Conditions: Vulvodynia
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 60
Healthy volunteers: no

Brief summary:
This study is designed to define optimal doses of Dysport and evaluate its efficacy and safety compared with placebo for the treatment of vulvodynia.

The study will consist of a dose escalation stage (Stage 1) and a dose expansion stage (Stage 2). Both Stage 1 and Stage 2 will consist of a double-blind period (with treatment cycle 1; Dysport or placebo) followed by an open label treatment period. One or two optimally safe and effective doses of Dysport selected from Stage 1 will be further investigated in the Stage 2.

Detailed description:

Arms:
arm 1: Intramuscular injection of Dysport on day 1 of each cycle. arm 2: Intramuscular injection on day 1 of cycle 1. arm 3: Depending upon the results from Stage 1 one or two doses of Dysport will be selected. Intramuscular injection of Dysport on day 1 of each cycle.

Interventions: intervention 1: Botulinum toxin type A intervention 2: Placebo
Intervention descriptions: intervention 1: Botulinum Toxin Type A (Dysport) using a vial of 500 U will be injected intramuscularly across pelvic floor muscles. intervention 2: The reconstituted solution will be injected intramuscularly across pelvic floor muscles.

Protocol document:
Prot_000.pdf: 


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INVESTIGATOR’S AGREEMENT 
 
Investigator Agreement and Signature: 
I have read and agree to Protocol D-FR-52120-236 entitled: A Phase II, Multicentre, 
Double-blind, Randomised, Placebo-controlled, Dose Escalation and Dose Finding Study to 
Evaluate the Efficacy and Safety of Dysport in Vulvodynia Patients. I am aware of my 
responsibilities as an investigator under the guidelines of Good Clinical Practice (GCP), local 
regulations (as applicable) and the study protocol. I agree to conduct the study according to 
these guidelines and to appropriately direct and assist the staff under my control, who will be 
involved in the study. 
   
NAME: 
 
TITLE: 
 
 
SIGNATURE: 
 
 
 
DATE: 
OFFICE: 
 
 
 
 
 
Sponsor's Representative Signature: 
NAME: 
  
TITLE: 
  
SIGNATURE:  
 
 
 
 
DATE: 
OFFICE: 
Ipsen Bioscience Inc. 
650 East Kendall Street 
Cambridge, Massachusetts 02142 
United States of America 
 
 
 
 
 
 
PPD
PPD
PPD


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COORDINATING INVESTIGATOR’S AGREEMENT 
 
Coordinating Investigator Agreement and Signature: 
I have read and agree to Protocol D-FR-52120-236 entitled: A Phase II, Multicentre, 
Double-blind, Randomised, Placebo-controlled, Dose Escalation and Dose Finding Study to 
Evaluate the Efficacy and Safety of Dysport in Vulvodynia Patients. I am aware of my 
responsibilities as an investigator under the guidelines of Good Clinical Practice (GCP), local 
regulations (as applicable) and the study protocol. I agree to conduct the study according to 
these guidelines and to appropriately direct and assist the staff under my control, who will be 
involved in the study. 
   
NAME: 
 
TITLE: 
PRINCIPAL/COORDINATING 
SIGNATURE: 
 
INVESTIGATOR 
 
DATE: 
OFFICE: 
 
 
  
 
Washington DC 20037 
 
USA 
PPD
PPD


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SUMMARY OF CHANGES 
The initial version of the protocol dated 09 February 2018 was subsequently amended as 
below: 
Table 1 
List of Protocol Amendments 
Amendment 
Release Date 
Amendment Form 
Version 2.0 
15 May 2018 
Appendix 6 
Version 3.0 
04 November 2018 
Appendix 7 
Version 4.0 
08 April 2019 
Appendix 8 
Version 5.0 
23 January 2020 
Appendix 9 
Version 6.0 
08 October 2020 
Appendix 10 


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SYNOPSIS 
Name of Sponsor/Company: Ipsen Innovation 
Name of Finished Product: Dysport 
Name of Active Ingredient(s): Botulinum toxin-A Hemagglutinin Complex (BTX-A-HAC) 
Title of Study: A phase II, multicentre, double-blind, randomised, placebo-controlled, dose 
escalation and dose finding study to evaluate the efficacy and safety of Dysport in vulvodynia 
patients  
Study Number: D-FR-52120-236  
Number of Planned Centres: Approximately 25 centres are planned to recruit subjects.   
Planned Study Period:  
Approximately 4 years  
Phase of Development: 
Phase II  
Study Type: interventional, dose finding safety and efficacy study 
Objectives:  
Primary Study Objective: 
Stage 1: 
• 
To assess the safety of increasing doses of Dysport in vulvodynia subjects with provoked 
vestibulodynia (PVD).  
Stage 2:  
• 
To assess the efficacy of Dysport compared to placebo in vulvodynia subjects with PVD. 
Secondary Study Objectives: 
Stage 1: 
• 
To assess the efficacy of increasing doses of Dysport compared to placebo in vulvodynia 
subjects with PVD 
• 
To determine the doses of Dysport to be administered in Stage 2 
• 
To assess the sensitivity of the endpoints used in Stage 1. 
Stage 2: 
• 
To define the optimal doses of Dysport with an acceptable benefit/risk profile for the 
treatment of vulvodynia with PVD  
• 
To assess effect of Dysport on: 
- 
Vulvar pain 
- 
Use of pain rescue medication (type, dose and frequency) 
• 
To determine if primary and secondary PVD subjects benefit from Dysport administration 
• 
To assess the time to retreatment 
• 
To assess the safety of Dysport.  
Exploratory Objectives: 
• 
To assess effect of Dysport on: 
- 
Clinical Global Impression (CGI) of the treatment effect (assessed by the investigator)  
- 
Patient Global Impression of severity of the pain (PGI-S) and Patient Global 
Impression of change in pain (PGI-C) 
• 
Emotional response, cognitive response and associated life interference as assessed on 
modified vulvar pain assessment questionnaire (mVPAQ) subscales  
• 
Sexual function  


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• 
To assess the efficacy of Dysport on the pelvic floor muscles pressure  
• 
To assess the efficacy of Dysport on depression  
• 
To assess the efficacy of Dysport on the quality of life. 
Methodology:  
This is a Phase II multicentre, double-blind, randomised, placebo-controlled, dose finding study to 
define the optimal doses of Dysport and evaluate its efficacy and safety compared to placebo in 
vulvodynia subjects with PVD. The study will consist of a dose escalation stage (Stage 1) and a 
dose expansion stage (Stage 2). Both Stage 1 and Stage 2 will consist of a double-blind period (with 
treatment cycle 1; Dysport or placebo) followed by an open-label treatment period (treatment cycles 
2 to 4 in which all subjects receive Dysport). Two optimally safe and effective doses of Dysport 
selected from Stage 1 (ranging from 100 U up to a maximum of 800 U) will be further investigated 
in the Stage 2. 
Stage 1 (Dose Escalation) Double-Blind Period: 
It is intended to enrol up to seven dose level cohorts of secondary PVD subjects (i.e. having a past 
history of pain-free intercourse or insertion of any object >1 cm diameter; hereafter referred to as 
PVD2 subjects). Each cohort will include 10 unique evaluable PVD2 subjects. Subjects in these 
cohorts will be randomised in a ratio of 4:1 (Dysport: 8 + Placebo: 2) in a dose-escalation manner 
starting with a total Dysport dose of 100 U, then 300 U, and thereafter increasing up to a maximum 
of 800 U by increments of 100 U.  
For Dysport doses equal to or above 400 U, cohorts of primary PVD subjects (i.e. having life-long 
provoked vestibular pain; hereafter referred to as PVD1 subjects), will be recruited in parallel with 
PVD2 cohorts and at the same Dysport dose as for the PVD2 cohorts. The first PVD1 cohort at 400 
U will include eight unique evaluable subjects who will be randomised in a ratio of 3:1 
(Dysport: 6 + Placebo: 2). Further PVD1 cohorts (i.e. above 400 U) will include 10 unique 
evaluable subjects randomised in a ratio of 4:1 (Dysport: 8 + Placebo 2). 
The recommendation for dose escalation/de-escalation and the staggering scheme for the subsequent 
cohort will be agreed at data review committee (DRC) meetings upon review of efficacy and safety 
data from the previous cohort(s). 
Subjects who discontinue prior to Week 6 for reasons unrelated to occurrence of dose limiting 
events (DLEs) may be replaced at the discretion of the investigator and sponsor. When all subjects 
in Stage 1 have completed 6 weeks of follow-up of treatment cycle 1, the DRC will meet again to 
enable selection of dose(s) to be assessed. PVD1 subjects will be recruited in Stage 2 based on the 
DRC review of efficacy and safety data obtained from PVD1 cohort(s) in Stage 1. 
Following evaluation of study eligibility at the Screening Visit (Day -14), subjects will receive 
study treatment injections in the pelvic floor muscles on Day 1 (Baseline Visit). Follow-up visits 
will be performed at:  
• 
Week 2 (telephone contact) 
• 
Week 6  
• 
Week 12 and  
• 
Every 6 weeks up until eligible for retreatment or up to a maximum of 48 weeks of 
follow-up.  
An intermediate analysis will be performed to review the unblinded data from all cohorts in Stage 1 
up to Cycle 1-Week 12 in an effort to select the two doses for Stage 2 taking into account the dosing 
recommendations from the DRC. 
Stage 2 (Dose Expansion):  
As for Stage 1, the maximum permitted dose in Stage 2 will be 800 U. Two dose levels identified 
from Stage 1, recommended by the DRC based on efficacy and safety data, will be investigated 
further and compared to placebo. It is intended to enrol 63 subjects in Stage 2 in the randomisation 


