two previous studies (Krychman et al., 
2017; DeRogatis et al., 2014), and from discussions with Key Opinion Leaders. Krychman et al. 
(2017) concluded that in a study of 186 women with vaginal laxity randomised to receive either 
surface-cooled radiofrequency therapy or placebo, the MCID for the FSFI total score over a 6-
month intervention period was an improvement of at least 4.8 points. The MCID was derived based 
on the proportion of subjects who experienced what they perceived to be a clinically meaningful 
treatment benefit relative to the change in total FSFI score. In another study (DeRogatis et al., 
2014), which evaluated the efficacy of bremelanotide in 397 women with hypoactive sexual desire 
disorder and female sexual arousal disorder, the MCID for the FSFI total score was pre-defined as 
an improvement of at least 4 points, over a 6-month intervention period. Whilst the current study is 
over a shorter period (4-week treatment) and is not in a cohort of women with a female sexual 
dysfunction diagnosis, a change of +4 points in total FSFI score is considered relevant and is 
consistent with previous studies utilising the FSFI. 
3 
INVESTIGATION DESIGN AND RATIONALE FOR DESIGN 
3.1 
Investigation Design  
This is a two-arm, parallel-design investigation to determine the effectiveness and safety of two 
personal lubricants. This investigation consists of two phases, a Tolerance Phase and a Treatment 
Phase. Following the screening visit, a subset of subjects will enter the Tolerance Phase and upon 
completion, will then enter the Treatment Phase. The remaining subjects will enter the Treatment 
phase only, following the screening visit. The investigation population involve pre- and post-
menopausal women, and this investigation has been stratified by menopausal status. All subjects 
will attend a screening visit, to assess subject eligibility. Eligible subjects will either enter the 
Tolerance Phase or the Treatment Phase. 
The Tolerance Phase consists of a 7-day washout period followed by two further visits. At visit 2, 
subjects will undergo the oral mucosal tolerance assessment carried out by the dermatologist at 
baseline, 30 minutes, and 2 hours after a single application of their allocated IP and the respective 
comparator. In addition to the oral mucosal tolerance assessment, subjects will undergo the 
vulvovaginal tolerance assessment carried out by the gynaecologist at baseline and 2 hours after 
a single application of their allocated IP. Upon completion of these assessments, subjects can 
leave the clinical site. Subjects will return to the clinical site for Visit 3 where oral mucosal tolerance 
assessment and vulvovaginal tolerance assessment will be performed 24 hours post single 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 42 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
clinically important change from baseline. 
 
 
taking into account the adjustment required to the significance level for testing 2 primary 
treatment comparisons, the study would require 24 subjects completing the 4-week treatment 
period in each of the 2 treatment groups. A study of this size would have 90% power for assessment 
of the primary endpoint. The individual FSFI domains are also of key importance in this study. 
 
 
 
 
 
For the study to be sufficiently powered for the primary endpoint and the individual FSFI domains, 
33 subjects will be randomised to each treatment group, which allows for a 10% attrition rate. 
A subset of 22 subjects will be selected in a 1:1 treatment ratio (see Section 6.3) to participate in 
the Tolerance Phase of the investigation, undergoing vulvovaginal and oral mucosal assessments, 
. Allowing for a 10% attrition rate this 
should ensure 20 subjects complete the Tolerance Phase. They will then move into the Treatment 
Phase, whereas the rest of the subjects in each arm will participate in the Treatment Phase only. 
4 
    SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Investigation Population 
A sufficient number of pre- and post-menopausal women will be screened from the clinical site’s 
database and / or through advertising to the public. 
66 subjects having provided informed consent and who meet the eligibility criteria will be 
randomised into the investigation to ensure 30 subjects per treatment group complete the 
investigation.  
The investigation population will include an approximate 1:1 ratio of pre- and post-menopausal 
women for both tolerance and treatment period per IP, with a difference of up to 40:60 split.  
There will be 1 clinical site in Germany participating in the investigation. 
4.2 
Inclusion Criteria 
The inclusion criteria comprise criterions which are applicable for all subjects (pre- and post-
menopausal) as well as additional criterions exclusive to each sub-population. Only subjects to 
whom all the following conditions apply will be included. 
4.2.1 
Universal Inclusion Criteria 
1. Subject and their male partner have provided written informed consent.  
2. Subject is female and both subject and their male partner are aged at least 18 years. Maximum 
age of female subject is 65 years. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 43 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
3. Subject and their male partner in a mutually monogamous heterosexual relationship (≥ 3 
months) who are sexually active, defined as having sexual intercourse at least once a week. 
(Note: The number of sexual intercourses may comprise twice in one week to account for a 
menstrual period break.) 
4. Female subject that agrees to have a gynaecological pelvic examination to ensure no significant 
disease findings and have intact skin and mucous in the test region (vaginal and vulvar / 
intimate area) except skin dryness as visually assessed by the gynaecologist at all the relevant 
time points. 
5. Female subject that agrees to an oral exam by a dermatologist to ensure no significant disease 
findings and have intact skin and mucous in the test region (oral cavity - including lips, inside 
lining of the lips, cheeks (buccal mucosa), teeth, gums, tongue, the floor of the mouth, roof of 
the mouth (hard palate) and area behind wisdom teeth (retromolar trigone). 
6. Subjects reporting mild to moderate vaginal dryness and dyspareunia during sex (when not 
using lubricant) in the past 3 months as confirmed by a score of 1 or 2 for vaginal dryness and 
1 or 2 for dyspareunia on the Verbal Rating Scale (VRS) of dyspareunia and vaginal dryness. 
4.2.2 
Pre-menopausal Inclusion Criteria 
1. Female of childbearing potential who is willing to use a highly effective method of contraception 
throughout the clinical investigation. A female is considered to be of childbearing potential 
following menarche and until becoming post-menopausal unless permanently sterile by 
methods including hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A highly 
effective method of contraception is defined as a method that can achieve a failure rate of less 
than 1% per year when used consistently and correctly. Such methods include combined 
(oestrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal and transdermal), progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable and implantable), intrauterine device 
(IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised 
partner (who has received medical assessment of the surgical success)(Recommendations 
related to contraception and pregnancy testing in clinical trials, Clinical Trials Facilitation and 
Coordination Group, Version 1.1, 2020). 
4.2.3 
Post-menopausal Inclusion Criteria 
1. Female subject in post-menopausal phase defined as having amenorrhea (absence of 
menstruation) for at least 12 consecutive months without an alternative medical cause 
(Recommendations related to contraception and pregnancy testing in clinical trials, Clinical 
Trials Facilitation and Coordination Group, Version 1.1, 2020). 
2. Female subject with premature menopause – due to surgical menopause or physiological 
menopause within the last 12 consecutive months of the screening visit (diagnosis to be 
confirmed as irreversible in subjects’ medical history) or after having received chemotherapy. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 44 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
4.3 
Exclusion Criteria 
The exclusion criteria comprise criterions which are applicable for all subjects (pre- and post-
menopausal) as well as additional criterions exclusive to each sub-population. Subjects to whom 
any of the following conditions apply must be excluded. 
4.3.1 
Universal Exclusion Criteria 
1. Female subject or their partner who has previously experienced an irritant or allergic reaction 
to any personal lubricant, vaginal moisturiser or female hygiene product or known to have any 
contact allergy or allergy/ hypersensitivity to the test product ingredients. 
2. Female subject with history of mucosal intolerance to warming agents. 
3. Female subject with continuous or intermittent oral allergy syndrome or burning mouth 
syndrome, or history of thereof (self-reported). 
4. Female subject with urinary, vaginal infection (fungal, bacterial) or sexually transmitted infection 
at screening visit, which in the opinion of the investigator would affect the study outcomes or 
the safety of the subject. 
5. Female subject that has any condition of the oral cavity, including oral infection, active oral 
herpes simplex virus, active canker sores or oral ulcers and erosions as determined by the 
investigator. 
6. Female subject who has had a positive cervical screening examination for human 
papillomavirus (HPV) within the 3 years of the screening visit (medical history/self-reported). 
7. Female subject presenting with signs of internal irritation, active psoriasis, lichen sclerosis, 
eczema or other active skin disorder upon clinical examination. 
8. Male partner of female subjects has broken skin or wounds in the intimate area (self-reported). 
9. Female subject with a history of skin disorder, which in the opinion of the investigator will affect 
study outcome. 
10. Female subject presenting clinically abnormal findings other than irritation e.g. lumps, open 
sores or blister type wounds during the physical examination (including the gynaecological 
examination) that in the opinion of the investigator will affect study outcome. 
11. Female subject that has had a suspicion of malignancy or history of malignancy within the past 
2 years (self-reported). 
12. Female subject with autoimmune conditions or any medical conditions which in the opinion of 
the investigator could compromise the immune function. 
13. Female subject who has had surgical cervical excision or vaginal and/or vulvar procedures, 
including laser and cosmetic procedures to the vulva or vagina in the previous year. 
14. Female subject that has any tooth ache or other dental/oral malady (self- reported). 
15. Female subject with ongoing dental/orthodontic procedures or any medical/surgical 
interventions involving the oral cavity (self-reported). 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 45 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
16. Female subject currently being treated with systemic medications or medicines (e.g. 
glucocorticosteroids, antibiotics, local oestrogen and other intravaginal products) that are acting 
locally in the vaginal area which may influence the clinical study outcomes. 
17. Female subject who has started, stopped, or changed hormonal treatments (for contraception, 
vaginal dryness, or any other condition) during the previous 3 months prior to screening or 
those intending or expecting a change in treatment during the investigation. 
18. Female subject who has used any kind of topical histamine and/or topical hormonal based 
product in the form of an intravaginal cream or moisturiser for local treatment of vaginal dryness 
in the past 3 months. 
19. Female subject taking steroid preparations, immunosuppressants or any other medication 
which in the opinion of the investigator may affect the test results:  
a. Anti-inflammatory or antihistamine within 1 week prior to the screening visit 
b. Cough suppressants or corticosteroids within 4 weeks prior to screening visit. 
c. Retinoids or immune suppressants within 6 months prior to screening visits. 
20. Female subject who has had any change to medication or treatment regimen for the treatment 
of diabetes mellitus during the previous 3 months prior to screening. 
21. Female subject using non-medicated, over the counter product, herbal/natural remedies on the 
vulva, vaginal opening and inside the vagina and is unwilling to stop at least 7 days prior to 
screening and throughout the duration of clinical investigation. 
22. Female subject showing vaginal prolapse and/or other medical conditions that could interfere 
with the investigation conduct and participation. 
23. Female subject using vaginal douches and is unwilling to stop its use at least 2 weeks prior to 
screening and throughout the duration of the clinical investigation. 
24. Female subject or their male partner that, in the opinion of the investigator, will be unable to 
comply fully with the study requirements or unable to tolerate the procedures described in the 
CIP. 
25. Female subject has participated in another investigation where a medicinal, medical device 
clinical investigation or any form of studies involved testing on female intimate area within 3 
months prior to screening. 
26. Female subject or their male partner has received an investigational product or participated in 
another trial involving a marketed or investigational drug in the 30 days (or for investigational 
agents with a long half-life, a washout of 5 half-lives) prior to screening. Or if the investigator 
believes that any previous participation in an investigational study would be to the detriment of 
the safety of the participant or the conduct of the study. 
27. Female subject or their male partner who is an employee at the site or a partner or first-degree 
relative of the Investigator. 
28. Female subject or their male partner fails to satisfy the investigator of fitness to participate for 
any other reason. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 50 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Table 5-1 Investigational Product – Quantitative Composition of Each Component per 
variant 
 
 
 
 the lubricants will be assembled 
to GMP standards by the IMSU and certified by Reckitt Research and Development (R&D) Quality. 
The IPs will be shipped directly from IMSU to the clinical site. 
5.2 
Non-Investigational Products 
Not applicable, as non-investigational product(s) is not to be supplied as part of this investigation.  

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 51 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
5.3 
Concomitant Therapies 
This section is applicable to both subjects and male partners.  
Any treatment considered necessary for the subject’s/male partner’s welfare may be administered 
and/or continued under the supervision of the investigator. Concomitant therapy, including 
prescription and non-prescription over-the-counter drugs, including vitamins, herbal and dietary 
supplements medication and non-pharmacological treatments such as physiotherapy, will be 
captured in the concomitant therapies page of the eCRF from the date of informed consent. Any 
changes in concomitant therapy during the investigation will be documented, including cessation 
of therapy, initiation of therapy and dose changes. The investigator will record the AE for which the 
concomitant therapy was administered in the eCRF. 
Female subjects are permitted to continue any prescribed oral contraception, contraceptive devices 
and HRT if this is ongoing at the time of screening and recorded on the concomitant therapy eCRF 
form. 
5.4 
Packaging and Labelling and Supply / Resupply 
A sufficient amount of IP and comparator to dispense to enrolled subjects will be packed and 
labelled along with spares in case of any issues / error during the investigation. The IPs and 
comparators will be labelled by the IMSU in accordance with EudraLex Volume 4 GMP Guidelines, 
Annex 13 - Manufacture of Investigational Medicinal Products, parts 26 to 33 (Labelling) and in 
accordance with directive 2003/94/EC as amended and including any other applicable national / 
state legislation or standards. The IPs and comparators will be assembled and shipped in bulk 
directly from the IMSU to the clinical site. 
5.5 
Storage Conditions 
At the clinical site the Investigator must keep all IP supplies, including comparators, in a secure 
area with restricted access. The IPs and comparators should be stored at room temperature, dry 
place, and away from direct sunlight. The correct storage conditions will be monitored and recorded 
weekly. Any excursions from the correct conditions must immediately be reported to the Sponsor, 
where appropriate action will be agreed and documented. 
5.6 
Masking 
This is an open label, parallel design clinical investigation and therefore is no intention to compare 
the IPs. For this purpose, the IPs and comparators will not be masked (i.e. the identity of the 
products will not be concealed). 
To minimize the evaluation bias, oral tolerance assessments will be performed by the dermatologist 
who will remain blinded to the randomisation in the Tolerance Phase. 
5.7 
Emergency Unblinding Procedures 
Not applicable, as per Section 5.6. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 52 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
5.8 
Accountability of Medical Device 
The investigator will keep all the investigational supplies in a secure storage facility, accessible to 
those individuals authorised by the Investigator to dispense IPs and comparators. The Investigator 
or designated individual will maintain an inventory, which will include the description and quantity 
of each IP and comparator received during the investigation, as well as the record of materials that 
are dispensed and returned (i.e. how much, to whom and when). This inventory will be subject to 
review by the investigation monitor during monitoring visits. 
5.9 
Return and Destruction  
The Investigator or designated individual will conduct a full IP and comparator supply reconciliation 
and will record the results of this reconciliation. Following review of this reconciliation 
documentation the clinical site will arrange for the return of all used and unused IPs and 
comparators to Reckitt IMSU to be destroyed at the end of the clinical investigation (upon 
finalisation of the Clinical Investigation Report (CIR). The IMSU reconciliation will be completed to 
confirm destruction. 
6 
INVESTIGATION PROCEDURES BY VARIABLE 
6.1 
Informed Consent 
Due to the exposure of the male partner to the IPs, the inclusion of the subject into the investigation 
will require consent from both female and male partner (separately). 
Prior to conducting any investigation-related activities, written informed consent must be obtained 
from the subject. No subject can enter the investigation before informed consent has been obtained. 
Upon signing the Informed Consent Form (ICF) the subject is enrolled into the investigation. 
All subjects will be provided with oral and written information describing the nature and duration of 
the investigation and the procedures to be performed. Enough time needs to be given to the subject 
to decide whether to participate or not. The Investigator must explain to each subject the nature of 
the investigation, its purpose, the procedures involved, the expected duration, the potential risks 
and benefits involved, and any potential discomfort. Each subject must be informed that 
participation in the investigation is voluntary and that she may withdraw from the investigation at 
any time and that withdrawal of consent will not affect her subsequent medical treatment or 
relationship with the treating physician. The subject must be informed that her medical records may 
be examined by authorised individuals other than their treating physician.  
The subject should understand the information provided and the ICF before signing and dating the 
ICF. The Investigator or person obtaining consent must also sign and date the form. Each subject 
will be given a copy of the signed informed consent and written information. 
The original signed ICF for each subject will be verified by the monitor and kept in the investigation 
centre investigational site files.   
If new information should become available during the investigation of which subjects need to be 
aware, an updated ICF will be provided and the above process will be followed to confirm subjects 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 53 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
are happy to continue with the investigation. For subjects who have completed the investigation, 
the Investigator will decide if this new information needs to be provided to them. 
6.2 
Male Partners 
Male partners of female subjects will be enrolled into the investigation and attend the clinical site 
for Visit 1 - Screening visit. Prior to conducting any investigation-related activities for the female 
subject, written informed consent will be obtained from the male partner. Each male partner will be 
provided with oral and written information describing the nature of the investigation, the IPs that his 
female partner will be testing and potential risks and benefits to them. Enough time needs to be 
given to the male partner to consider the participation. A female subject is free to participate in the 
investigation. However, if her male partner decides not to provide informed consent or withdraws 
from the investigation before completion, this means that the female subject will be withdrawn/can 
no longer participate. Each male partner must be informed that participation in the investigation is 
voluntary and that he may withdraw from the investigation at any time and that withdrawal of 
consent will not affect his subsequent medical treatment or relationship with the treating physician. 
The male partner must be informed that his medical records may be examined by authorised 
individuals other than their treating physician.   
The original signed ICF for each male partner will be verified by the monitor and kept in the 
investigation centre investigational site files. If new information should become available during the 
investigation of which male partners need to be aware, an updated ICF will be provided and the 
above process will be followed to confirm male partners are happy to continue with the investigation. 
For female subjects who have completed the investigation, the Investigator will decide if this new 
information needs to be provided to male partners. 
The eligibility of male partners will be assessed by the Investigator according to Section 4. Medical 
history and prior therapies (refer to Section 6.6), sex and age, lubricant use history will be collected  
The CIP requires male partner to attend the clinical site for Visit 3 in the Treatment Phase and 
complete questionnaires as described in Section 7. During the investigation, if the male partner 
experiences any AE/ADE, the event must be collected. The reporting can be via a contact by the 
male partner with the clinical site or via the female subject at each visit or via the male partner at 
his visit. Instructions on how to report an AE/ADE and any changes in medication and consult with 
the clinical site for any safety concern will be described in the ICF.  
6.3 
Randomisation 
This is an open label investigation and eligible subjects will be randomised to one of the two 
treatment groups by the use of a randomisation schedule generated in SAS version 9.4 and 
provided by the clinical research organisation (CRO). 
Eligible subjects will be randomised in a 1:1 ratio to one of the two treatment regimes using 
permuted blocks of fixed size of 4. The randomisation will be stratified by menopausal status, 
namely pre-menopausal for Strata 1 or post-menopausal for Strata 2. There will be no more than 
60% of subjects allocated from one strata.  

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 54 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
22 subjects will be selected in a 1:1 treatment allocation ratio to participate in the Tolerance Phase 
of the investigation. To ensure that an approximately even distribution of pre- and post-menopausal 
women participate in the Tolerance Phase (up to a maximum of 60% from any one strata), subjects 
will be enrolled into the Tolerance Phase in sequential order as they are randomised into the main 
study until a maximum of 13 subjects are chosen from one strata. As soon as the first 13 subjects 
from one strata are enrolled into the Tolerance Phase, the remaining subjects will be chosen 
sequentially from the other strata. Enrolling subjects into the Tolerance Phase in sequential order 
will ensure an approximately even distribution from both treatment groups. 
The randomisation schedule will also allocate which side of the mouth (left or right) the subjects 
will apply the test IP or the respective comparator, for the oral tolerance assessment in the tolerance 
phase. Assignment will be such that each test and comparator are assigned equally to the left and 
right side. The application always starts on the left-hand side. 
In the oral assessment, IP A is always tested against Comparator A and IP B is always tested 
against Comparator B. 
6.4 
Administration of Medical Device 
6.4.1 
Tolerance Phase 
6.4.1.1 
Vulvovaginal Tolerance Phase 
Subjects will be trained by the clinical site staff on the amount and how to apply their allocated IP 
to the vagina and intimate area. A single application, approximate 3 g amount of the IP, will be 
dispensed from the product container and applied to the vagina and vaginal area with fingers as 
per instructions for use and as per training given at the clinical site. 
6.4.1.2 
Oral Mucosal Tolerance Phase 
Each subject will test one IP and one comparator according to the randomisation schedule. A pea-
sized application of the allocated IP will be applied to the inner linings of the upper and lower lips 
of the subjects on one side of the mouth by the clinical site staff. A pea-sized application of the 
respective comparator will be applied to the other side of the mouth, again on the inner linings of 
the upper and lower lips of the subjects by the clinical site staff. The location of application (left or 
right side of the mouth) of the IP and its respective comparator will be determined according to the 
randomisation schedule. The application always starts on the left-hand side. 
Oral tolerance assessments must be performed by the same trained dermatologist who will remain 
blinded to the randomisation in the Tolerance Phase. 
6.4.2 
Treatment Phase 
Subjects will engage in vaginal penetrative sex at least once per week but will not be prohibited 
from engaging in other forms of sexual activity (e.g. receptive oral/anal sex, non-penetrative and 
penetrative masturbation with a sex toy, partner’s fingers or solo). Subjects will not be prohibited 
from using condoms, but this will not be the only form of contraception and the use will be captured 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 55 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
in the diary. At product dispensing, subjects will be provided with a demonstration of a 3 g amount 
of lubricant for reference. The subjects will be asked to apply their allocated IP to the vagina and 
intimate area in approximately 3 g increments. The number of re-applications required during 
sexual intercourse will be recorded in the diary. Subjects can apply the IP up to 4 times per day 
where 3 g is considered to be a single application. Subjects will be expected to use their applicated 
IP at least once a week over a 4-week period.  The number of penetrative penile/vaginal sexual 
intercourses may comprise twice in one week to account for a menstrual period break. 
Regular lubricant users will be instructed to use the lubricant as they would normally i.e. for vaginal, 
anal and / or oral sexual intercourse, ensuring that the IP is used at least once a week for vaginal 
penetrative sexual intercourse. Those subjects who do not usually engage in anal or oral will be 
instructed to use the product for vaginal sex only, for safety purposes. Only the lubricant (IP) 
dispensed by the clinical site is permitted for use during the investigation. Subjects will be instructed 
to not use any other vaginal products, remedy, vaginal moisturiser. The weight of the IP will be 
recorded when dispensed and again when subjects return to the clinical site following the 4-week 
use period. 
Subjects that use the IP less than once a week during penetrative penile/vaginal sexual intercourse 
and/or do not follow the study restrictions e.g. use of other vaginal product other than the dispensed 
IP are forms of non-compliance, in which case subjects will be reminded of the need to remain 
compliant and what this may mean to their participation in the investigation. 
6.5 
Demographics 
Baseline characteristics and demographic information will be recorded. This will include: 
1. For female subjects and their male partners: 
 