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ratio of 1:1:1 (Dysport high dose: 21; Dysport low dose: 21 and Placebo: 21). Following the review 
of data available from Stage 1, the sample size may be formally recalculated for Stage 2 after the 
intermediate analysis. 
Following evaluation of study eligibility during a 14-day screening period, subjects will receive 
study treatment injections in the pelvic floor muscles on Day 1 (Baseline Visit). Treatment 
paradigm and follow-up visits will be the same as in Stage 1. 
Open-Label Period (Stage 1 and Stage 2): 
From Week 12 onwards of the double-blind period, subjects will be assessed for the need for 
retreatment at each visit. Subjects who require retreatment will be provided subsequent treatment 
with Dysport in the open-label period of the study and can receive up to three treatment cycles with 
Dysport administered at least 12 weeks apart. Dysport dose levels, that are approved by the DRC 
will be used for retreatment and will not exceed 800 U. Retreatment with Dysport will be provided 
to subjects when this is in the best interest of the subject based on investigator’s judgement, the 
subject has not experienced any unacceptable adverse event (AE) as judged by the investigator and 
at least 12 weeks have elapsed since the last treatment received.  
Study Duration (Stage 1 and Stage 2): 
Individual subject participation in this study will be for a maximum of 54 weeks:  
• 
Screening: 2 weeks (plus 2 weeks window) 
• 
Follow-up: a maximum of 48 weeks follow-up plus 2 weeks window period for the EOS 
Visit depending on the number of treatments administered and the treatment intervals.  
The subject’s participation in the study will be considered to have ended 36 to 48 weeks after the 
first dose, but not before 12 weeks have elapsed after the last dose.  
The number of treatment cycles will depend on the duration of each treatment cycle. A subject can 
receive a maximum of four treatment cycles of Dysport including the one received in the 
double-blind period. The minimum follow-up duration will be 36 weeks and the maximum follow-
up duration will be 48 weeks plus a 2-week window period for the EOS Visit, (the end of the study 
will not occur before 12 weeks have elapsed from the last treatment cycle), as calculated from 
Cycle 1-Day 1. 
Number of Subjects Planned:  
The study will include approximately 180 female subjects (up to 118 in Stage 1 if all cohorts are 
reached, and 63 in Stage 2).  
Diagnosis and Criteria for Inclusion: 
Note: Lettered inclusion and exclusion criteria indicate an update or deletion following an 
amendment to the protocol (e.g. a=criterion amended once, b=criterion amended twice, c=criterion 
amended three times). 
Inclusion Criteria: 
(1a) 
Female subjects aged 18 years or above. 
(2) 
Willing to provide a written informed consent prior to any study related procedures. 
(3) 
Criterion 3 is removed by protocol amendment. 
(4) 
Are premenopausal, as evidenced by a serum follicle stimulating hormone (FSH) level of 
<35 mIU/mL as assessed at the Screening Visit. 
(5) 
Have a negative pregnancy test at screening. 
(6) 
Willing to practice a highly effective form of contraception method at the beginning of the 
study, for the duration of the study and for a minimum of 12 weeks following last 
administration of study drug. Highly effective methods of contraception are defined as 
methods of birth control which result in a low failure rate (i.e. less than 1% per year) when 
used consistently and correctly such as implants, injectables, combined oral contraceptives, 


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intrauterine devices, or vasectomised partner. The double barrier method (condom and 
spermicide) may be considered an acceptable form of birth control if determined appropriate 
for the subject by the investigator. 
(7) 
Have vulvodynia with provoked vestibular pain for at least 6 months and for no more than 
15 years. 
(8a) 
Have provoked pain at the posterior vestibule on a Q-tip test, with pain at positions 5, 6 and 
7 o’clock (must be bilateral pain) at the Screening Visit. 
(9a) 
Are able to tolerate the smallest dilator size (diameter 0.5 inches) at the Screening Visit, i.e. 
agree to the next successive dilator size to be tested for pain response (i.e. the two smallest 
sized dilators (#1 and 2) are to be tested).  
(10a) Pain score ≥5 on an 11-point Numeric Rating Scale (NRS) for the Dilator Maximum Tested 
Size (DMTS) at the Baseline Visit. 
(11a) Willing to abstain from sex therapy (defined as a therapy primarily focused on the 
management of vulvar pain) for the duration of screening and up to at least Week 6 of the 
first treatment cycle.  
(12b) In Stage 1, Cohorts 1, 2, 3, 5, 7, 9 and 11 will include subjects with secondary vulvodynia 
(i.e. having a past history of pain-free intercourse or insertion of any object >1 cm diameter). 
In Stage 1, Cohorts 4, 6, 8, 10 and 12 will include subjects with primary vulvodynia (having 
life-long provoked vestibular pain). In Stage 2, subjects with either primary or secondary 
vulvodynia may be enrolled as approved by the DRC. 
(13) 
Willing and able to comply with study restrictions, able to attend the clinic for the required 
duration of assessments during the study period and willing to return to the clinic for the 
follow-up evaluation as specified in the protocol. 
(14) 
If the subject has received oral antidepressants, anxiolytics or anti-epileptics, then the dose of 
these medications should have been stable for at least 6 months prior to the Screening Visit 
and expected to remain stable throughout the first treatment cycle. 
Exclusion Criteria: 
(1a) 
Have provoked pain on a Q-tip test at the anterior vestibule (anywhere between 9 and 
3 o’clock or more anteriorly) at the Screening Visit.  
(2b) 
Able to tolerate the 6th (diameter 1¼ inches) dilator size (i.e. agree to the next successive 
dilator size to be tested for pain response) at the Baseline Visit (i.e. at least one of the two 
largest sized dilators (#7 and/or 8) is tested). 
(3a) 
Any non-provoked (i.e. spontaneous) vulvar pain in the past 6 months prior to the Screening 
Visit. Note: pain provoked by any vestibular pressure (including but not limited to sitting, 
bicycling or tight clothing) is considered provoked pain. 
(4a) 
Deep pain during intercourse in the past 6 months prior to the Screening Visit. 
(5a) 
Score of 4 or 5 on any of the 3 pain questions (questions #17, 18 or 19) of the modified 
Female Sexual Function Index (mFSFI) questionnaire.  
(6) 
Criterion 6 is removed by previous protocol amendment. 
(7a) 
Significant depressive disorder, e.g. having a score ≥20/27 on the Patient Health 
Questionnaire (PHQ-9) scale at the Baseline Visit. 
(8b) 
Genitourinary or gastrointestinal conditions/history including:  
- 
Skin disease at the vestibule such as lichen sclerosus, lichen planus, vaginal or vulvar 
atrophy, desquamative inflammatory vaginitis and allergic vulvitis. 
- 
Severe endometriosis (severe defined as requiring regular medications to manage the 
endometriosis symptoms).  
- 
Severe bladder and bowel symptoms e.g. diagnosed interstitial cystitis/Bladder Pain 
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disease. 
- 
Genitourinary or rectal cancer. 
- 
Congenital urogenital abnormalities (e.g. vaginal septa, imperforate hymen, urethral 
diverticulum). 
- 
Pain in urethra (diagnosis based on subject’s interview and physical examination). 
- 
Symptomatic urogenital prolapse at physical examination. 
- 
History of traumatic or post radiotherapy vulvar lesions. 
- 
Pudendal neuralgia. 
- 
Other conditions that according to the investigator’s judgement may interfere with 
treatment or impact the study outcome. 
(9a) 
Previous surgery/conditions including: 
- 
Hysterectomy 
- 
Vestibulectomy 
- 
Urologic surgery 
- 
Perianal surgery 
- 
Genital trauma or mutilation/cutting 
- 
Other surgery/conditions that according to the investigator’s judgement may impact 
on the study outcome. 
(10) 
Vaginal infections (bacterial vaginosis, presence of candidiasis or trichomoniasis) at 
Screening Visit. 
(11) 
Current infection at the injection site(s). 
(12) 
Unable to receive intramuscular injections. 
(13) 
History of hypersensitivity to Dysport or drugs with a similar structure or any excipient used 
in the formulation. 
(14) 
Clinically significant history of alcohol/drug abuse the last 24 weeks prior to screening or 
clinically significant alcohol/drug dependence within 2 years prior to screening. Exceptions 
include caffeine or nicotine abuse/dependence. 
(15a) Positive urine test for illicit drugs (drugs of abuse) at screening. In the event a subject tests 
positive for cannabinoids (tetrahydrocannabinol), the investigator will evaluate the subject’s 
ability to abstain from cannabis during the study. If in the investigator’s clinical judgement, 
the subject will abstain, the subject may be enrolled after consultation with the Medical 
Monitor. Note: at the discretion of the investigator, positive drug screens for prescribed 
medications will not be considered exclusionary. 
(16c) Has received any of the following: 
- 
Pelvic floor physical therapy initiated, stopped or modified (frequency or type of 
physical therapy) during the last 12 weeks prior to Baseline (physical therapy includes 
but is not limited to: internal/external myofascial release by physiotherapist, 
biofeedback, home pelvic floor exercises, self-taught exercises, use of vaginal 
dilators, etc.).  
- 
Sex therapy in the past 6 weeks prior to Baseline. 
- 
Previous treatment with any botulinum toxin (BTX) for any indication within the last 
1 year. 
- 
Treatment for vestibular pain, with hormonal creams, in the last 1 week prior to 
Screening unless continued at the same dosing regimen throughout the study. 
- 
Currently receiving treatment for stress or urge urinary incontinence. 
- 
Treatment with any of the following drugs that could affect neuromuscular function: 


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curare-like nondepolarising agents, lincosamides, polymyxins, anticholinesterases, 
aminoglycoside antibiotics (topical use is permitted except at the vulvar vestibular 
region), tizanidine and baclofen, within the last 4 weeks prior to Baseline or during 
the study. 
- 
Injections of steroids in the vulva within the last 4 weeks prior to the Screening Visit 
or planned use during the study. 
- 
Treatment with an investigational drug within the last 4 weeks prior to Baseline or 
scheduled treatment with such a drug during the study period. 
- 
Is likely to require treatment during the study with drugs that are not permitted by the 
study protocol. 
(17) 
Any mental condition rendering the subject unable to understand the nature, scope and 
possible consequences of the study, and/or evidence of an uncooperative attitude, as judged 
by the investigator.  
(18) 
Abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the 
opinion of the investigator, might jeopardise the subject’s safety or compromise compliance 
with the objectives and/or procedures of this protocol or preclude the administration of BTX. 
(19) 
Female subject who is pregnant or planning to become pregnant during the study, or is 
currently lactating (breastfeeding). 
Test Product, Dose and Mode of Administration: 
Study treatment kits will be designed to maintain the blind (for the subject, investigator and 
delegated person reconstituting the product) during the double-blind period. 
The investigational medicinal product (IMP), Dysport, will be provided as a white, lyophilised 
powder in glass vials containing 300 U or 500 U of BTX-A-HAC. 
Before each administration, the powder will be reconstituted at the study site with 0.9% sterile 
(preservative free) sodium chloride for injection. 
A total volume of 2.5 mL of the reconstituted treatment will be injected intramuscularly at five 
needle insertion points at 10 injection sites (5 mm (superficial) and 10 mm (deep) depths at each 
needle insertion point) across the four pelvic floor muscles: pubococcygeus, bulbospongiosus, 
superficial transverse perineal muscle and deep transverse perineal muscle. 
Injection procedures are described in the ‘Study Treatment Administration - Training Manual’ 
(included in the Study Manual). Training on injection procedures will be provided to each 
investigator performing IMP administration.  
Duration of Treatment: 
Each subject will receive one IMP administration during the double-blind period followed by one to 
three treatments with Dysport in the open-label period (if clinically indicated) at least 12 weeks 
apart. The maximum total follow-up duration will be for up to 48 weeks, plus a 2-week window 
period for the EOS Visit, from the first IMP dose administered and not before 12 weeks have 
elapsed since the last treatment dose. 
Reference Therapy, Dose and Mode of Administration:  
Study treatment kits will be designed to maintain the blind (for the subject, investigator and 
delegated person reconstituting the product) during the double-blind period.  
The comparator will be a matching placebo, i.e. undistinguishable from the active IMP (Dysport), 
which will be injected during the double-blind period (i.e. treatment cycle 1 of Stage 1 and Stage 2) 
of the study. 
Placebo will be provided as a white, lyophilised powder in glass vials, and will be similar in size, 
colour and appearance to the active IMP (Dysport). It will be composed of only the excipients 
contained within Dysport, without the addition of the active substance.  


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A total volume of 2.5 mL of the reconstituted treatment will be injected intramuscularly at five 
needle insertion points at 10 injection sites (5 mm (superficial) and 10 mm (deep) depths at each 
needle insertion point) across the four pelvic floor muscles: pubococcygeus, bulbospongiosus, 
superficial transverse perineal muscle and deep transverse perineal muscle. 
Injection procedures are described in the ‘Study Treatment Administration - Training Manual’ 
(included in the Study Manual). Training on injection procedures will be provided to each 
investigator performing IMP administration.  
Criteria for Evaluation (Endpoints): 
Primary Endpoint and Evaluation:  
Stage 1:  
• 
Safety endpoints between Baseline and Cycle 1-Week 6, including the incidence of any 
DLE. 
Stage 2:  
• 
Mean change from Baseline to Cycle 1-Week 6 in the vaginal dilator induced pain as 
reported on an 11-point NRS (using the DMTS reported at Baseline).  
Secondary Endpoints and Evaluations: 
• 
Mean change from Baseline to each post-treatment visit in the vaginal dilator induced pain as 
reported on the 11-point NRS (using the DMTS reported at Baseline). 
• 
Proportion of subjects who reported at least a 30% decrease in vaginal dilator induced pain 
as reported on the 11-point NRS (using the DMTS reported at Baseline) at each post-
treatment visit. 
• 
Proportion of subjects who reported at least 2-point decrease in vaginal dilator induced pain 
as reported on the 11-point NRS (using the DMTS reported at baseline) at each 
post-treatment visit. 
• 
Mean change from Baseline to each post-treatment visit in the dilator size that provokes 
maximum tolerated pain. 
• 
Mean change from Baseline to each post-treatment visit in the composite score for the 
vaginal dilator induced pain and dilator size.  
• 
Mean change from Baseline to each post-treatment visit in pain during insertion of vaginal 
dilator number 6 size as reported on the 11-point NRS. 
• 
Mean change from Baseline to each post-treatment visit in the pain during intercourse as 
reported on the 11-point NRS.  
• 
Mean change from Baseline to each post-treatment visit in the number of intercourse 
instances in subjects with partners.  
• 
Use of pain rescue medication (type, dose, number of pills taken and frequency). 
• 
Proportion of subjects who reported at least a 50% decrease in vaginal dilator induced pain 
as reported on the 11-point NRS (using the DMTS reported at Baseline) at each post-
treatment visit. 
• 
Proportion of subjects having reported at least a 30% decrease in pain during insertion of 
vaginal dilator number 6 size on the mean of the NRS values at each post treatment visit. 
• 
Proportion of subjects having reported at least 2-point decrease in pain during insertion of 
vaginal dilator number 6 size on the mean of the NRS values at each post treatment visit. 
• 
Proportion of subjects having reported at least a 50% decrease in pain during insertion of 
vaginal dilator number 6 size on the mean of the NRS values at each post-treatment visit. 
Safety Endpoints and Evaluations: 
The safety and tolerability of Dysport will be assessed throughout the study by evaluating: 
• 
Incidence of treatment emergent adverse events (TEAEs), serious AEs (SAEs), clinically 


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significant AEs, DLEs, AEs (or SAEs) leading to discontinuations and AEs of special 
interest (AESIs). 
• 
Absolute values, values classified as abnormal/normal and change from Baseline in the 
clinical laboratory test results (including nonfasting clinical biochemistry and haematology 
parameters). 
• 
Number of subjects who seroconvert for BTX antibodies following treatment with Dysport. 
• 
Clinical evaluation of concomitant medication usage (except rescue medication) and 
therapies. 
Exploratory Endpoints: 
• 
Mean CGI (as assessed by the investigator) of the treatment effect at each post treatment 
visit.  
• 
Mean PGI-C (as assessed by the subject) at each post-treatment visit. 
• 
Mean change from baseline in PGI-S (as assessed by the subject) at each visit. 
• 
Mean change from Baseline to each post-treatment visit in each of the mVPAQ subscales.  
• 
Mean change from Baseline to each post-treatment visit in the mFSFI total score and domain 
scores. 
• 
Mean change from Baseline in the pelvic floor muscle pressure as measured by perineometry 
in all subjects in Stage 1 up to 400 U and in a subset of subjects in Stage 2. 
(Note: in Stage 2, this endpoint will be evaluated in subjects who have never had a vaginal 
delivery (including an attempted vaginal delivery), and at study sites that were provided a 
perineometer to assess pelvic floor muscle pressure) 
• 
Resting vaginal pressure 
• 
Maximal ‘squeeze’ pressure. 
• 
Mean change from Baseline in the depression score using PHQ-9 scale. 
• 
Mean change from Baseline in quality of life (QoL) using 36-item Short Form Survey 
(SF-36). 
Statistical Methods: 
Method of Randomisation:  
Stage 1: For the PVD2 cohorts, subjects will be randomised with a 4:1 (Dysport: placebo) ratio. For 
the PVD1 cohort(s), subjects will be randomised with a 3:1 (Dysport: placebo) ratio for Dysport 
400 U and then randomised at 4:1 for Dysport 500 U and up to a maximum of 800 U.  
Stage 2: Subjects will be randomised to Dysport high dose, Dysport low dose, or placebo with a 
1:1:1 allocation. Randomisation will be stratified by pain onset subtype (two levels: primary, i.e. 
having life-long PVD, secondary, i.e. having acquired PVD after period of pain-free penetrative 
activities).  
Sample Size and Power Considerations:  
Stage 1: With 8 evaluable subjects on active treatment per PVD2 dose cohort and if there are 
0 DLEs in a cohort, there is at least 80% probability that the true incidence of DLEs at the 
corresponding dose will not be greater than 18%. With 16 evaluable subjects on active treatment in 
PVD2 and PVD1 dose cohorts, and if there are 0 DLEs in the two cohorts, there is at least 80% 
probability that the true DLEs at the corresponding dose will not be greater than 9%. The ability to 
confidently rule out smaller true DLE incidence at a dose level will come from observations on 
subjects in Stage 2.  
Stage 2: The study sample size required to have at least 80% power to detect a 2-point improvement 
between Dysport and the placebo group on mean change from baseline to Week 6 in the vaginal 
dilator induced pain as reported on a numeric pain rating scale (using the DMTS), assuming a 
common standard deviation of 3-point and using a one-sided 0.10 level test is 21 subjects per arm. 


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At the end of Stage 2, if the true DLE rate is 6% or greater, there is at least 80% probability to 
observe at least 1 DLE in 29 subjects (8 in Stage 1 and 21 in Stage 2). Therefore, if there are no 
observed DLEs in both Stage 1 and Stage 2 at a dose level, then there is good confidence that the 
true DLE rate is no more than 6%. If the dose chosen in Stage 2 has been tested on two cohorts 
(PVD1 and PVD2) in Stage 1, at the end of Stage 2, if the true DLE rate is 5% or greater, there is at 
least 80% probability to observe at least one DLE in 37 subjects (16 in Stage 1 and 21 in Stage 2). 
Therefore, if there are no observed DLEs in both Stage 1 and Stage 2 at a dose level, then there is 
good confidence that the true DLE rate is no more than 5%. 
Following the review of data available from Stage 1, the sample size may be formally recalculated 
for Stage 2 after the intermediate analysis. 
Statistical Procedure for the Efficacy Testing:  
Change from baseline to Week 6 in pain measurement at the DTMS will be analysed using analysis 
of covariance adjusting for baseline pain at the DTMS and pain onset subtype (primary and 
secondary PVD).  
Hypothesis tests will be one-sided. The planned statistical comparisons at one-sided 0.10 level do 
not adjust for two treatment comparisons and consequently the experiment-wise type I error rate 
may be up to 20%. Non-parametric tests may also be carried out to evaluate robustness of results. 
Subject who discontinue prior to Week 6 for reasons unrelated to safety may be replaced at the 
discretion of the investigator and sponsor. Sensitivity analyses will be carried out to evaluate the 
impact of missing data where appropriate. 
Data Review Committee (DRC) Meetings:  
A DRC will be established to make recommendations for dose escalation and dose de-escalation 
(within the Dysport dose range of 100 U up to a maximum of 800 U) or study termination in 
Stage 1. If no subject reports a clinically significant AE in a cohort, the DRC will meet once all 
evaluable subjects have reached Week 6 of a cohort to review the efficacy and safety data and 
recommend the dose for the next cohort or proceed to Stage 2.  
If any subject reports a clinically significant AE, then further enrolment into the cohort, as well as 
retreatment in open label cycles at the current dose, will be suspended and an ad hoc DRC meeting 
will be scheduled to review the safety data and make a recommendation with regards to further 
conduct of the cohort and of Stage 1. At the end of Cycle 1-Week 6 for all subjects in Stage 1, the 
DRC will meet to review efficacy and safety data and recommend the two doses of Dysport to be 
assessed in the Stage 2 of the study. The DRC will also recommend if further PVD1 cohort(s) are 
required or if PVD1 subjects should be removed from Stage 2. 
In Stage 2 of the study, ad hoc DRC meetings will be scheduled to review efficacy and safety data 
in the event of an emergency safety issue. 
Primary Analysis: 
A primary unblinded analysis will be conducted once all Stage 2 subjects have reached the 
Cycle 1-Week 12 visit; this will include all available safety and efficacy data from subjects in 
Stage 1 and Stage 2 subjects until the cut-off date.  
A final analysis will be carried out once all subjects have completed end of study evaluation. 
Intermediate Analysis: 
At the point when the DRC recommends moving to Stage 2 of the study, an intermediate unblinded 
analysis will be performed. Available data from all double-blind periods of all cohorts from Stage 1 
until the last subject has completed their Cycle 1-Week 12 visit will be considered in the analysis. 
Descriptive statistics of the TEAEs and selected efficacy endpoints will be carried out. 
Following the review of data available from Stage 1, the sample size may be formally recalculated 
for Stage 2 after the intermediate analysis. 