Sex 
 
Age 
2. For female subjects only: 
 
Menopausal status 
 
Ethnicity 
 
Date of last menstruation period 
 
Height (in metres to the nearest cm) 
 
Weight (kg to the nearest 0.1 kg; in indoor clothing and without shoes). 
Body Mass Index (BMI) will be calculated as follows: Body weight (kg) / [Height (m)]2 
6.6 
Medical History and Prior Therapies 
This section is applicable to both subjects and male partners.  
Details of all relevant current and historical medical diseases, conditions or surgeries, i.e. 
gynecologically and orientated including ovariectomy, hysterectomy, cancer and dental/oral health 
oriented including dental/oral procedures, and the duration, will be recorded. All prior therapies 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 56 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
such as prescription or non-prescription drugs, including vitamins, herbal and dietary supplements 
and non-pharmacological treatments such as physiotherapy will also be recorded. Medical history 
for all prior therapies should be recorded. In addition, risk of STI, pregnancy and method of 
contraception to be used during the investigation will also be recorded. 
6.7 
Physical Examination 
A complete physical examination of the subject will be performed by the Investigator or a medically 
qualified delegate (e.g. Principal Investigator / Co-Investigator) at Visit 1 – Screening Visit. A 
completed physical examination or selected examinations are to be performed if deemed 
necessary in the opinion of the Investigator in subsequent visits. 
The examination will include at least general appearance, skin/subcutaneous tissue, 
ears/eyes/nose/mouth/throat, 
head/neck, 
respiratory, 
cardiovascular, 
gastrointestinal, 
musculoskeletal, neurological and lymph nodes (via visual inspection and palpation). Other body 
systems can be examined if required, at the discretion of the Investigator or delegate. 
Subjects will also undergo a gynaecological examination by the gynaecologist (for both Tolerance 
Phase and Treatment Phase) and an oral examination by the dermatologist (for Tolerance Phase 
only). The gynaecological examination will include the pelvic examination, performed by the 
gynaecologist and any test per local practice to confirm the absence of infection, skin abnormalities 
and other health issues that would exclude the subject. The gynaecological examination will also 
involve checking for cutaneous irritancy (erythema, oedema, vulvar/vaginal dryness, leucorrhoea) 
and using a 5-point scale (1 = none; 2 = slight; 3 = minimal; 4 = moderate; 5 = severe) conducted 
in accordance with the principles described in assessing vaginal irritation in research (Mauck et al., 
2000). The oral examination (for Tolerance Phase only) will involve checking the oral cavity for 
signs and symptoms of irritation including erythema, erosions on lips or oral mucosa, oedema and 
any other signs of clinical irritancy or conditions of the oral cavity as recognisable by the 
dermatologist. 
6.8 
Pregnancy Test 
Urinary samples for pregnancy testing (for subjects of childbearing potential only) will be collected 
and prepared according to the Standard Operating Procedures (SOPs) of the clinical site 
conducting the analysis. 
6.9 
Verbal Rating Scale (VRS) of Dyspareunia and Vaginal Dryness 
Subjects reporting regular discomfort during sexual intercourse when not using lubricant, will be 
asked to verbally rate the intensity of their dyspareunia (painful intercourse) and vaginal dryness in 
the previous three months prior to the screening visit using the 4-point VRS of Dyspareunia and 
Vaginal dryness. Subjects will be asked to rate the two symptoms using the following scale: 
Dyspareunia 0-3 intensity scale: 
 
No pain [Absent (0)] 
 
Mild pain [Mild (1)] 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 57 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
 
Moderate pain [Moderate (2)] 
 
Severe pain [Severe (3)] 
Vaginal Dryness 0-3 intensity scale: 
 
No dryness [Absent (0)] 
 
Mild dryness [Mild (1)] 
 
Moderate dryness [Moderate (2)] 
 
Severe dryness [Severe (3)] 
Those subjects that rate the intensity of their dyspareunia and vaginal dryness or just vaginal 
dryness a score of 1 (mild) or 2 (moderate) would meet the inclusion criterion. 
6.10 
Lubricant Use History 
Subjects and male partners will be asked about their experience in using a lubricant(s), information 
such as (but not limited to) will be captured; user or non-user of lubricant, when does the subject 
use lubricant (i.e. for oral, anal, vaginal sexual intercourse), frequency of lubricant use. 
6.11 
Tolerance Phase Variables 
6.11.1 
Vaginal Epithelial Tolerability (VET) Assessment 
Vaginal tolerability of the IP will be evaluated by the gynaecologist at baseline, 2 hours and 24 
hours post single application. The gynaecologist will examine the vaginal dermal tissue for signs 
and symptoms of erythema, oedema, vulvar membrane dryness, leucorrhoea and other each sign 
and symptom will be scored using the following 5-point scale (in accordance with the principles 
described in assessing vaginal irritation in research (DeRogatis et al., 2014)): 
 
1 = None 
 
2 = Slight 
 
3 = Minimal 
 
4 = Moderate 
 
5 = Severe 
6.11.2 
Global Assessment of Vulvovaginal Tolerance 
At the end of the Tolerance Phase (or withdrawal if earlier) the gynaecologist will make a ‘global 
assessment’ of vulvovaginal tolerance for each subject for each IP based on measured parameters, 
any clinical signs of irritancy observed, subject’s perception of vulvovaginal tolerance (SPQ – 
Tolerance); taking into account the expected degree of irritancy for this type of product, using the 
following 5-point scale: 
 
1 = Very Good 
 
2 = Good 
 
3 = Acceptable  
 
4 = Poor 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 58 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
 
5 = Very Poor 
6.11.3 
Overall Vulvovaginal Tolerance Rating Statement 
At the end of the Tolerance Phase, the gynaecologist will make an overall summary assessment 
of vulvovaginal tolerance of the IP, driven by Global Assessment of Vulvovaginal Tolerance and 
taking into consideration all tolerance assessments across all subjects and the nature of the product 
in its intended use, in the following format: 
The product is very well / well / moderately well / not well / not at all well tolerated by all / most / 
some / a few subjects.  
6.11.4 
Oral Mucosal Tolerance 
Oral mucosal tolerability of the IPs and comparator will be evaluated by the dermatologist via a lip 
test at baseline, 30 minutes, 2 hours and 24 hours post single application to the upper and lower 
inner lip. The dermatologist will examine the oral mucosa for signs and symptoms of erythema, 
erosions on lips or oral mucosa, oedema and any other signs of clinical irritancy as recognisable 
by the expert. Signs/symptoms will be scored using the following scale: 
 
1= none 
 
2 = slight 
 
3 = minimal 
 
4 = moderate 
 
5 = severe   
The presence of any adverse reactions (e.g., difficulty in breathing, oedema elsewhere on face, 
and anaphylaxis) will be recorded.  
6.11.5 
Global Assessment of Oral Mucosal Tolerance 
At the end of the Tolerance Phase (or withdrawal if earlier) the dermatologist will make a ‘global 
assessment’ of oral mucosal tolerance of each IP and comparator based on measured parameters, 
any clinical signs of irritancy observed, subject’s perception of oral mucosal tolerance (SPQ – 
Tolerance); taking into account the expected degree of irritancy for this type of product, using the 
following 5-point scale: 
 
1 = Very Good 
 
2 = Good 
 
3 = Acceptable 
 
4 = Poor 
 
5 = Very Poor 
6.11.6 
Overall Oral Mucosal Tolerance Rating Statement 
At the end of the Tolerance Phase, the dermatologist will make an overall summary assessment of 
tolerance of each IP and comparator driven by Global Assessment of Oral Mucosal Tolerance and 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 59 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
taking into consideration all oral mucosal tolerance assessments across all subjects and the nature 
of the product in its use for oral sex, in the following format:  
The product is very well / well / moderately well / not well / not at all well tolerated by all / most / 
some / a few subjects. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
6.11.9 
Subject Perceived Questionnaire (SPQ) – Tolerance Phase 
As part of the Tolerance Phase, subjects will be asked about their perception of tolerance post 
application. The subjects’ perception of vulvovaginal tolerance and oral mucosal tolerance will be 
determined at 24 hours post application through a 5-point agreement scale (Likert scale) listed as:  
 
Strongly Agree 
 
Agree 
 
Neither Agree nor Disagree 
 
Disagree 
 
Strongly Disagree 
In addition, the subject' perception of intensity of the sensation provided by the IP on vulvovaginal 
tolerance and oral mucosal tissue will be determined at 24 hours post application. This will be rated 
by subjects on an 11-point numeric rating scale (NRS), where 0 = “There is no sensation from the 
lubricant”; 5 = “The intensity of the sensation provided by the lubricant is just right”; 10 = “The 
intensity of the sensation provided by the lubricant is unbearable”. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 60 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
6.12 
Treatment Phase Variables 
6.12.1 
Female Sexual Function Index (FSFI) 
The FSFI is a 19-item self-report questionnaire (paper) to measure sexual functioning in women. 
The questionnaire assesses six domains of sexual function (sexual desire, sexual arousal, 
lubrication, orgasm, satisfaction and pain) as well as a total score. The questionnaire requires a 4-
week recall. 
6.12.2 
Subject Diary 
Subjects will be required to complete a paper diary for the run-in phase and a paper diary for the 4-
week IP use period to capture the information (but not limited to): 
 
Date and time of IP use 
 
Number of vaginal penetrative sex occasions 
 
Site of IP application (for each sex occasion) 
 
Number of IP applications per sex occasion 
 
Details of additional sexual activity outside of vaginal penetrative sex  
 
Condom use 
 
Comments on experience with the IP during initial entry versus deeper penetration/thrusting 
 