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TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ...................................................................................... 2 
COORDINATING INVESTIGATOR’S AGREEMENT..................................................... 3 
SUMMARY OF CHANGES ................................................................................................... 4 
SYNOPSIS ................................................................................................................................ 5 
TABLE OF CONTENTS ....................................................................................................... 14 
LIST OF ABBREVIATIONS ................................................................................................ 20 
1 
BACKGROUND INFORMATION ............................................................................ 22 
1.1 
Introduction ................................................................................................................... 22 
1.2 
Name and Description of Investigational Medicinal Product(s) .............................. 23 
1.3 
Findings from Nonclinical and Clinical Studies ......................................................... 23 
1.3.1 
Summary of Nonclinical Studies ................................................................ 23 
1.3.2 
Summary of Clinical Studies ...................................................................... 24 
1.4 
Known and Potential Risks and Benefits to Human Subjects .................................. 24 
1.5 
Selection of Investigational Medicinal Products and Dosages .................................. 25 
1.6 
Compliance Statement .................................................................................................. 25 
1.7 
Population to be Studied .............................................................................................. 26 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES ..................................... 27 
2.1 
Purpose of the Study ..................................................................................................... 27 
2.2 
Study Objectives ........................................................................................................... 27 
2.2.1 
Primary Study Objective ............................................................................. 27 
2.2.2 
Secondary Study Objectives ........................................................................ 27 
2.2.3 
Exploratory Objectives ................................................................................ 28 
3 
STUDY DESIGN ........................................................................................................... 29 
3.1 
General Design and Study Schema ............................................................................. 29 
3.1.1 
Stage 1 (Dose Escalation) ........................................................................... 29 
3.1.1.1 
Definitions of Clinically Significant Adverse Event and Dose Limiting 
Event ............................................................................................................ 30 
3.1.1.2 
DRC Meetings .............................................................................................. 31 
3.1.2 
Stage 2 (Dose Expansion) ........................................................................... 31 
3.2 
Primary and Secondary Endpoints and Evaluations ................................................ 35 
3.2.1 
Primary Endpoints and Evaluations .......................................................... 35 
3.2.2 
Secondary Efficacy Endpoints and Evaluations ........................................ 35 
3.2.3 
Safety Endpoints and Evaluations ............................................................. 36 
3.3 
Exploratory Endpoints ................................................................................................. 36 
3.4 
Biobanking ..................................................................................................................... 36 
3.5 
Randomisation and Blinding ....................................................................................... 36 
3.6 
Maintenance of Randomisation and Blinding ............................................................ 38 


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3.7 
Study Treatments and Dosage ..................................................................................... 38 
3.7.1 
Study Treatments ......................................................................................... 38 
3.7.2 
Study Dosage and Administration .............................................................. 39 
3.7.2.1 
Stage 1 .......................................................................................................... 40 
3.7.2.2 
Stage 2 .......................................................................................................... 41 
3.7.3 
Retreatment Criteria (Stage 1 and Stage 2) ............................................... 41 
3.8 
Study Duration .............................................................................................................. 42 
3.9 
Stopping Rules and Discontinuation Criteria ............................................................ 42 
3.10 Source Data Recorded on the Case Report Form ...................................................... 42 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 44 
4.1 
Inclusion Criteria .......................................................................................................... 44 
4.2 
Exclusion Criteria ......................................................................................................... 45 
4.3 
Rationale for Inclusion/Exclusion Criteria ................................................................. 47 
4.4 
Subject Withdrawal Criteria and Procedures ........................................................... 47 
5 
STUDY PROCEDURES .............................................................................................. 48 
5.1 
Study Schedule .............................................................................................................. 48 
5.2 
Study Visits .................................................................................................................... 54 
5.2.1 
Procedures for Screening and Enrolment - Visit 1 (Day -14 (-14 days/ 
+3 days)) ...................................................................................................... 54 
5.2.1.1 
Screening – Visit 1 - Day -14 (-14 days/ +3 days) ...................................... 54 
5.2.2 
Procedures During Double-Blind Period – Treatment Cycle 1 (Stage 1 
+ Stage 2) ..................................................................................................... 56 
5.2.2.1 
Baseline Visit (Day 1) .................................................................................. 56 
5.2.2.2 
Week 2 – Telephone Contact (Day 15 ±3 days) ........................................... 56 
5.2.2.3 
Week 6 Visit (Day 43 ±5 days) ..................................................................... 56 
5.2.2.4 
Week 12 Visit (Day 85 +14 days) ................................................................ 57 
5.2.2.5 
Weeks 18, 24, 30 and/or 36 – Additional Visits (Day 127, 169, 211 
and/or 253 ±14 days) ................................................................................... 58 
5.2.3 
Procedures During Open-Label Period – Treatment Cycles 2 to 4 
(Stage 1 + Stage 2) ...................................................................................... 59 
5.2.3.1 
Day 1 Visit (Treatment Visit) ....................................................................... 59 
5.2.3.2 
Week 2 – Telephone Contact (Day 15 ±3 days) ........................................... 59 
5.2.3.3 
Week 6 Visit (Day 43 ±5 days) ..................................................................... 59 
5.2.3.4 
Week 12 Visit (Day 85 ±14 days) ................................................................. 60 
5.2.3.5 
Weeks 18 and/or 24 – Additional Visits (Day 127 or 169 ±14 days)........... 60 
5.2.4 
End of Study Visit or Early Withdrawal Visit ............................................ 61 
6 
TREATMENT OF SUBJECTS ................................................................................... 63 
6.1 
Investigational Medicinal Product Preparation Storage and Accountability ......... 63 
6.1.1 
Investigational Medicinal Product Storage and Security .......................... 63 
6.1.2 
Investigational Medicinal Product Preparation ........................................ 63 


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6.1.3 
Investigational Medicinal Product Accountability .................................... 63 
6.2 
Study Drugs Administered ........................................................................................... 63 
6.2.1 
Treatments Administered ............................................................................ 63 
6.2.1.1 
Dysport ......................................................................................................... 63 
6.2.1.2 
Placebo ........................................................................................................ 64 
6.2.2 
Reconstitution and Administration Procedure .......................................... 64 
6.3 
Concomitant Medication/Therapy .............................................................................. 66 
6.4 
Lifestyle Restrictions/Recommendations .................................................................... 67 
6.5 
Procedures for Monitoring Subject Compliance ....................................................... 67 
6.6 
Priority Order on Study Procedures ........................................................................... 68 
7 
ASSESSMENT OF EFFICACY .................................................................................. 69 
7.1 
Primary Endpoint(s) and Evaluation(s) ..................................................................... 69 
7.2 
Secondary Efficacy Endpoints and Evaluations ........................................................ 69 
7.3 
Exploratory Efficacy Endpoints and Evaluations ..................................................... 70 
7.4 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data ......... 72 
7.4.1 
Dilator Test (Vaginal Dilator Induced Pain) ............................................. 72 
7.4.2 
Patient Reported Questionnaires and Assessments ................................... 73 
7.4.2.1 
Modified Vulvar Pain Assessment Questionnaire (mVPAQ) ....................... 73 
7.4.2.2 
Assessment of Intercourse and Vaginal Dilator (Number 6 Size) Insertion 
Details .......................................................................................................... 73 
7.4.2.3 
Modified Female Sexual Function Index (mFSFI) ...................................... 74 
7.4.2.4 
Patient Global Impression (PGI) ................................................................. 74 
7.4.2.5 
Use of Pain Rescue Medications .................................................................. 75 
7.4.2.6 
Patient Health Questionnaire (PHQ-9) ....................................................... 75 
7.4.2.7 
36-Item Short Form Health Survey (SF-36) ................................................ 75 
7.4.2.8 
Pain Catastrophizing Scale (PCS) ............................................................... 75 
7.4.3 
Investigator-Reported Assessments ............................................................ 76 
7.4.3.1 
Q-tip ............................................................................................................. 76 
7.4.3.2 
Clinical Global Impression (CGI) ............................................................... 76 
7.4.3.3 
Measurement of Pelvic Floor Muscle Pressure ........................................... 76 
8 
ASSESSMENT OF SAFETY ....................................................................................... 77 
8.1 
Adverse Events .............................................................................................................. 77 
8.1.1 
Definition of an Adverse Event .................................................................. 77 
8.1.2 
Categorisation of Adverse Events ............................................................... 77 
8.1.2.1 
Intensity Classification ................................................................................. 77 
8.1.2.2 
Causality Classification ............................................................................... 77 
8.1.2.3 
Assessment of Expectedness ......................................................................... 77 
8.1.2.4 
Laboratory Test Abnormalities .................................................................... 78 
8.1.2.5 
Abnormal Physical Examination Findings .................................................. 78 
8.1.2.6 
Other Investigation Abnormal Findings ...................................................... 78 


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8.1.3 
Clinically Significant Adverse Events and Dose Limiting Events ............ 78 
8.1.4 
Adverse Events of Special Interest ............................................................. 78 
8.1.5 
Recording and Follow-up of Adverse Events ............................................. 79 
8.1.6 
Reporting of Serious Adverse Events ......................................................... 79 
8.1.7 
Pregnancy .................................................................................................... 81 
8.1.8 
Deaths .......................................................................................................... 81 
8.1.9 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events .......................................................................................................... 81 
8.1.10 
Reporting 
to 
Competent 
Authorities 
(CAs)/IECs/IRBs/Other 
Investigators ................................................................................................ 82 
8.2 
Clinical Laboratory Tests ............................................................................................ 82 
8.2.1 
Haematology ................................................................................................ 82 
8.2.2 
Blood Biochemistry ..................................................................................... 82 
8.2.3 
Pregnancy Test ............................................................................................ 82 
8.2.4 
Drug of Abuse ............................................................................................. 83 
8.2.5 
Putative Antibody Testing ........................................................................... 83 
8.2.6 
Vaginal Evaluation for Yeast and Bacterial Infection .............................. 83 
8.3 
Physical Examination ................................................................................................... 83 
8.4 
Local Tolerance ............................................................................................................. 83 
8.5 
Vital Signs ...................................................................................................................... 83 
9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS .......... 84 
10 
EXPLORATORY BIOMARKERS AND BIOBANKING ....................................... 85 
11 
STATISTICS ................................................................................................................. 86 
11.1 Analyses Populations .................................................................................................... 86 
11.1.1 
Populations Analysed .................................................................................. 86 
11.1.2 
Reasons for Exclusion from the Analyses ................................................. 86 
11.2 Sample Size Determination .......................................................................................... 87 
11.3 Significance Testing and Estimations ......................................................................... 88 
11.4 Statistical/Analytical Methods ..................................................................................... 88 
11.4.1 
Demographic and Other Baseline Characteristics .................................... 88 
11.4.2 
Subject Disposition and Withdrawals ......................................................... 88 
11.4.3 
Efficacy Evaluation ..................................................................................... 88 
11.4.4 
Adjustment for Country/Centre Effect ....................................................... 89 
11.4.5 
Handling of Withdrawals, Discontinuations or Missing Data .................. 89 
11.4.6 
Data Analyses Timepoints .......................................................................... 89 
11.4.6.1 
Data Review Committee (End of Stage 1 - Cycle 1-Week 6) ....................... 89 
11.4.6.2 
Primary Analysis (End of Stage 2 Cycle 1-Week 12) .................................. 90 
11.4.7 
Safety Evaluation ........................................................................................ 90 
11.5 Subgroup Analyses ....................................................................................................... 90 
11.6 Intermediate Analyses .................................................................................................. 90 


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12 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ............................... 92 
13 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 93 
13.1 Protocol Amendments and Protocol Deviations ........................................................ 93 
13.1.1 
Protocol Amendments ................................................................................. 93 
13.1.2 
Protocol Deviations and Exceptions........................................................... 93 
13.2 Information to Study Personnel .................................................................................. 94 
13.3 Study Monitoring .......................................................................................................... 94 
13.3.1 
Data Review Committee .............................................................................. 94 
13.4 Investigator’s Regulatory Obligations ........................................................................ 95 
13.5 Audit and Inspection .................................................................................................... 95 
13.6 Data Quality Assurance ................................................................................................ 95 
14 
ETHICS ......................................................................................................................... 96 
14.1 Compliance with Good Clinical Practice and Ethical Considerations .................... 96 
14.2 Informed Consent for Participation in the Study ...................................................... 96 
14.3 Health Authorities and Independent Ethics Committees/Institutional Review 
Boards ............................................................................................................................ 97 
14.4 Confidentiality Regarding Study Subjects ................................................................. 97 
15 
DATA HANDLING AND RECORD KEEPING ....................................................... 98 
15.1 Data Recording of Study Data ..................................................................................... 98 
15.2 Data Management ......................................................................................................... 98 
15.3 Record Archiving and Retention ................................................................................. 99 
16 
FINANCING AND INSURANCE ............................................................................. 100 
16.1 Contractual and Financial Details ............................................................................. 100 
16.2 Insurance, Indemnity and Compensation ................................................................ 100 
17 
REPORTING AND PUBLICATIONS OF RESULTS ........................................... 101 
17.1 Publication Policy ....................................................................................................... 101 
17.2 Clinical Study Report ................................................................................................. 101 
18 
REFERENCES ............................................................................................................ 102 
19 
LIST OF APPENDICES ............................................................................................ 104 


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LIST OF TABLES 
Table 1 
List of Protocol Amendments ............................................................................... 4 
Table 2 
Study Procedures and Assessments – Double-Blind Treatment Period ......... 49 
Table 3 
Study Procedures and Assessments – Open-Label Treatment Period ........... 52 
Table 4 
Blood Volume for Collection .............................................................................. 54 
Table 5 
Composition of Dysport ...................................................................................... 63 
Table 6 
Composition of Matching Placebo ..................................................................... 64 
Table 7 
Permitted Pain Rescue Medications during Stage 2 ........................................ 67 
Table 8 
Secondary Efficacy Endpoints and Evaluations ............................................... 69 
Table 9 
Exploratory Efficacy Endpoints and Evaluations ............................................ 71 
 
LIST OF FIGURES 
Figure 1 
Study Design ........................................................................................................ 33 
Figure 2 
Study Flow Chart ................................................................................................ 40 
Figure 3 
Study Treatment – Sites of Administration ...................................................... 65 
Figure 4 
Numeric Pain Rating Scale ................................................................................. 72 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
Wording Definition  
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
BTX 
Botulinum Toxin 
BTX-A 
Botulinum Toxin-A 
BTX-A-HAC 
Botulinum Toxin-A Hemagglutinin Complex 
CA 
Competent Authorities 
CFR 
Code of Federal Regulations (United States of America) 
CGI 
Clinical Global Impression 
CRO 
Contract Research Organisation 
DLE 
Dose Limiting Event 
DTMS 
Dilator Maximum Tested Size 
DRC 
Data Review Committee 
EDC 
Electronic Data Capture 
EOS 
End of Study 
eCRF 
Electronic Case Report Form 
ePRO 
Electronic Patient-Reported Outcome  
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GPS 
Global Patient Safety 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
i.m. 
Intramuscular 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFSFI 
modified Female Sexual Function Index 
mITT 
modified Intent to Treat 
mVPAQ 
modified Vulvar Pain Assessment Questionnaire 


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ABBREVIATION 
Wording Definition  
NSAIDS 
Nonsteroidal Anti-inflammatory Drugs 
NRS 
Numeric Rating Scale 
OTC 
Over the Counter 
PD 
Pharmacodynamics 
PGI-C 
Patient Global Impression of Change in Pain 
PGI-S 
Patient Global Impression of Severity of Pain 
PHQ-9 
Patient Health Questionnaire-9 
PP 
Per Protocol 
PRN 
As per Need 
PVD 
Provoked Vestibulodynia 
QoL 
Quality of Life 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SF-36 
36-item Short Form Survey 
SD 
Standard Deviation 
TEAE 
Treatment Emergent Adverse Event 
TFLs 
Tables, Figures and Listings 
TMF 
Trial Master File 
USA 
United States (of America) 
WHO 
World Health Organisation 


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1 
BACKGROUND INFORMATION 
1.1 
Introduction 
Vulvodynia is defined as vulvar pain of at least 3 months' duration, without a clear 
identifiable cause, and which may have potential associated factors. The vulvar pain can be 
either localised, generalised or mixed; it could be either provoked (insertional or contact) or 
spontaneous or both; the onset vulvodynia can be primary or secondary [1]. The chronic 
vulvar pain is often associated with sexual dysfunction and affective distress [2]. Vulvodynia 
is a fairly prevalent condition with lifetime estimates ranging from 8% to 28% based on the 
prevalence studies in women of reproductive age group in the general population [3, 4, 5]. 
Vulvodynia affects young women [6], with the average age of occurrence being 
approximately 40 years, although a high prevalence is observed in all decades of life until age 
of 70 years [2, 3].  
Provoked vestibulodynia (PVD), previously known as vulvar vestibulitis, is the most common 
form of vulvodynia and occurs when pain is localised in the vulvar vestibule and triggered by 
any vestibular contact (sexual or otherwise). In a population-based study, 64.8% of 
vulvodynia patients had provoked pain only [3].  
There is currently no approved drug for the treatment of vulvodynia. A typical treatment plan 
for a woman with vulvodynia starts with treatments that are considered non-pharmacological 
(e.g. psychological treatments, physiotherapy) and, depending on her response to treatment, 
can progress to multiple different medication treatments, that are used as off label treatment 
for the condition without any established proof of benefit (e.g. tricyclic antidepressants, local 
anaesthetic agents, topical hormones, anti-inflammatory agents, pain modulators, local nerve 
block and anticonvulsant medications). If these treatments fail, then surgical intervention 
(e.g. vestibulectomy for localised provoked vestibulodynia) is recommended [7], however 
only a minority of patients may be suitable for vestibulectomy [8]. Although surgical 
treatment may be successful, it is associated with postoperative complications such as 
decreased vaginal lubrication and worsening of pain, hence is best reserved for refractory 
cases [2].  
There are relevant and convincing medical observations and arguments to suggest that 
neuromuscular disorder of the pelvic floor muscles may be responsible for PVD characterised 
by localised provoked pain at the vaginal vestibule. Several studies provide significant 
evidence that patients with PVD have greater muscular hypertonia in the muscles in the 
superficial area of the perineum, which become painful and that the hypertonic pelvic 
musculature plays a role in the etiology, maintenance, and exacerbation of PVD [9]. Eighty 
percent of patients of PVD have muscular hypertonia of the pelvic floor muscles 
demonstrable by electromyography, and 90% of these patients tend to have associated vulvar 
allodynia [10]. Bohm-Starke found that an intraepithelial hyperplasia of the C-nerve fibres 
was present in the vestibular tissue, along with the presence of various pain neurotransmitters 
such as glutamate or substance P [6, 11]. All these factors support the neuromuscular 
hypothesis of the disease with an abnormal pain transmission [10]. Other treatment 
approaches for the condition, like physiotherapy are also aimed at the rehabilitation of the 
pelvic floor musculature to normalize the muscle tone, to increase elasticity of tissues at the 
vaginal opening, to desensitize the vulvo-vestibular area and decrease the patient’s protective 
guarding reactions to vaginal penetration by exercises, manual techniques, biofeedback, and 
electrical stimulation [9]. 


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Botulinum toxin (BTX) is a neurotoxin that acts on the presynaptic motor neuron, cleaves the 
SNARE proteins thereby inhibiting the release of acetylcholine and thus leading to a 
reduction in muscle tone [12]. Aligned with the known pharmacological and 
pharmacodynamic action of Dysport® on the injected muscles, there is strong evidence to 
suggest its effectiveness in the treatment of vulvodynia by causing muscle relaxation of the 
affected pelvic floor muscles, and by inhibiting the release of neuropeptides and 
neurotransmitters involved in chronic pain and inflammation (Substance P and calcitonin gene 
related peptide) [6, 10, 13]. As a consequence, local treatment with Dysport in patients with 
vulvodynia is expected to provide relief from vulvar pain, subsequently improving the sexual 
function of women and their quality of life.  
Considering the unmet need for an effective treatment for vulvodynia patients and the 
suggested efficacy of botulinum toxin-A (BTX-A) in the various published studies for this 
indication, Ipsen proposes to conduct a randomised, double-blind, placebo-controlled study 
designed to define optimal doses of Dysport and evaluate its efficacy and safety compared 
with placebo for the treatment of vulvodynia. 
1.2 
Name and Description of Investigational Medicinal Product(s) 
Botulinum toxin-A is a potent neurotoxin isolated from the bacterium Clostridium botulinum, 
a gram-positive, spore-forming anaerobe. Botulinum toxin-A, a single chain protein with a 
molecular weight of approximately 150000 Daltons (Da), is one of seven different serotypes 
(classed A through G) of BTX produced by this organism. Proteins endogenous to the 
bacterium cleave the single chain protein, resulting in a di-chain neurotoxin containing a light 
chain (molecular weight of approximately 50000 Da) and a heavy chain (molecular weight ca. 
100000 Da) that remain linked by inter-chain disulfide and noncovalent bonds. 
Dysport is a freeze-dried preparation of Clostridium BTX-A-haemagglutinin complex 
(BTX-A-HAC) formulated with lactose (bulking agent) and human serum albumin. 
A more detailed description of the product is given in Section 6.2.1.1. 
Further details can also be found in the Dysport IB. 
1.3 
Findings from Nonclinical and Clinical Studies 
1.3.1 
Summary of Nonclinical Studies 
An extensive nonclinical development program for Dysport exists, including pharmacology, 
distribution, and toxicology studies (including repeat use). In this program, animals (both 
males and females) have been treated by intramuscular administration of Dysport in striated 
muscles (gluteus and gastrocnemius muscles). Dysport was also studied nonclinically in the 
detrusor muscle.  
In vivo pharmacodynamic (PD) studies conducted in rats (rat muscle force test and muscle 
glycogen depletion) showed significant decreased mass and force of intramuscular injection in 
the gastrocnemius muscle and inhibition of glycogen depletion in injected rat muscles.  
Distribution studies performed with BTX-A have demonstrated that the majority of the toxin 
remained localised at the injection site, supporting the local effect of the toxin.  
The results of the single or repeat dose (up to 6 months) toxicity studies demonstrated that 
BTX-A administered in striated muscle has been locally well tolerated by the animal species 
used and that it possesses no potential for producing nonpharmacologically related toxicity or 
specific target organ effects. The effects on injected muscles (decrease in muscle and 
myofibre size) were related to the pharmacological activity of BTX-A and were consistent 
with the results of the PD rat muscle force test. They were reversible and appeared to cause no 