Any changes in medication 
 
Any AEs 
 
Any other comments 
6.12.3 
Subject Perceived Questionnaire (SPQ) – Treatment Phase 
During the Treatment Phase, subjects and male partners will be asked about their perception of the 
allocated IP, after first IP use (within 24 hours of intercourse) and after 4 weeks of IP use. Their 
perception will follow the 5-point agreement scale (Likert scale) listed as: 
 
Strongly Agree 
 
Agree 
 
Neither Agree nor Disagree 
 
Disagree 
 
Strongly Disagree 
6.12.4 
Global Evaluation of Product Effectiveness, Tolerability and Usability 
At the end of the Treatment Phase (or withdrawal if earlier) subjects will be asked to provide their 
global evaluation of their allocated IP after using their allocated IP for 4-week. Subjects will be asked 
to rate their agreement using the following scale: 
 
Very Satisfied 
 
Somewhat Satisfied 
 
Neither Satisfied nor Dissatisfied 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 61 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
 
Somewhat Dissatisfied 
 
Very Dissatisfied 
6.12.5 
Patients Global Impression of Change (PGIC) 
At the end of the Treatment Phase (or withdrawal if earlier) subjects and male partners will be 
asked to complete a PGIC (Hugh H and Jennifer B, 2004). PGIC is a patient reported scale to 
assess patient perception of change in a condition or symptom following treatment. The 
subjects and male partners will be asked to rate the change in sexual intimacy experienced 
within their couple after using their allocated IP for 4-week.  PGIC will be presented in a form 
of the visual analogue scale (VAS): 
 
-3 (Much Worse) 
 
-2 
 
-1 
 
0 (No Change) 
 
1 
 
2 
 
3 (Much Better) 
 
 
 
 
 
6.13 
Adverse Events  
During scheduled visits, non-leading questions (‘Are you experiencing any symptoms or 
complaints? / Have you felt unwell, suffered any complaints or taken any medication since… / Have 
you had any symptoms of complaints since the last time you were asked?’) will be used to collect 
any AE/ADE experienced by the subject/male partner. Additionally, spontaneously reported 
AEs/ADEs will be collected. AE/ADE of male partners can be reported via a contact by the male 
partner with the clinical site or via the female subject at each visit or via the male partner at his visit. 
The observation period for an individual subject/male partner will start after giving informed consent 
and will finish at the last visit of the Treatment Phase for the given individual subject/male partner. 
All AEs/ADEs that arise during the observation period will be recorded and an assessment of the 
AEs/ADEs will be performed as per Section 8.1 by a medically qualified Investigator. If a 
subject/male partner has an AE/ADE that is still ongoing at the last visit, an attempt will be made 
by the Investigator to follow this up as per Section 8.3.   
If an untoward medical occurrence happens after the subject/male partner has signed the consent 
form but before administration of the device, it should be reported as an AE, including those 
associated with investigation procedures.

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 62 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
7 
INVESTIGATION PROCEDURES BY VISIT 
7.1 
Investigation Flow Chart / Table of Investigation Procedures and Assessments 
Table 7-1 Schedule of Assessments – Tolerance Phase 
Period 
 
 
Procedure 
Screen
ing 
Tolerance Phase 
Treatment 
Phase 
Visit 1 
7-Day 
Wash-
Out 
Period 
Visit 21 
Vi
sit 
32 
Ru
n-
In 
Ph
as
e 
Vi
sit 
23 
Vi
sit 
34 
Ba
sel
ine 
30 
mi
ns 
2 
hr
s 
24 
hr
s 
Informed consent (including male partners) 
X 
 
 
 
 
 
 
 
 
Inclusion / Exclusion (including male partners) 
X 
 
X5 
 
 
X5 
 
X5 
X5 
Verbal Rating Scale (VRS) of Dyspareunia and Vaginal Dryness6 
X 
 
 
 
 
 
 
 
 
Demographics (including male partners) 
X 
 
 
 
 
 
 
 
 
Medical history & prior therapies (including male partners) 
X 
 
 
 
 
 
 
 
 
Concomitant medication (including male partners) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
X7 
 
 
X7 
 
X7 
X7 
Pregnancy test 
X 
 
 
 
 
X8 
 
 
X8 
Lubricant Use History 
X 
 
 
 
 
 
 
 
 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 63 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Period 
 
 
Procedure 
Screen
ing 
Tolerance Phase 
Treatment 
Phase 
Visit 1 
7-Day 
Wash-
Out 
Period 
Visit 21 
Vi
sit 
32 
Ru
n-
In 
Ph
as
e 
Vi
sit 
23 
Vi
sit 
34 
Ba
sel
ine 
30 
mi
ns 
2 
hr
s 
24 
hr
s 
Randomisation9 
X 
 
 
 
 
 
 
 
 
Vaginal Epithelial Tolerability Assessment 
 
 
X 
 
X 
X 
 
 
 
Global Assessment of Vulvovaginal Tolerance 
 
 
 
 
 
X 
 
 
 
Overall Vulvovaginal Tolerance Rating Statement 
 
 
 
 
 
X 
 
 
 
Oral Examination/Assessment 
 
 
X 
X 
X 
X 
 
 
 
Global Assessment of Oral Tolerance 
 
 
 
 
 
X 
 
 
 
Overall Oral Tolerance Rating Statement 
 
 
 
 
 
X 
 
 
 
SPQ – Tolerance Phase 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSFI Questionnaire 
 
 
 
 
 
 
 
X 
X 
SPQ – Treatment Phase (including male partners) 
 
 
 
 
 
 
 
X11 
X 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 66 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
7.2 
Visit 1 – Screening Visit 
At the screening visit, subjects and male partners will be informed about the investigation as 
described in Section 6.1 and Section 6.2. They will be asked to provide written informed consent 
for their participation in the investigation, prior to performing any investigation specific assessments. 
Once informed consent has been obtained, the subjects will undergo clinical assessments 
consisting of: 
 
Demographics (including male partners) 
 
Medical history and prior therapies (including male partners) 
 
Physical examination, including gynaecological examination and oral examination  
 
The last menstrual period (the first date and the last date) 
 
Pregnancy test (for subjects of childbearing potential only) 
 
Concomitant medication and AEs (including male partners) 
 
Completion of VRS of dyspareunia and vaginal dryness 
 
Lubricant use history 
Once screening activities have been completed and results are available confirming the subject’s 
suitability to enter the investigation as per the inclusion/exclusion criteria, subjects and male 
partners will be reminded of the investigation’s restrictions as per Section 4.4. Subjects will be 
randomised into one of two treatment groups using 
. Each group will 
include an approximate 1:1 ratio of pre-menopausal to post-menopausal females, with an allowed 
difference of up to 40:60 (up to a maximum of 60% in either sub-population). 
A subset of 22 subjects will undergo the Tolerance Phase of the investigation prior to entering the 
Treatment Phase per the randomisation schedule. Subjects entering the Treatment Phase directly 
will be issued a diary and instructed to complete during the run-in phase. 
All assessments conducted during the screening visit are detailed in Section 6 and summarised in 
Table 7-1. All clinical assessments and test results will be entered into each subject’s eCRF. 
7.3 
Tolerance Phase 
7.3.1 
Wash-Out Period 
Subjects participating in the Tolerance Phase, will undergo a 7-day wash-out period. During this 
period, subjects are not permitted to use any personal lubricants or other remedies for vaginal 
dryness and will be asked to refrain from engaging in vaginal sex or any other vaginal penetrative 
sexual activity e.g. digital stimulation or use of sex toys. Subjects will also be prohibited from using 
any new oral products that are irregular to their normal dental hygiene routine or eating any new 
foods outside their normal diet.  
 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 67 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
7.3.2 
Visit 2 
Visit 2 should be conducted within 10 days after Visit 1. All requirements in the wash-out period 
must be followed until subjects attend the clinical site for Visit 2. 
Following a 7-day wash-out period, subjects will return to the clinical site for the Tolerance Phase, 
where subjects’ continued eligibility will be confirmed. Physical examination will be carried out if 
necessary, in the opinion of the investigator.  
Once on the clinical site, subjects will be provided with a snack and drink, ahead of an oral water 
rinse. After the oral water rinse subjects will participate in an additional 30-minute oral wash out 
period during which they will be asked to refrain from using any oral products or consuming any 
foods/drinks. If necessary, subjects may have water, and this will be recorded. 
The following baseline assessments and measurement will be performed prior to IP application: 
 
Vaginal Epithelial Tolerability (VET), performed by the gynaecologist 
 
Oral examination by the dermatologist after additional 30-minute wash-out  
 
 
 
 
 
 
For the vulvovaginal assessments, subjects will be trained by the site staff on how to apply the IP 
to the vagina and intimate area and will then make the single application of lubricant at the clinical 
site in preparation for the 2-hour post application vulvovaginal assessment. For the oral 
assessments, the clinical site staff will apply a pea-sized application of the IP and the respective 
comparator to the inner linings of the upper and lower lips of the subject on both sides of the mouth, 
according to the randomisation schedule. Subjects will be assessed at 30 minutes (±15 minutes) 
post application (oral mucosal tolerance only) and 2 hours (±15 minutes) post application (VET, oral 
mucosal tolerance, 
 In the first 2 
hours post application, subjects will be asked to refrain from consuming any foods/drinks. If 
necessary, subjects may have water, and this will be recorded. 
Subject’s last menstrual period (the first date and the last date) will be recorded if the data is different 
from Visit 1. AEs will be collected using a general non-leading question.  In addition, spontaneously 
reported AEs will be collected. Concomitant medication changes will be recorded. 
While subjects are at home, they will be instructed to abstain from any vaginal penetrative activity 
including sexual activity or insertion of tampons and will refrain from using any vaginal products 
such as moisturisers or intimate washes. They will also be instructed to eat and drink as normal 
however again will be prohibited from using any new oral products that are irregular to their normal 
dental hygiene routine or eating any new foods outside their normal diet. Subjects will not be 
provided with any product to take home as there will be no additional applications during the 
Tolerance Phase. 
All assessments conducted during the Visit 2 are detailed in Section 6 and summarised in Table 7-
1. All clinical assessments and test results will be entered into each subject’s eCRF. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 68 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
7.3.3 
Visit 3 
Subjects will return to the clinical site for their 24-hour assessment. After confirmation of continued 
eligibility, subjects will undergo the following clinical assessments within the window of 24 hours ±2 
hours: 
 
Vaginal Epithelial Tolerability (VET), performed by the gynaecologist 
 
Oral Assessment by the dermatologist 
 
 
 