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long term impairment of neuromuscular junction. When administered by the intradetrusor 
route, no histopathological modification of the bladder or adjacent reproductive organs was 
detected. The effects seen in the single dose intradetrusor studies in rats were consistent with 
the ones observed in previous striated muscle studies after single and repeated administrations 
on rats. Dysport was locally well tolerated by both routes of administration. 
The drug was not teratogenic in rats and rabbits and no effects were observed in the pre and 
postnatal study on the F1 generation in rats (male and females). The drug did not alter male or 
female rat fertility except at doses inducing localised muscle paralysis and alteration of 
general conditions (severe decreased body weight and food consumption). Given in 21-day 
old rats (corresponding to children of 2 years old), Dysport did not affect postnatal growth, 
reproductive, neurological and neurobehavioral development.  
The existing nonclinical development program for Dysport conducted in striated and in 
detrusor muscles provides a robust and adequate safety and efficacy data set to support the use 
of Dysport as a treatment option in female patients with vulvodynia when injected in the 
pelvic floor striated muscles. 
Further details can also be found in the Dysport IB. 
1.3.2 
Summary of Clinical Studies 
No previous clinical studies have been conducted by Ipsen with Dysport in this indication of 
vulvodynia. This is the first study that will be conducted by Ipsen in this indication. The body 
of clinical evidence mostly consists of data from several small scale published studies in the 
treatment of vulvodynia and other related conditions (e.g. vaginismus) conducted either with 
Dysport [14, 15] or with other BTX-A formulations [6, 10, 12, 13, 16, 17, 18, 19, 20]. 
1.4 
Known and Potential Risks and Benefits to Human Subjects 
Dysport was first approved for the treatment of blepharospasm and hemifacial spasm in the 
United Kingdom in 1990. Since then Dysport® has been approved in over 85 countries for a 
range of indications. The posology and safety of Dysport has been established in numerous 
clinical studies and there is over 25 years of postmarketing experience. 
Dysport is generally well-tolerated, although temporary paralysis of nontargeted muscle 
groups may occur. Adverse events (AEs) resulting from a possible remote spread of the toxin 
from its site of injection have been reported (including excessive muscle weakness and 
aspiration pneumonia resulting from dysphagia). Local spread of the toxin from the injection 
site has also been reported and therefore the safety profile is dependent on the site of 
injection. Most AEs are of mild or moderate severity and of limited duration. The profile of 
adverse reactions reported during postmarketing use reflects the pharmacology of the product 
and AEs seen during clinical studies. There have been occasional reports of hypersensitivity.  
Adverse reactions that are considered expected in patients treated across a variety of 
indications can be found in the current Dysport IB and in the Dysport Company Core Safety 
Information. 
Based on published data in the treatment of vulvodynia and other related conditions 
(e.g. vaginismus) with Dysport or other BTX-A formulations and the mechanism of action of 
Dysport, urinary incontinence and faecal incontinence may also be observed in patients 
injected in pelvic floor muscles.  
Treatment with Dysport in female patients with vulvodynia is expected to provide an 
improvement in the provoked pain (at intercourse or from any kind of vestibular pressure) and 


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therefore potentially an improvement in the associated sexual function, depression and quality 
of life. 
Based on clinical evidence available from published data supporting the efficacy of BTX-A in 
adult female patients with vulvodynia, the known mechanism of action of Dysport and the 
proposed range of Dysport doses to be tested (100 U up to a maximum of 800 U) that fall 
within the range of approved doses for Dysport (up to 1500 U in adult patients), the 
benefit/risk balance is expected to be favourable for evaluation in this patient population.  
Additional information regarding potential risks and benefits may be found in the current 
Dysport IB. 
1.5 
Selection of Investigational Medicinal Products and Dosages 
The selection of Dysport doses to be evaluated in the dose escalation stage of the study are 
based on the clinical evidence from published studies with Dysport and other BTXs in the 
literature as well as the sponsor’s clinical experience with Dysport in various indications 
involving targeted treatment of hypertonic muscles at several anatomical sites.  
In a study by Bertolasi 2009 [15] injection of the levator ani muscle with low mean doses of 
Dysport (24 U±12 U) led to some reduction in vulvar pain in patients with PVD with 
vaginismus and no major AEs were reported with Dysport administration. Amongst the 
approved indications in the US, for the treatment of glabellar lines, Dysport 50 U achieves a 
clinical effect (i.e. causes muscle relaxation) when administered at 5 injection sites in three 
muscles in the glabellar area (two corrugators and one procerus) that have a relatively small 
muscle mass and no events suggestive of remote distribution of toxin have been reported in 
this indication at this dose. In this study, Dysport is to be injected at 5 sites across 6 muscles 
of the pelvic floor: bulbospongiosus (left and right), pubococcygeus (left and right), deep 
transverse muscle and superficial transverse muscle. Based on sponsor experience, a total 
Dysport dose of 100 U distributed between 6 muscles of the pelvic floor should be a safe 
starting dose, which may show some degree of muscle relaxation. 
Ipsen proposes to progressively escalate Dysport doses from 100 U and 300 U, and then 
increasing up to a maximum dose of 800 U by increments of 100 U. Dysport doses up to 
400 U are supported by data from the study by Ghazizadeh 2004 [14], in which the starting 
dose of 150 U Dysport injected into the levator ani (puborectalis) muscles in patients with 
vaginismus did not provide sufficient clinical improvement in some patients, following which 
the dose was gradually increased to 400 U for subsequent patients that lead to satisfactory 
relief from vaginismus in 95.8% of patients. No adverse effects were reported in this study 
with Dysport doses of 150 U to 400 U. Administration of Dysport doses above 400 U and up 
to a maximum of 800 U during the study will be based on recommendation by the DRC 
following review of safety and efficacy data from previous cohorts. 
A more detailed description of administration procedures is given in Section 6.2.2.  
1.6 
Compliance Statement 
The study will be conducted in compliance with independent ethics committees/institutional 
review boards (IECs/IRBs), informed consent regulations, the Declaration of Helsinki and 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines, 
Food and Drug Administration (FDA), 21 Code of Federal Regulation (CFR) Part 11, 
Electronic Records, Electronic Signatures, and FDA, Guidance for Industry: Computerized 
Systems Used in Clinical Trials. Any episode of noncompliance will be documented. 
In addition, the study will adhere to all local regulatory requirements.  


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Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject emergency study contact cards, 
subject recruitment procedures (e.g. advertisements), any written information to be provided 
to subjects and a statement from the IEC/IRB that they comply with GCP requirements. The 
IEC/IRB approval must identify the protocol version as well as the documents reviewed. 
1.7 
Population to be Studied 
The study will recruit premenopausal adult female subjects aged 18 years or above. 
In order to establish the preliminary efficacy of Dysport in this dose finding study, a subset of 
vulvodynia subjects suffering from provoked vestibular pain is selected. It is hypothesised 
that pelvic floor muscle hypertonicity underpins the posterior vestibular pain experienced and 
consequently these subjects are likely to respond to treatment with Dysport. This will ensure 
enrolment of a homogenous target population and limit intersubject variability. 
Subjects suffering from PVD for at least 6 months duration but no more than 15 years, having 
pain at the posterior vestibule will be enrolled into the study. The subjects should have taken a 
stable physiotherapy (if any) for at least 12 weeks prior to the entry into the study and not 
have received any BTX for any indication within the last 1 year. 


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2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1 
Purpose of the Study 
Dysport, a BTX-A-HAC, is already approved in the US and in many other countries 
worldwide for the treatment of a variety of clinical conditions in adult patients like cervical 
dystonia, upper and lower limb spasticity, that are associated with muscular hypertonicity, and 
pain in several patients. 
The therapeutic value of BTX-A is derived from its ability to specifically and potently 
decrease muscular overactivity, thereby reducing the muscle tone for an extended duration 
and ameliorating the associated pain.  
Based on the known mode of action of Dysport, Ipsen proposes to expand the treatment 
profile of Dysport and potentially add a new indication for the treatment of vulvodynia.   
This study is a double-blind, randomised, parallel group, placebo-controlled study designed to 
define optimal doses of Dysport and evaluate its efficacy and safety compared with placebo 
for the treatment of vulvodynia. Treatment of vulvodynia patients with PVD with Dysport is 
expected to provide not only an improvement in the provoked pain (at intercourse or from any 
kind of vestibular pressure) but also potentially an improvement in the associated sexual 
function, depression and quality of life. 
2.2 
Study Objectives 
2.2.1 
Primary Study Objective 
Stage 1 
The primary objective of the study is to assess the safety of increasing doses of Dysport in 
vulvodynia subjects with PVD.  
Stage 2 
The primary objective of the study is to assess the efficacy of Dysport compared to placebo in 
vulvodynia subjects with PVD. 
2.2.2 
Secondary Study Objectives 
The secondary objectives of the study are as follows: 
Stage 1 
• 
To assess the efficacy of increasing doses of Dysport compared to placebo in 
vulvodynia subjects with PVD 
• 
To determine the doses of Dysport to be administered in Stage 2 
• 
To assess the sensitivity of the endpoints used in Stage 1. 
Stage 2 
• 
To define the optimal doses of Dysport with an acceptable benefit/risk profile for the 
treatment of vulvodynia with PVD  
• 
To assess effect of Dysport on: 
- 
Vulvar pain  
- 
Use of pain rescue medication (type, dose and frequency) 
• 
To determine if primary and secondary PVD subjects benefit from Dysport 
administration 
• 
To assess the time to retreatment 
• 
To assess the safety of Dysport.  


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2.2.3 
Exploratory Objectives 
The exploratory objectives of the study are as follows: 
• 
To assess effect of Dysport on: 
- 
Clinical Global Impression (CGI) of the treatment effect (assessed by the 
investigator)  
- 
Patient Global Impression of severity of the pain (PGI-S) and Patient Global 
Impression of change in pain (PGI-C) 
• 
Emotional response, cognitive response and associated life interference as assessed on 
modified Vulvar Pain Assessment Questionnaire (mVPAQ) subscales  
• 
Sexual function  
• 
To assess the efficacy of Dysport on the pelvic floor muscles pressure  
• 
To assess the efficacy of Dysport on depression  
• 
To assess the efficacy of Dysport on the quality of life. 