 
Subjects will be asked to complete the SPQ – Tolerance Phase at the clinical site. At the end of the 
Tolerance Phase, the gynaecologist will complete a Global Assessment of Vulvovaginal/Oral 
Mucosal Tolerance for each subject and provide an Overall Vulvovaginal/Oral Mucosal Tolerance 
Rating Statement for each IP. The Investigator (in consultation with the gynaecologist and the 
dermatologist) will determine if the subject remains eligible to enter the Treatment Phase of the 
investigation, as per the inclusion/exclusion criteria and given that the subject has not experienced 
any untoward medical occurrence. Additionally, subjects will be issued a diary and instructed to 
complete during the run-in phase as they enter the Treatment Phase. 
Subject’s last menstrual period (the first date and the last date) will be recorded if the data is different 
from Visit 2. AEs will be collected using a general non-leading question. In addition, spontaneously 
reported AEs will be collected. Concomitant medication changes will be recorded. 
All assessments conducted during the Visit 3 are detailed in Section 6 and summarised in Table 7-
1. All clinical assessments and test results will be entered into each subject’s eCRF. 
7.4 
Treatment Phase 
7.4.1 
Run-In Phase  
Following the confirmation of subject’s eligibility, subjects entering the Treatment Phase will 
undergo a 4-week run-in phase. Those subjects that have completed the Tolerance Phase of the 
investigation, will move into the 4-week run-in phase of the Treatment Phase. During this run-in 
phase, subjects will be asked to refrain from using any personal lubricants or remedies for vaginal 
dryness during sexual activity. Subjects will be asked to consent to engaging in vaginal penetrative 
sex at least once per week during this 4-week period. The number of sexual intercourses may 
comprise twice in one week to account for a menstrual period break. Subjects will be asked to 
record into their diary the number and frequency of coital acts during this period, including when 
subjects were unable to have sexual intercourse without the use of a lubricant and/or for menstrual 
bleeding (pre-menopausal women).  
7.4.2 
Visit 2 – Baseline 
This is Visit 4 for subjects undergone the Tolerance Phase. This visit should be conducted within 
±3 days after the completion of the 4-week Run-In Phase. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 69 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Subjects will return to the clinical site following the run-in phase, where the following will be 
performed: 
 
Assess subject’s continued eligibility as per inclusion/exclusion criteria 
 
Physical examination, including gynaecological examination (if necessary, in the opinion of 
the Investigator) 
 
Completion of FSFI by the subject 
 
 
 
 
 
Collection of diary and review for compliance 
 
Issuing new diary for the IP use period & SPQ – Treatment Phase 
 
Weigh and dispense IP 
 
Recording of AEs and concomitant medication changes  
 
Recording subject’s last menstrual period (the first date and the last date) 
Upon completion of the FSFI, subjects will be trained on how to apply the IP to the vagina. Subject’s 
allocated IP (as per the randomisation schedule) will be weighed prior to being dispensed for the 
subject to use at home for a 4-week IP use period. Subjects will be instructed to use their allocated 
IP when engaging in vaginal penetrative intercourse at least once a week. Regular lubricant users 
will be instructed to use the lubricant as they usually would i.e. for vaginal, anal and/or oral sexual 
intercourse, ensuring that the IP is used at least once a week for penile/vaginal intercourse. For 
safety purposes, those subjects who do not usually engage in anal or oral will be instructed to use 
the IP for penile/vaginal sexual intercourse only. 
Subjects will also be issued a diary to record number of sex occasions, site of lubricant application 
and number of lubricant applications per sex occasion. Additionally, subjects will be instructed that 
the subject and the male partner should complete an SPQ – Treatment Phase after the first use of 
the IP at home, within 24 hours of the intercourse. Subjects will be reminded of the study restrictions 
as per Section 4.4, after which subjects will be permitted to leave the clinical site. 
All assessments conducted during Visit 2 are detailed in Section 6 and summarised in Table 7-1. 
All clinical assessments and test results will be entered into each subject’s eCRF. 
7.4.3 
Visit 3 (End of Investigation) 
This is Visit 5 for subjects who have participated in the Tolerance Phase. This visit should be 
conducted within ±3 days after the completion of the 4-week IP use period. 
Subjects and male partners will return to the clinical site after the 4-week IP use period, where there 
following assessments will be performed: 
 
Completion of FSFI by the subject 
 
Completion of an SPQ – Treatment Phase by the subject and the male partner 
 
Completion of Global Evaluation of Product Effectiveness, Tolerability and Usability by the 
subject 
 
Completion of PGIC by the subject and the male partner 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 70 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
 
Physical examination, including gynaecological examination (if necessary, in the opinion of 
the Investigator) 
 
Collection of diary and review for compliance 
 
Collect and weigh returned IP 
 
 
 
 
 
Recording of AEs and concomitant medication changes (including the male partner) 
 
Recording subject’s last menstrual period (the first date and the last date) 
All assessments conducted during the Visit 3 are detailed in Section 6 and summarised in Table 7-
1. All clinical assessments and test results will be entered into each subject’s eCRF. 
7.5 
Unscheduled Visits 
If unscheduled visits occur, the Investigator must record the reason for unscheduled visit, including 
any AEs/ADEs that the subject or the male partner has experienced since their last visit, 
concomitant medication changes, withdrawal (if deemed appropriate) and any clinical assessments 
deemed appropriate for their clinical care. 
Unscheduled visits should not alter the timing of the routine investigation schedule. 
8 
SAFETY REPORTING 
In this investigation, safety reporting is applicable for both female subjects and male partners by 
following the process described in this section, which the term of ‘subject’ refers to both female and 
male partners.  
Safety Reporting in the investigation are in compliance with the Regulation (EU) 2017/745, the 
guidance of MDCG 2020-10/1 and the guidelines on medical devices, MEDDEV 2.7/3 revision 3, 
May 2015. 
8.1 
Adverse Event Definitions 
Adverse Event 
An Adverse Event (AE) is any untoward medical occurrence, unintended disease or injury or any 
untoward clinical signs (including an abnormal laboratory finding) in subjects, users or other 
persons, in the context of a clinical investigation, whether or not related to the investigational 
medical device.   
This definition includes events that are anticipated as well as unanticipated events. 
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. 
This includes any adverse event resulting from insufficiencies or inadequacies in the instructions 
for use, the deployment, the implantation, the installation, the operation, or any malfunction of the 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 71 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
investigational medical device. This includes any event that is a result of a use error or intentional 
abnormal use of the investigational medical device. This includes any AE resulting from insufficient 
or inadequate instructions for use, deployment, implantation, installation, operation, or any 
malfunction of the investigational medical device. This includes any event that is a result of a use 
error or intentional misuse.    
Device Deficiency 
Any inadequacy in the identity, quality, durability, reliability, safety or performance of an 
investigational device, including malfunction, misuse or use errors or inadequacy in information 
supplied by the manufacturer. 
Serious Adverse Event 
A Serious Adverse Event (SAE) is any AE that led to any of the following:  
a. 
death,  
b. 
serious deterioration in 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.  
A planned hospitalisation for pre-existing condition, or a procedure required by the CIP, without a 
serious deterioration in health, is not considered to be an SAE. 
This includes device deficiencies that might have led to a SAE if  
a. suitable action had not been taken or  
b. intervention had not been made or  
c. if circumstances had been less fortunate.  
Serious Adverse Device Effect 
A Serious Adverse Device Effect (SADE) is an ADE that has resulted in any of the consequences 
characteristic of a SAE. 
Unanticipated Serious Adverse Device Effect  
An Unanticipated Serious Adverse Device Effect (USADE) is an effect which by its nature, 
incidence, severity or outcome has not been identified in the current version of the risk analysis 
report.  
Anticipated Serious Adverse Device Effect  
Anticipated SADE (ASADE): an effect which by its nature, incidence, severity or outcome has been 
previously identified in the current version of risk analysis report.  

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 72 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
8.2 
Assessment of Adverse Events 
All AEs that arise after the subject has given informed consent will be recorded in the subject’s 
source documents and eCRF. AEs can be reported spontaneously by the subject or in response to 
non-leading questioning, observation by the Investigator or be a significant laboratory abnormality. 
All AEs, ADEs, SAEs, SADEs and USADEs are collected, fully investigated and documented.  
SAE / SADE / USADEs should be followed until resolution or stabilisation. Subjects with ongoing 
SAE / SADE / USADEs at investigation termination will be further followed up until recovery or until 
stabilisation of the disease after termination. 
For each SAE, a causality assessment of the event to the investigational device, the comparator or 
the investigation procedure must be performed. For each AE, the relationship between the use of 
the investigational device (including the medical - surgical procedure) and the occurrence of each 
adverse event shall be assessed and categorized. The relationship must be determined by the 
Investigator (if medically qualified) or by a medically qualified Co-Investigator. 
 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 73 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Relationship 
Description 
Not related 
Relationship to the investigational device, comparator or procedures can 
be excluded when:  
 
the event is not a known side effect of the product category the 
device belongs to or of similar devices and procedures. 
 
the event has no temporal relationship with the use of the 
investigational device or the procedures related to application of 
the investigational device. 
 
the serious adverse event does not follow a known response 
pattern to the investigational device (if the response pattern is 
previously known) and is biologically implausible. 
 
the discontinuation of investigational device application or the 
reduction of the level of activation / exposure - when clinically 
feasible - and reintroduction of its use (or increase of the level of 
activation / exposure), do not impact on the serious adverse event. 
 
the event involves a body-site or an organ that cannot be affected 
by the device or procedure. 
 
the serious adverse event can be attributed to another cause (e.g. 
an underlying or concurrent illness / clinical condition, an effect of 
another device, drug, treatment or other risk factors). 
 
the event does not depend on a false result given by the 
investigational device used for 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 serious adverse event. 
Possible 
 
The relationship with the use of the investigational device or comparator, 
or the relationship with 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 procedures, seems relevant and / or the event 
cannot reasonably explained by another cause. 
Causal 
Relationship 
The serious adverse event is associated with the investigational device, 
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. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 75 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Concomitant medications are coded by the CRO using the WHO dictionary (including ATC 
coding). 
8.3 
Reporting of Adverse Events 
In the event of an SAE, SADE, USADE or device deficiency that could have led to an SAE, the 
Investigator must report the event using the appropriate form to the Sponsor’s Adverse Event 
Management Team (AEMT) by email: 
including in the email vendor and Sponsor 
Study Managers within 24 hours of knowledge of the event. 
The out of hours emergency phone number is 
 if consultation is required 
by the Investigator.  
This emergency phone number will be confirmed to the Investigator at the Investigation Initiation 
Visit.  
All SAE / SADE / USADE forms must be provided via email including reports of device deficiency 
that could have led to a SAE/ SADE/ USADE. Any inconsistencies in the information received from 
the Investigator will be clarified on an updated SAE / SADE form. The Investigator must retain a 
copy of all the forms in the Investigator Site File. 
The Investigator, if required by regulations, must inform their local Independent Ethics Committee 
(IEC) / Research Ethics Committee (REC) / Institutional Review Board (IRB) of all SAE / SADE / 
USADEs and reportable Device Deficiencies occurring in the investigation as per Sponsor 
instructions as described in the Safety Management Plan.   
SAE / SADE / USADEs, Device Deficiencies will be reported to the appropriate regulatory 
authorities by the Sponsor in accordance with the authorities’ requirements. The Sponsor is 
responsible for expedited reporting of all SAE / SADE / USADEs and reportable Device Deficiencies 
to relevant authorities. The Investigator is responsible for expedited reporting of all SAE / SADE / 
USADEs and reportable device deficiencies to the IECs / IRBs as required by regulations. If the 
event requires expedited reporting, the AEMT and Investigator will take actions as per the 
investigation specific Safety Management Plan.  
The Investigator must report all reportable events to the sponsor immediately but not later than 24 
hours after investigational site investigation personnel’s awareness of the event.  
8.4 
Follow-up of Adverse Events 
All SAE / SADE / USADEs and all AE / ADEs that have not resolved by the end of the investigation 
will be followed up by the Investigator until resolution or until the Investigator believes there will be 
no further change, whichever is the earlier. This may involve the subject making additional visits to 
the site.  
In the case of loss to follow-up, at least two documented attempts to contact the subject must be 
made by the Investigator or designee before this is defined.  
The end of the investigation is defined as the last visit of the last subject in the investigation.  