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3 
STUDY DESIGN 
3.1 
General Design and Study Schema 
This is a Phase II multicentre, double-blind, randomised, placebo-controlled, dose finding 
study to define the optimal doses of Dysport and evaluate its efficacy and safety compared to 
placebo in vulvodynia patients with PVD. Study treatment will be injected at 5 needle 
insertion points at 10 injection sites in the vestibular area. The study will consist of a dose 
escalation stage (Stage 1) and a dose expansion stage (Stage 2). The purpose of the dose 
escalation will be to determine the Dysport doses to be further investigated in Stage 2. The 
study will include approximately 180 premenopausal female subjects (up to 118 in Stage 1 if 
all cohorts are reached, and 63 in Stage 2) aged 18 years or above with a diagnosis of PVD 
associated with provoked pain at the posterior vestibule. Both Stage 1 and Stage 2 will consist 
of a double-blind period (treatment cycle 1; Dysport or placebo) followed by an open-label 
treatment period (treatment cycles 2 to 4; all subjects receive Dysport). Overall study duration 
and period for individual subject participation are provided in Section 3.8.  
An overview of the study design is presented in Figure 1.  
3.1.1 
Stage 1 (Dose Escalation)  
It is intended to enrol up to seven dose level cohorts of secondary PVD subjects (i.e. having a 
past history of pain-free intercourse or insertion of any object >1 cm diameter; hereafter 
referred to as PVD2 subjects) evaluating Dysport doses ranging from 100 U up to a maximum 
of 800 U (total dose administered) to find two optimally safe and effective doses of Dysport 
that will be further investigated in the Stage 2. Additional dose level cohorts within this dose 
range (100 U and up to a maximum 800 U) may potentially be added based on the 
recommendations from the DRC. 
Each PVD2 cohort will include 10 unique evaluable PVD2 subjects who will be randomised 
via the interactive response system (IRS) to the two double-blind parallel treatment arms in 
4:1 ratio:  
• 
Dysport (N=8) or  
• 
Placebo (N=2).  
Cohort 4 will include 8 unique evaluable primary PVD subjects (i.e. having life-long 
provoked vestibular pain; hereafter referred to as PVD1 subjects), at the same Dysport dose as 
for the PVD2 Cohort 3, who will be randomised via the IRT to the two double-blind parallel 
treatment arms in 3:1 ratio:  
• 
Dysport (N=6) or  
• 
Placebo (N=2).  
Further PVD1 cohorts (i.e. above 400 U) will include 10 unique evaluable subjects 
randomised in a ratio of 4:1 (Dysport N=8 and Placebo N=2). 
In an event, when the last subject in a cohort is being randomised, if an additional subject has 
been screened, this subject may be accepted in the cohort and be randomised. 
At Screening, all subjects will be allocated a subject number. Subjects will be evaluated for 
eligibility during a Screening Visit at Day -14. Following confirmation of eligibility for the 
study, subjects will be allocated to one of the above two treatment groups. Subjects will 
receive study treatment injections in the pelvic floor muscles on Day 1 (Baseline Visit). 
Follow-up visits will be performed at: 
• 
Week 2 (telephone contact) 


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• 
Week 6  
• 
Week 12 and  
• 
Every 6 weeks up to a maximum of 48 weeks of follow-up.  
The screening and postbaseline assessments to be performed at each visit are discussed in 
Section 5.2. Assessments to be performed at the End of Study (EOS) or Early Withdrawal 
(EWD) visit are presented in Section 5.2.4. 
Once all PVD2 and PVD1 evaluable subjects in a dose level have reached the Week 6 visit, 
the dose escalation for the subsequent cohort will be agreed at the DRC meeting upon review 
of the available efficacy and safety data. The maximum dose to which escalation is permitted 
will be 800 U. The definitions for clinically significant AEs and dose limiting events (DLEs) 
is provided in Section 3.1.1.1. The assessments to be performed by the Data Review 
Committee (DRC) and their timings are discussed in Section 3.1.1.2. Subject who withdraw 
or discontinue prior to Week 6 in the double-blind period for reasons unrelated to occurrence 
of DLEs may be replaced at the discretion of the investigator and sponsor. Replacement 
subjects will receive the same treatment as the subject they replace. Stage 1 will be stopped as 
soon as the dose of 800 U has been tested or otherwise recommended by the DRC. 
At the end of Cycle 1 – Week 6 for all PVD2 subjects in Stage 1, the DRC will meet to 
review efficacy and safety data and recommend the two doses of Dysport to be assessed in the 
Stage 2 of the study. PVD1 subjects will be recruited in Stage 2 following DRC review of the 
efficacy and safety data of PVD1 cohort(s) in Stage 1. 
An intermediate analysis will be performed to review the unblinded data from all cohorts in 
Stage 1 up to Cycle 1-Week 12 in an effort to select the two doses for Stage 2 taking into 
account the dosing recommendations from the DRC. 
From Week 12 onwards of the double-blind period, subjects will be assessed for the need for 
retreatment at each visit. Subjects who require retreatment will be provided subsequent 
treatment with Dysport in the open-label period of the study. Dysport dose levels, that are 
approved by the DRC will be used for retreatment and will not exceed 800 U. Subjects not 
requiring or not eligible for retreatment will be evaluated every 6 weeks ±2 weeks (Additional 
Visit(s)) until they need retreatment or they complete at least 36 weeks of follow-up. The 
number of treatment cycles will depend on the duration of each treatment cycle, and thus the 
minimum follow-up duration will be 36 weeks and the maximum follow-up duration will be 
48 weeks (the end of the study will not occur before 12 weeks have elapsed from the last 
treatment cycle), as calculated from Cycle 1-Day 1. 
The screening and postbaseline assessments to be performed at each visit are discussed in 
Section 5.2. Assessments to be performed at the EOS or EWD visit are presented in 
Section 5.2.4. 
Retreatment criteria are presented in Section 3.7.3. Retreatment dose schedule for Stage 1 is 
presented in Section 3.7.2.1.  
3.1.1.1 
Definitions of Clinically Significant Adverse Event and Dose Limiting Event 
A clinically significant AE is defined as:  
• 
Drug-related severe AE or drug related serious AE 
• 
Treatment emergent faecal incontinence, defined as new onset faecal incontinence that 
lasts for more than 4 days and that in the investigator’s opinion is not due to any other 
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• 
Treatment emergent urinary incontinence, defined as: new onset, or a significant and 
sudden deterioration in any pre-existing urinary incontinence in the investigator’s 
opinion, that lasts for more than 4 days and that in the investigator’s opinion is not due 
to any other cause.  
A DLE for the purpose of this study is defined as a clinically significant AE that would 
preclude another drug administration at the same dose level in a given subject. 
3.1.1.2 
DRC Meetings 
A DRC will be established to make recommendations for dose escalation, dose de-escalation, 
progression from Stage 1 to Stage 2 or study termination in Stage 1 of the clinical study (see 
Section 13.3.1 for the composition and operation of the DRC). The maximum dose to which 
escalation will be permitted will be 800 U. 
If no subject reports a clinically significant AE in a cohort, the DRC will meet once all PVD2 
and PVD1 evaluable subjects of a dose level have reached Week 6 to review the unblinded 
efficacy and safety data and recommend the dose for the next cohort. The DRC may 
recommend to reassess the previously used dose level based on the review of efficacy and 
safety data from the cohort(s). 
If any subject reports a clinically significant AE (as defined in Section 3.1.1.1), then further 
enrolment into the cohort, as well as retreatment in open label cycles at current dose, will be 
suspended and an ad hoc DRC meeting will be scheduled.  
During the ad-hoc meeting, the DRC will review blinded data of the subject(s) with clinically 
significant AE and all available efficacy and safety data from the cohort. The DRC may 
request to break the blind to confirm if the significant AE is a DLE, and based on this 
assessment, if enrolment in the cohort may continue. 
At the end of Cycle 1-Week 6 visit for all subjects in Stage 1, the DRC will meet to review all 
safety and efficacy data from the cohort(s) and recommend the two doses to be assessed in 
Stage 2. The DRC will also recommend if further PVD1 cohort(s) are required or if PVD1 
subjects should be removed from Stage 2. 
In Stage 2 of the study, ad hoc DRC meetings will be scheduled to review efficacy and safety 
data in the event of an emergency safety issue. 
3.1.2 
Stage 2 (Dose Expansion)  
Two dose levels identified from Stage 1, recommended by the DRC based on efficacy and 
safety data, will be investigated further and compared to placebo in Stage 2. As for Stage 1, 
800 U will be the maximum permitted dose in Stage 2. It is intended to enrol 63 subjects in 
the randomisation ratio of 1:1:1:  
• 
Dysport high dose (optimal highest safe and efficacious dose): 21 subjects 
• 
Dysport low dose (selected based on safety and efficacy considerations observed in 
Stage 1): 21 subjects, and  
• 
Placebo: 21 subjects.  
Following the review of data available from Stage 1, the sample size may be formally 
recalculated for Stage 2 after the intermediate analysis.  
Subjects will be evaluated for eligibility during a Screening Visit at Day -14. Subjects will 
receive study treatment in the pelvic floor muscles on Day 1. Treatment paradigm and 
follow-up visits will be the same as in Stage 1. From Week 12 visit onwards, the need for 
retreatment will be assessed at each visit.  


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The screening and postbaseline assessments to be performed at each visit are discussed in 
Section 5.2.  
Retreatment criteria are presented in Section 3.7.3. Retreatment dose for Stage 2 is presented 
in Section 3.7.2.2.  
The number of treatment cycles will depend on the duration of each treatment cycle, and thus 
the minimum follow-up duration will be 36 weeks and the maximum follow-up duration will 
be 48 weeks (the end of the study will not occur before 12 weeks have elapsed from the last 
treatment cycle), as calculated from Cycle 1-Day 1.  
 