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 76 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
All SAE/SADE/USADEs and all AE/ADE that cause premature withdrawal of the subject from the 
investigation and have not resolved by the end of the clinical investigation will be followed up by 
the Investigator until resolution or until the Investigator believes there will be no further change. 
This may involve the subject making additional visits to the site. The minimum data required are 
the subject number, suspected investigational product, final outcome and date, which may be 
obtained by the Investigator in a documented telephone conversation with the subject or subject’s 
general practitioner (GP) / Primary Care Physician (PCP). 
Subjects who experience the onset of an (S)AE after the last visit (end of the investigation) will not 
need to be recorded. 
8.5 
Misuse and Medical Device administration Errors 
The Sponsor defines “misuse” as situations where the medical device is intentionally and 
inappropriately used not in accordance with the authorised product information. 
All incidences of misuse are reportable to the Sponsor irrespective of the presence of an associated 
AE. The misuse and any associated untoward event will be captured on an AE / ADE eCRF page 
or on a SAE / SADE / USADE form. 
Medical device administration errors are any unintentional errors in administration which relates to: 
 
Using / being administered an incorrect medical device 
 
Using / being administered the medical device by the wrong route of administration / 
application 
 
The accidental administration of the medical device to a person who is not a subject within 
the investigation 
Medical device administration errors are reportable to the Sponsor irrespective of the presence of 
an associated AE. Medical device administration errors with or without an associated untoward 
event will be captured on an AE / ADE eCRF page or on a SAE / SADE / USADE form. 
8.6 
Pregnancy 
Pregnancy in a female subject is considered a collectable event and will be recorded as an AE in 
all cases. It will be qualified as an SAE only if it fulfils SAE criteria. 
Pregnant subjects must immediately be withdrawn from the clinical investigation and the Sponsor 
must be promptly notified of the event. Any pregnancy during the investigation will be reported to 
the Sponsor within 24 hours of becoming aware of the pregnancy. The course and outcome of the 
pregnancy should be followed up carefully by the Sponsor Pharmacovigilance personnel (Drug 
Safety Officer) as part of their safety monitoring responsibilities and will not form part of the 
investigation dataset. Any abnormal outcome regarding the mother or the child should be 
documented and reported.  

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 77 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
9 
STATISTICAL CONSIDERATIONS 
All statistical analysis will be conducted by the Vendor. The statistical software that will be used for 
the analysis will be SAS® version 9.4 or newer. All data will be listed by treatment group. 
In general, continuous data will be summarised by treatment group using the following descriptive 
statistics: n, mean, standard deviation, median, minimum and maximum.  Categorical data will be 
summarised by treatment group as the number and percentage of subjects in each category. 
9.1 
Statistical Analysis Plan 
Details of statistical methods and analysis will be documented in the Statistical Analysis Plan (SAP) 
which will be finalised before the first subject is screened. 
If there are any deviations to the proposed statistical analysis as described in this protocol these 
will either be documented in a protocol amendment and/or the final SAP prior to First Subject First 
Visit with the rationale and impact of the changes addressed. 
9.2 
Interim Analysis 
No interim analysis will be performed.  
9.3 
Analysis Datasets 
The Full Analysis Set (FAS) will include all randomised subjects who enter the Treatment Phase of 
the study. The FAS will be used to assess the primary endpoint and all other endpoints that are 
assessed during the Treatment Phase, with the exception of adverse events. Subjects will be 
assigned to treatment to which they were randomised. 
For the FSFI (total score and percentage of subjects achieving at least a 4-point change in total 
score), an analysis will also be performed on the Per Protocol (PP) population. The PP population 
will exclude subjects who have not been compliant with the requirements of at least one coital act 
per week during both the run-in and 4-week IP use period of the Treatment Phase, as well as using 
IP at least once per week for penile/vaginal intercourse during the treatment period. In addition, 
subjects who use less than 80% of their assigned product (<9.6g) will be removed from the PP 
population. Subjects may be excluded from the PP population due to other reasons that may impact 
the evaluation of study products and these will be identified prior to database lock. Subjects will be 
assigned to treatment received. 
The Safety Population will include all randomised subjects and will include subjects who take part 
in the Tolerance Phase and/or the Treatment Phase. The Safety Population will be used for 
producing demographic, adverse event and other safety tables. Subjects will be assigned to 
treatment received. 
9.4 
Subject Disposition and Characteristics 
Subject disposition and demographic characteristics will be presented by treatment group and 
overall. Frequencies and percentages will be used to present the number of subjects that 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 79 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
For the primary analysis, the Total FSFI Score at Visit 3 of the Treatment Phase is compared to its 
baseline value using a paired t-test. The statistical testing is carried out separately for each IP and 
consequently a single null and alternative hypothesis is defined for each IP. This results in two 
individual hypothesis pairs, which apply analogously to the following example for both IPs: 
H0: The Total FSFI score at Visit 3 of the Treatment Phase shows no difference from the 
corresponding baseline score.  
H1: The Total FSFI score at Visit 3 of the Treatment Phase shows a difference from the 
corresponding baseline score.  
Theses hypotheses are expressed mathematically by 
H0: µBaseline = µV3 
H1: µBaseline ≠ µV3 
where µBaseline is the mean total FSFI Score at Baseline and µV3 is the mean total FSFI Score at Visit 
3 of the Treatment Phase. 
Since the primary endpoint is being evaluated for each product separately, the resulting p-values 
will be compared to a critical alpha threshold that will be adjusted according to the Bonferroni-Holm 
method to ensure the Family Wise Error is controlled at 5%. For each treatment group, the Total 
FSFI will be summarised as actual scores at baseline and at 4 weeks, as well as change from 
baseline, using N, mean, standard deviation (SD), standard error (SE), median, minimum and 
maximum. The mean change from baseline in Total FSFI will also be presented with Bonferroni-
corrected 97.5% confidence intervals (CI) to account for the 2 treatment comparisons. If the within-
subject differences are not Normally distributed, a Wilcoxon signed rank test will be used to 
compare the change from baseline. In this case, Hodges-Lehmann 97.5% confidence intervals will 
be calculated. 
Additionally, the number and percentage of subjects (including a 95% confidence interval calculated 
using the Wilson score method) achieving a 4-point improvement in Total FSFI at 4 weeks will be 
presented by treatment group. This will indicate the percentage of subjects who achieve the pre-
defined MCID. 
The handling of missing response on the FSFI is described in Section 9.8. 
9.5.1.2 
Secondary Analysis 
The analyses described in Section 9.5.1.1 will be repeated for the PP population. In addition, for 
each treatment group, the Total FSFI will be summarised as actual scores at baseline and at 4 
weeks, as well as change from baseline for the pre- and post-menopausal subgroups (using the 
FAS population). No hypothesis testing will be performed for the subgroup analyses. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 80 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
9.5.2 
Secondary Endpoints 
9.5.2.1 
Secondary Endpoint Analyses 
For each of the secondary endpoints, hypothesis testing will not be performed, unless stated 
otherwise. Since the secondary endpoints are for supportive evidence only, no adjustments to p-
values will be made. 
The secondary endpoints are: 
Treatment Phase: 
 
Number and percentage of subjects who achieve at least 4-point increase in total FSFI 
between baseline and 4 weeks.  
For each treatment group and overall, the number and percentage of subjects who achieve an 
improvement of at least 4 points in the FSFI total score will be determined. The percentage and the 
95% CI based on the Wilson Score method will be presented. 
 
Number and percentage of subjects who transition from sexual dysfunction (≤26.55 total 
FSFI score) to sexual function (>26.55 total FSFI score) between baseline and 4 weeks.  
For each treatment group and overall, the number and percentage of subjects who transition from 
sexual dysfunction (≤26.55 total FSFI score) to sexual function (>26.55 total FSFI score) between 
baseline and 4 weeks will be determined. Also, the number of subjects categorised as sexual 
function at 4 weeks will be compared to the number categorised as sexual function at baseline, 
using McNemar’s test. This comparison will be performed by treatment group and overall. 
 
Change from baseline in the FSFI individual domain scores (desire, arousal, lubrication, 
orgasm, satisfaction, and pain) at 4 weeks. 
For each treatment group, the FSFI individual domain scores will be summarised as actual scores 
at baseline and at 4 weeks, as well as change from baseline, using n, mean, standard deviation 
(SD), median, minimum and maximum. Also, for each treatment group, the scores at 4 weeks will 
be compared to baseline using a paired t-test or Wilcoxon signed rank test, as appropriate. 
For this secondary endpoint, the following pairs of hypotheses apply, formulated analogously for all 
domain scores: 
H0: The FSFI domain score at Visit 3 of the Treatment Phase shows no difference from the 
corresponding baseline score.  
H1: The FSFI domain score at Visit 3 of the Treatment Phase shows a difference from the 
corresponding baseline score.  
Since testing is done within the non-confirmatory secondary endpoints, there is no adjustment for 
multiple testing. 
 
SPQs after first use at home and after 4 weeks 
For each treatment group, for females and males separately, responses to the SPQ questions will 
be summarised at each time point (after first use at home and at the end of 4 weeks) as the number 
and percentage of subjects in each category (Strongly Agree, Agree, Neither Agree or disagree, 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 81 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Disagree, Strongly Disagree), and also the number and percent in the top 2 categories (Strongly 
Agree, Agree) for each question. 
 
Subjects’ Global Evaluation of product effectiveness, tolerability and device usability after 4 
weeks 
For each treatment group, the number and percentage of subjects answering in each category 
(Greatly Satisfied, Very Satisfied, Moderately Satisfied, Satisfied, Dissatisfied, Very Dissatisfied) 
will be presented. 
 
Patient Global Impression of Change at 4 weeks 
For each treatment group, for females and males separately, the number and percentage in each 
of the PGIC categories (-3, -2, -1, 0, +1, +2, +3) at the end of 4 weeks will be summarised using a 
frequency table. In addition, the number and percentage of subjects who record an improvement of 
at least 2 points (including a 95% confidence interval calculated using the Wilson score method) 
will be presented.  
Tolerance Phase: 
Since only approximately 10 subjects from each treatment group will participate in the Tolerance 
Phase, all endpoints will be summarised using descriptive statistics only, with no hypothesis testing. 
 
Vaginal Epithelial Tolerability (none, slight, minimal, moderate, severe) 
For each treatment group, the number and percentage of subjects assessed in each category (None, 
Slight, Minimal, Moderate, Severe) at each time point (baseline, 2 and 24 hours after single use) 
will be presented. 
 
Subject Perception of Vulvovaginal Tolerance of the two personal lubricants determined 
through Subject Perceived Questions at 24 hours post single application. 
For each treatment group, the number and percentage of subjects in each category (Strongly Agree, 
Agree, Neither Agree or disagree, Disagree, Strongly Disagree), and also the number and percent 
in the top 2 categories (Strongly Agree, Agree) will be presented. 
 
Global Assessment of Vulvovaginal Tolerance for each subject at 24 hours post single 
application as determined by the gynaecologist. 
At the end of the Tolerance Phase the gynaecologist will make a global assessment of vulvovaginal 
tolerance, and the number and percentage of subjects in each category (Very Good, Good, 
Acceptable, Poor, Very Poor) will be presented by treatment group. 
 
Overall Vulvovaginal Tolerance Rating Statement for each personal lubricant as determined 
by the gynaecologist. 
At the end of the Tolerance Phase, the gynaecologist will make an overall summary assessment of 
vulvovaginal tolerance of the IP as very well / well / moderately well / not well / not at all well tolerated 
by all / most / some / a few subjects. 
 
An assessment of the oral mucosal tolerance of the personal lubricants at baseline, 30 
minutes, 2 and 24 hours post single application to the upper and lower inner lip as assessed 
by dermatologist. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 82 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
At each timepoint, the number and percentage of subjects in each category (None, Slight, Minimal, 
Moderate, Severe) will be presented for by treatment group and for each comparator group. 
 
Subject Perception of Oral Mucosal Tolerance of the two personal lubricants determined 
through Subject Perceived Questions at 24 hours post single application. 
For each treatment group, the number and percentage of subjects in each category (Strongly Agree, 
Agree, Neither Agree or disagree, Disagree, Strongly Disagree), and also the number and percent 
in the top 2 categories (Strongly Agree, Agree) will be presented. 
 
Global Assessment of Oral Mucosal Tolerance for each subject at 24 hours post single 
application as determined by the dermatologist. 
At the end of the Tolerance Phase the gynaecologist will make a global assessment of Oral Mucosal 
tolerance, and the number and percentage of subjects in each category (Very Good, Good, 
Acceptable, Poor, Very Poor) will be presented by treatment group. 
 
Overall Oral Mucosal Tolerance Rating Statement for each personal lubricant as determined 
by the dermatologist. 
At the end of the Tolerance Phase, the gynaecologist will make an overall summary assessment of 
Oral Mucosal tolerance of each IP and comparator as very well / well / moderately well / not well / 
not at all well tolerated by all / most / some / a few subjects. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.6 
Description Statistics and Listings 
Data related to the primary and secondary endpoints will be summarised using descriptive 
statistics where appropriate, and subject-level data will be provided in data listings. 
Product usage will be summarised using descriptive statistics (total amount used and number 
of times product was used). Sexual activity will be summarised using descriptive statistics. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 83 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
9.7 
Adverse Events  
AEs from both the Tolerance Phase and Treatment Phase will be summarised together. Safety 
endpoints will include incidence of treatment-emergent AEs (TE AEs), ADEs (TE ADEs) and 
concomitant medications.  
The MedDRA (the most recent version) will be used to classify all AEs with respect to system organ 
class and preferred term. AE summaries will include only TE AEs and TE ADEs, which will be 
summarised (incidence and frequency) for each treatment group. In addition, TE AEs and TE ADEs 
will be summarised according to relationship to the device and study procedures. AEs for females 
and their male partners will be summarised separately. 
Concomitant medication usage will be listed.  
9.8 
Handling of Missing Data and Drop-outs 
All data will be analysed as collected; missing data due to premature discontinuation or any other 
reason will be left as missing. For the FSFI, in order to minimise the number of missing values for 
the FSFI subscale and Total scores, missing item responses will be handled as follows. A subscale 
score will be calculated as long as at least half of the items on the given subscale have valid, non-
missing responses. Specifically, each subscale must have at least two non-missing responses, 
except for Desire, which has only two items and requires only one non-missing response. The Total 
FSFI score will be calculated as long as at least five out of the six subscale scores are present. 
Scores calculated in the presence of missing items will be pro-rated so that the theoretical minimum 
and maximum values are the same as those scores from complete data. 
10 
DATA HANDLING AND RECORD KEEPING 
10.1 
Case Report Forms 
For each enrolled subject, an eCRF using fully validated software that conforms to 21 CFR Part 11 
requirements, will be maintained. In the event of a screen failure, data will be recorded in the eCRF 
up until the point of screen failure. The Investigator is responsible for the quality of the data recorded 
in the eCRF. The data recorded should be a complete and accurate account of the subject’s record, 
collected during the study. Subjects and male partners must not be identified in the eCRF by name 
or initials. 
The Investigator and clinical site staff who have been delegated responsibility for entering data into 
the eCRF at each visit will be trained in the use of the eCRFs before being given access to the 
eCRF and before the first subject first visit. The Investigator must certify that the data entered into 
the eCRF is complete and correct. 
The Investigator agrees to complete the eCRFs in a timely fashion after completion of each subject 
and make them available to the study monitor for full inspection. In addition, any data queries raised 
should be answered promptly. Following monitoring and data management review of each subject’s 
eCRF, the Investigator will electronically sign the eCRF. Re-signature by the Investigator may be 
required prior to database lock after resolution of data queries identified at the data review meeting. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 84 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Before acceptance, the study monitor will review the eCRFs for completeness and adherence to 
the protocol. Upon completion of monitoring and once Data Management has entered data into the 
database, performed all edit checks, and all queries answered, the study database will be declared 
clean and all access will be removed.  
10.2 
Specification of Source Documents 
Source data must be available at the clinical site to document the existence of the investigational 
subjects. Source data must include the original documents relating to the investigation, as well as 
the medical treatment and medical history of the subject. The Investigator and monitor will identify 
the data that will be recorded directly on the eCRF and for this data the eCRF will be considered 
the source document (i.e. no prior written or electronic record of the data). The monitor will confirm 
this at the Initiation Visit. 
Source data (e.g. ICF, medical history, concomitant medication, questionnaires) contained in the 
subject records will be held in the ISF. 
Where source data are in the form of a computer print-out (e.g. laboratory data) they will be signed 
and dated by the Investigator, confirming that the print-out is a true and faithful record of the data. 
These print-outs will be filed in the ISF.  
The Investigator agrees to provide direct access to source data for investigation-related monitoring, 
audits, IEC / REC / IRB review, and regulatory inspection(s). Direct access to source data requires 
that the subject gives written, documented consent to this. 
No investigation records should be destroyed without prior written agreement by the Sponsor. 
10.3 
Data Management 
The data management group at the CRO will be responsible for eCRF development and data 
management activities. 
Access to the eCRF will be by password and the eCRF will be backed up. 
Any changes made by the Investigator and clinical site staff who have been delegated responsibility 
for entering data into the eCRF will be captured via an audit trail in the system. 
Automatic validation programs check for data discrepancies and, by generating appropriate error 
messages, allow the data to be confirmed or corrected before transfer of the data to the Biometrics 
group. The monitor is also able to raise queries in the eCRF as required. 
Coding will be done manually outside of the eCRF and checked. Coding of AEs/ ADEs and medical 
history will be done using the most recent version of MedDRA V25.1 (or the most recent version if 
this has changed during the course of the clinical investigation) by the CRO.  
Concomitant medications will be coded by the CRO using the latest version of the WHO dictionary 
(including ATC coding). All coding will be checked by the Sponsor using the most up-to-date version 
of MedDRA and WHO dictionary.  

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 85 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
10.4 
Reporting of CIP Deviations 
Site staff should make monitor aware of any deviation from the CIP as soon as possible after 
occurrence. Waivers for inclusion / exclusion criteria are not allowed. 
10.5 
Retention of Essential Documentation 
The Investigator should retain all essential documents (as defined in ICH E6 or according to other 
national and international regulations) until at least 10 years after the completion of the investigation 
(defined as last subject last visit in the investigation). These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by an agreement 
with the Sponsor. It is the responsibility of the Sponsor to inform the Investigator when these 
documents no longer need to be retained. 
Subject files and other source data must be kept for the maximum period of time permitted by the 
Clinical Unit, hospital, institution or private practice. The Investigator must notify the Sponsor of the 
retention period if this is shorter than described above. 
11 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Monitoring 
The Sponsor/CRO will organise regular monitoring visits to be performed at intervals agreed with 
the Investigator. The anticipated monitoring frequency will be stated in the Monitoring Plan. 
Monitoring will also involve, as appropriate, correspondence and telephone contacts. 
On-site monitoring includes source data verification (SDV) which is the procedure whereby the data 
contained in the eCRFs are compared with the primary source data and thereby verified as accurate. 
It will be performed in such a way as to preserve subject confidentiality, taking into account all 
ethical and legislative requirements. The Investigator or designated clinical site staff, must be 
available at some time during the monitoring visit to review the data and resolve any queries and 
to allow direct access to the subject’s records for SDV. 
SDV will include as a minimum verification for all subjects and male partners, subject/male partner 
identity (age, sex and subject number), record of entry into the study and signature of the informed 
consent. In addition, details of SAEs in the subject’s notes will be verified. Details included in the 
subject’s notes as a minimum:  
 
Clinical Investigation number, brief description or title of study 
 
Date that the subject gave written consent 
 
All visit dates 
 
All SAEs 
 
All concomitant medications 
At a site visit the eCRFs should be complete and available in order that the accuracy of their 
completion may be checked. Each completed eCRF for each subject must be signed electronically 
by the Investigator, to verify the data and statements submitted. Similarly, all alterations on paper 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 86 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
records must be initialled and dated by the Investigator or designated clinical site staff, explained 
as necessary, with the original mistake left legible. 
11.2 
Audits and Inspections 
For the purpose of ensuring compliance with the CIP, ICH GCP, ISO 14155:2020 and applicable 
regulatory requirements, clinical studies sponsored by Reckitt may be subject to an independent 
audit at the investigation site which will be conducted by personnel from an appropriate Quality 
Assurance Unit. Full consultation with the Investigator will be made prior to and during such audit, 
which will be conducted according to Quality Assurance Unit SOPs. 
As soon as the Investigator is notified of a planned inspection by a Regulatory Authority, he / she 
must inform the Sponsor promptly and allow the Sponsor to participate in the inspection as 
permitted by applicable regulations and local laws. 
11.3 
Sponsor Policy on Fraud in Clinical Studies 
In accordance with GCP, it is the Sponsor’s policy to always follow-up suspected cases of fraud. 
12 
ETHICAL AND REGULATORY ASPECTS 
12.1 
Ethics Review and Regulatory Authority Approval 
This investigation will only be undertaken when written approval from an independent and 
appropriately constituted IEC/ REC/ IRB has been obtained. Documented approval must be 
provided to the Sponsor before any CIP related procedures. 
This clinical investigation will be submitted to the Regulatory Authority (RA) and to the IEC/ REC/ 
IRB by the investigator/ the CRO. 
The Investigator must also provide the Sponsor with a list of constituted IEC/ REC/ IRB members 
that includes each member’s name and profession. 
Any amendments to the CIP must be submitted to the RA and the constituted IEC/ REC/ IRB for 
approval unless where necessary to eliminate apparent immediate hazards to subjects/male 
partners and any administrative changes must be notified. 
The Investigator or designated clinical site staff will notify the constituted IEC/ REC/ IRB within 15 
days of the end of the clinical investigation (or within 24 hours if the investigation is terminated 
prematurely due to safety reasons). 
The CRO will notify the RA within 15 days of the end of the clinical investigation (or within 24 hours 
if the clinical investigation is terminated prematurely due to safety reasons).  
12.2 
Early / Premature Termination of the Investigation 
Reasons for early termination of the Clinical Investigation may include, but are not limited to: 
 
Recall of IP when replacements are not available. 
 
Unacceptable data quality. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 87 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
 
Withdrawal of approval from the Regulatory Authority or IEC / REC / IRB. 
 
Unresolved non-compliance with GCP or with the CIP that compromises the subject’s/male 
partners rights or safety or the study data. 
 
Serious breach in GCP suspected or substantiated. 
If the decision is made by the Sponsor to terminate the study, the Investigator at the site will be 
notified as soon as possible. It is the responsibility of the Investigator to ensure that the IEC / REC 
/ IRB will be informed of the decision to terminate the study. The Investigator will also inform 
participating subjects/male partners that the study has been terminated, discontinue treatment (if 
required), and arrange for appropriate follow-up as necessary. 
The Investigator will agree with the Sponsor on the fate of all Clinical Investigation materials 
following investigation termination.  
Clinical Investigation records must be retained as noted in Section 10.5. 
The Sponsor will notify the Regulatory Authority of the investigation termination. 
13 
COMPENSATION, INDEMNITY AND INSURANCE 
13.1 
Clinical Investigation Agreement 
Before the investigation commences, a contract between the Sponsor and the CRO, who employs 
the Investigator, will be signed in which financial aspects of the study (including financial disclosure) 
as well as responsibilities and obligations will be described. 
13.2 
Insurance 
If required and in accordance with applicable regulatory and legal requirements, Reckitt will take 
out appropriate insurance policies on behalf of the Investigator and staff who conduct part or all of 
this investigation and/or on behalf of the subjects participating in the investigation. 
14 
REPORTING, PUBLICATION AND PRESENTATION 
The clinical investigation will be registered in a publicly accessible database before the start of 
recruitment activities in accordance with national regulations. 
A CIR will be prepared according to ISO 14155:2020 (Annex D) as part of the Sponsor’s 
commitment to GCP. The report will be a record of the total investigation conduct and findings and 
will be subject to approval by the Investigator who will sign the final report. 
The investigation data will be owned by the Sponsor. The Sponsor retains the right to publish the 
data independently of the Investigator. The Sponsor agrees that before it publishes the results, it 
will provide the Investigator with at least 30 days for full review prior to submission of the manuscript 
to the publisher. The Investigator must submit any proposed manuscript to the Sponsor for approval 
prior to submission for publication. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 88 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
15 
REFERENCES 
Affinito P, Palomba S, Sorrentino C, Di Carlo C, Bifulco G, Arienzo MP and Nappi C. Effects of 
post-menopausal hypoestrogenism on skin collagen. Maturitas 33: 239-247, 1999. 
Bachmann G, Nevadunsky NS, Diagnosis and treatment of atrophic vaginitis. Am Fam Physician 
61:3090-6, 2000. 
Basson R, Brotto LA, Laan E, Redmond C, Utian WH. Assessment and management of women’s 
sexual dysfunctions: problematic desire and arousal. J Sex Med, 2:291-300, 2005. 
Berman JR, Adhikari SP, Goldstein I. Anatomy and physiology of female sexual function and 
dysfuction: classification, evaluation and treatment options. Eur Urol, 38:20-9, 2000. 
Brincat M, Moniz CJ, Studd, JW, Darby A, Magos A, Emburey G & Versi E. Long term effects of 
the menopause and sex hormones on skin thickness. British Journal of Obstetrics and Gynaecology, 
92: 256-259, 1985. 
Carter J, Lachetti C, Andersen BL, Barton DL, Bolte S and Damast S. Interventions to Address 
Sexual Problems in Peopleith Cancer: American Society of Clinical Oncology Clinical Practice 
Guideline Adaptation of Cancer Care Ontario Guideline. Journal of Clinical Oncology, 36(5), 2018. 
Couzi RJ, Helzlsouer KJ, Fetting JH. Prevalence of menopausal symptoms among women with a 
history of breast cancer and attitudes towards estrogen replacement therapy. J Clin Oncol, 
13:2737-44, 1995. 
Davies SR, Guay AT, Shifren JL, Mazer NA. Endocrine aspects of female sexual dysfunction. J sex 
Med, 1:82-6, 2004. 
Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burger HG. A prospective population-based 
study of menopausal symptoms. Obstet Gynecol, 96(3):351-358, 2000. 
DeRogatis L, Edelson J, Jordan R, Greenbetg S, Portman D. Bremelanotide for Female Sexual 
Dysfunctions: Responder Analyses from a Phase 2B Dose-Ranging Study. Poster presented at the 
62nd Annual Clinical Meeting of the American College of Obstetricians and Gynecologists, 2014. 
Easley EB. Sex problems after the menopause. Clin Obstet Gynecol, 21(1):269-277, 1978. 
Greendale GA & Judd HL. The menopause: health implications and clinical management. J Am 
Geriatr. Soc 41:426-436, 1993. 
Goldstein I, Alexander JL. Practical aspects in the management of Vaginal Atrophy and Sexual 
Dysfunction in perimenopausal and postmenopausal women.J Sex Med 2 (suppl 3) 154-165, 2005.  
Hugh Hurst, Jennifer Bolton, Assessing the clinical significance of change scores recorded on 
subjective outcome measures. Journal of Manipulative and Physiological Therapeutics, Volume 27, 
Issue 1, Pages 26-35, 2004.  
Kalogeraki A, Tamiolakis D, Tzardi M, et al., Cigarette smoking as a risk factor for intraepithelial 
lesion of the cervix uteri In vivo, 10:613-16, 1996. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 89 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Kingsberg SA, Wysocki S, Magnus L, Krychman ML. Vulvar and vaginal atrophy in postmenopausal 
women: findings from REVIVE (Real Women’s Views of Treatment Options for Menopausal Vaginal 
ChangEs) survey. J Sex Med 10:1790-9, 2013. 
Krychman M, Rowan CG, Allan BB, DeRogatis L, Durbin S, Yacoubian A, Wilkerson D. Effect of 
Single-Treatment, Surface-Cooled Radiofrequency Therapy on Vaginal Laxity and Female Sexual 
Function: The VIVEVE I Randomized Controlled Trial. J Sex Med, 14:215-225, 2017 
Leiblum S, Bachmann G, Kemmann E, Colburn D, Swartzman L, Vaginal Atrophy in the post-
menopausal woman JAMA, 249:2195-2198, 1983. 
MaCoy N, Davidson J. A longitudinal study of the effects of menopause on sexuality Maturitas, 
7:203-210, 1985. 
Mauck, CK, Baker JM, Birnkrant DB, Rowe PJ, Gabelnick HL.  The use of Colposcopy in Assessing 
Vaginal Irritation in Research.  AIDS, 14: 2221-2227, 2000. 
Nappi RE and Kokot-Kierepa M Vaginal Health: Insights, views & attitudes (VIVA) – results from 
an international survey. Climacteric, 15:36-34, 2012. 
Nappi RE, Palacios S. Impact of vulvovaginal atrophy on sexual health and quality of life at 
postmenopause. Climacteric. 2014 Feb;17(1):3-9.  
Notelovitz M. Gynecologic problems of menopausal women:III Changes in extragenital tissues and 
sexuality. Geriatrics, 33:51-53, 1978. 
Palacios S. Managing urogenital atrophy. Maturitas, 63:315-18, 2014. 
Panay N, Fenton A. Vulvovaginal atrophy – a tale of neglect. Climacteric 17:1-2, 2014. 
Pastore LM, Carter RA, Hulka BS, Wells E. Self-reported urgogenital symptoms in postmenopausal 
women: Womens Health initiative Maturitas, 49: 292-303, 2004. 
Recommendations related to contraception and pregnancy testing in clinical trials, Clinical Trial 
Facilitation Group, Version 1.1 21-Sep-2020. 
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, 
Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J; Writing Group for the Women's 
Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy 
postmenopausal women: principal results From the Women's Health Initiative randomized 
controlled trial. JAMA. 2002 Jul 17;288(3):321-33.  
Sarrel PM. Sexuality in the middle years. Obstet Gynecol North Am, 14(1):49-52, 1987. 
Semmens JP, Tsai CC, Semmens EC, Loadholt CB. Effects of estrogen therapy on vaginal 
physiology during menopause. Obstet Gynecol. 1985 Jul;66(1):15-8.  
Shearer MR, Shearer ML. Sexuality and sexual counselling in the elderly. Clin Obstet Gynecol 
20(1):197-209, 1977. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 90 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
Simon JA, Kokot-Kierepa M, Goldstein J, Nappi RE. Vaginal Health in the United states: results 
from the Vaginal Health: Insights, views & Attitudes survey. Menopause; 20:1043-8, 2013. 
Sodeberg MW, Brystrom B, Kalamajski S, Malmstrom A and Ekman-Ordeberg G. Gene 
expressions of small leucine-rich repeat proteoglycans and fibulin-5 are decreased in pelvic organ 
prolapse. Molecular Human Reproduction 15: 251-257, 2009. 
Stenberg A, Heimer G, Ulmsten U, Cnattingius S. Prevalence of genitourinary and other climacteric 
symptoms in 61-year-old women. Maturitas.;24(1-2):31-36, 1996. 
Steunkel CA; Davis SR: Gompel A; Lumsden MA: Murad MH; Pinkerton JV; Santen RJ. Treatment 
of symptoms of the menopause. An endocrine society clinical practice guideline. Journal of Clinical 
Endocrinology Metabolism, 100:11, 2015. 
World Health Organization (WHO). Use and procurement of additional lubricants for male and 
female condoms: WHO/UNFPA/FHI360 Advisory Note. WHO Advisory Note. 2012;1-8. 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 91 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
16 
APPENDICES 
16.1 
Appendix 1:  Female Sexual Function Index (FSFI) 
 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 92 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 93 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 94 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 95 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009  
 

 
Clinical Investigation Plan  
Investigation No: 
5025003 
Protocol Version:  
V3.0, 27-Oct-2022 
Page 96 of 96 
 
D8199934 V6.0, Appendix 2 – Clinical Investigation Plan 
Change Control: CC220523-009