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3.2 
Primary and Secondary Endpoints and Evaluations 
3.2.1 
Primary Endpoints and Evaluations 
Stage 1  
• 
Safety endpoints between Baseline and Cycle 1-Week 6, including the incidence of any 
DLE. 
Stage 2  
• 
Mean change from Baseline to Cycle 1-Week 6 in the vaginal dilator induced pain as 
reported on an 11-point numeric rating scale (NRS) (using the dilator maximum tested 
size (DMTS) reported at Baseline).  
3.2.2 
Secondary Efficacy Endpoints and Evaluations 
The following secondary evaluations will be performed for Stage 1 and Stage 2: 
• 
Mean change from Baseline to each post-treatment visit in the vaginal dilator induced 
pain as reported on the 11-point NRS (using the DMTS reported at Baseline). 
• 
Proportion of subjects who reported at least a 30% decrease in vaginal dilator induced 
pain as reported on the 11-point NRS (using the DMTS reported at Baseline) at each 
post-treatment visit. 
• 
Proportion of subjects who reported at least 2-point decrease in vaginal dilator induced 
pain as reported on the 11-point NRS (using the DMTS reported at baseline) at each 
post-treatment visit. 
• 
Mean change from Baseline to each post-treatment visit in the dilator size that provokes 
maximum tolerated pain. 
• 
Mean change from Baseline to each post-treatment visit in the composite score for the 
vaginal dilator induced pain and dilator size. 
• 
Mean change from Baseline to each post-treatment visit in pain during insertion of 
vaginal dilator number 6 size as reported on the 11-point NRS. 
• 
Mean change from Baseline to each post-treatment visit in the pain during intercourse 
as reported on the 11-point NRS.  
• 
Mean change from Baseline to each post-treatment visit in the number of intercourse 
instances in subjects with partners.  
• 
Use of pain rescue medication (type, dose, number of pills taken and frequency). 
• 
Proportion of subjects who reported at least a 50% decrease in vaginal dilator induced 
pain as reported on the 11-point NRS (using the DMTS reported at Baseline) at each 
post-treatment visit. 
• 
Proportion of subjects having reported at least a 50% decrease in pain during insertion 
of vaginal dilator number 6 size on the mean of the NRS values at each post-treatment 
visit. 
• 
Proportion of subjects having reported at least a 30% decrease in pain during insertion 
of vaginal dilator number 6 size on the mean of the NRS values at each post-treatment 
visit. 
• 
Proportion of subjects having reported at least 2-point decrease in pain during insertion 
of vaginal dilator number 6 size on the mean of the NRS values at each post-treatment 
visit. 


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3.2.3 
Safety Endpoints and Evaluations 
The safety and tolerability of Dysport will be assessed throughout the study by evaluating: 
• 
Incidence of treatment emergent AEs (TEAEs), serious AEs (SAEs), clinically 
significant AEs, DLEs, AEs (or SAEs) leading to discontinuations and AEs of special 
interest (AESIs). 
• 
Absolute values, values classified as abnormal/normal and change from Baseline in the 
clinical laboratory test results (including nonfasting clinical biochemistry and 
haematology parameters).  
• 
Number of subjects who seroconvert for BTX antibodies following treatment with 
Dysport. 
• 
Clinical evaluation of concomitant medication usage (except rescue medication) and 
therapies. 
3.3 
Exploratory Endpoints 
• 
Mean CGI (as assessed by the investigator) of the treatment effect at each 
post-treatment visit.  
• 
Mean PGI-C (as assessed by the subject) at each post-treatment visit. 
• 
Mean change from Baseline in PGI-S (as assessed by the subject) at each visit. 
• 
Mean change from Baseline to each post-treatment visit in each of the mVPAQ 
subscales.  
• 
Mean change from Baseline to each post-treatment visit in the modified Female Sexual 
Function Index (mFSFI) total score and domain scores. 
• 
Mean change from Baseline in the pelvic floor muscles pressure as measured by 
perineometry in all subjects in Stage 1 up to 400 U and in a subset of subjects in 
Stage 2) 
(Note: in Stage 2 this endpoint will be evaluated in subjects who have never had a 
vaginal delivery (including an attempted vaginal delivery), and at study sites that were 
provided a perineometer to assess pelvic floor muscle pressure) 
- 
Resting vaginal pressure 
- 
Maximal ‘squeeze’ pressure. 
• 
Mean change from Baseline in the depression score using Patient Health Questionnaire 
(PHQ-9) scale. 
• 
Mean change from Baseline in quality of life (QoL) using 36-item Short Form Survey 
(SF-36). 
3.4 
Biobanking 
No biobanking of sample will be performed for this study. 
3.5 
Randomisation and Blinding 
All of the investigational medicinal product (IMP) will be similar in size, colour and 
appearance allowing the blinded conditions of the first cycle of the study to be maintained 
(Stage 1 and Stage 2).  
During the double-blind period of Stage 1 and Stage 2, subjects and investigators will be 
blinded to treatment assignment (i.e. Dysport/placebo). 
During the double-blind period of Stage 2 subjects and investigators will also be blinded to 
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For Stage 1, the sponsor’s randomisation manager who is a statistician, independent from the 
study, will prepare: 
• 
A list of randomisation numbers (List A1). It will be produced in blocks, on an 
unbalanced ratio (4 Dysport: 1 placebo) and will be stratified by cohort. For Cohort 4, 
Dysport randomisation numbers will be deactivated randomly to get an unbalanced 
ratio (3 Dysport: 1 placebo).  
• 
A list of treatment numbers/treatment which will be dispatched to the sites (List B1). It 
will be produced in blocks, on an unbalanced ratio (3 Dysport: 2 placebo). 
For Stage 2, the sponsor’s randomisation manager will prepare: 
• 
A list of randomisation numbers (List A2). It will be produced in blocks, on a balanced 
ratio (1 placebo: 1 Dysport low dose: 1 Dysport high dose) and will be stratified by 
pain onset subtype (primary and secondary PVD). 
• 
A list of treatment numbers/treatment which will be dispatched to the sites (list B2). It 
will be produced in blocks, on a balanced ratio (1 placebo: 1 Dysport low dose: 
1 Dysport high dose). 
Mirror lists of randomisation numbers will also be produced to randomise the replacement 
subjects, so that the subject to be replaced and her replacement are assigned to the same 
treatment arm.  
The randomisation as well as the treatment number(s) assignation at drug dispensation, will 
be managed by an Interactive Response Technology (IRT). After eligibility is confirmed, at 
Baseline (V2), subjects will be assigned to a randomisation number and to the associated 
treatment arm, in sequential order within each study centre and within each level of strata. In 
Stage 1, from Cohort 3 onwards, the IRT will also consider the subject pain-onset subtype for 
cohort/randomisation number assignation. 
Subjects meeting the eligibility criteria will be assigned to a randomisation number, and will 
be allocated to the associated treatment arm, by IRT. A treatment number will be also 
allocated by IRT each time drug is dispensed. The IRT will also manage all the logistical 
aspects of treatments (e.g.: drug supplies, replacement of lost, damaged, quarantined, expiring 
and expired kits). 
This service provides site staff and project team members with a 24-hour per day, 7-day per 
week service (additional details may be found in the IRT reference manual provided to each 
site). In case of medical or technical randomisation or dispensation queries, a 24-hour helpline 
is available –supporting information is provided in the investigator site file.  
Recruitment will stop in each cohort of Stage 1 (and respectively in Stage 2) once 10 (or 8 in 
Cohort 4 only) and respectively 63 evaluable subjects have been randomised with the 
expected ratio.  
Randomised subjects who terminate their study participation for any reason before 
administration of the first dose of randomised study drug will retain their randomisation and 
treatment numbers (i.e. these numbers will not be reused). The next subject will be given 
another randomisation number and another treatment number, even if she should receive the 
same treatment. Non-evaluable subjects will be replaced with a mirror list, so that the 
replacement subject is assigned to the same treatment arm as the replaced subject. 
The sponsor’s randomisation manager will keep the master lists. A copy of lists of treatment 
numbers (lists B1 and B2) will be confidentially supplied to the Ipsen PharmSciences,
 
. Similarly, a copy of lists of randomisation/treatment 
numbers (lists A1, B1, A2 and B2) will be also confidentially supplied to the Contract 
CCI


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Research Organisation (CRO) in charge of IRT. Finally, a copy of lists concerning stage 1 
(lists A1 and B1) will be also confidentially supplied to the independent statistician in charge 
of tables, figures and listings (TFLs) for the DRC. The master lists and the copies supplied to 
Ipsen PharmSciences, CRO in charge of IRT and to the independent statistician in charge of 
TFLs for DRC will be kept confidential in a secure location. Access to the randomisation lists 
must be restricted until authorisation is given to release them for final analysis. 
3.6 
Maintenance of Randomisation and Blinding 
In an emergency situation, which requires the identification of the study treatment group, the 
investigator may break the treatment code immediately, or as quickly as possible, if he/she 
finds it is in the best interest of the trial subject. The investigators have direct and immediate 
access to break the treatment code through the IRT. At the earliest opportunity, the 
investigator is requested to inform the blinded monitor in charge of his/her centre that the 
blind has been broken for an emergency. 
In addition, a set of hard copy sealed code break envelopes will be held by Global Patient 
Safety (GPS) at Ipsen, in case of IRT failure (this set will be prepared by Ipsen randomisation 
manager). 
If code-break was performed using the IRT, the investigator must store the email notification 
revealing unblinded treatment in a sealed envelope. The investigator will then sign, date and 
provide reason for the code break on the emergency code break form and on the sealed 
envelope. The date and reason for identifying the treatment group will be recorded in the 
electronic case report form (eCRF). 
Finally, if needed, DRC will be able to unblind any subject of Stage 1, with the hard copy 
sealed code break envelope of her randomisation number (this set of envelopes will be 
prepared by Ipsen randomisation manager) or using the IRT.  
3.7 
Study Treatments and Dosage 
3.7.1 
Study Treatments 
The test product, Dysport, will be provided in glass vials containing 300 U or 500 U 
(nominal) of BTX-A-HAC as white lyophilised powder for reconstitution with preservative 
free 0.9% sodium chloride for injection. Detailed description of Dysport composition is 
provided in Section 6.2.1.1. 
The reference therapy for the double-blind period in this study (Stage 1 and Stage 2) is a 
matching placebo. Detailed description of the placebo composition is provided in 
Section 6.2.1.2  
Details on the injection sites and injection procedure are presented in Section 6.2.2. 
The IMPs will be packaged by Ipsen PharmSciences, 
 
 and delivered to an interim storage facility. A sufficient quantity of IMP will be 
supplied as well as an acknowledgement of receipt form.  
The sponsor’s representative will receive a Certificate of Analysis for each batch of IMP used 
in the study and Material Data Safety Sheet for both active and placebo IMP.  
The core label texts for all packaging units will be translated or adjusted, to follow applicable 
regulatory requirements, national laws in force and in accordance with the local languages. A 
description of the core text of the IMP labels is displayed below: 
• 
Name, address and telephone number of the sponsor (the main contact for information 
on the product, clinical study and emergency unblinding), 
• 
Study Number, 
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• 
Pharmaceutical dosage form, 
• 
Route of administration, 
• 
Directions for use (reference may be made to a leaflet), 
• 
Quantity of dose units, 
• 
Batch number, 
• 
A specific blank space to enter the visit number (to be completed on site), 
• 
“Caution: new drug limited by Federal Law to investigational use,” 
• 
Investigational drug to be used by qualified investigators only, 
• 
“For clinical trial use only,” 
• 
Specific blank space to enter the investigator's name (to be completed on site), 
• 
Storage conditions, 
• 
Expiry date, 
• 
Treatment number, 
• 
A specific blank space to enter the subject ID (to be completed on site) 
• 
A specific blank space to enter the site number (to be completed on site). 
The investigator, or designee, will only dispense IMPs to subjects included in this study. Each 
subject will only be given the IMP carrying her number. The dispensing for each subject will 
be documented in the eCRF. 
3.7.2 
Study Dosage and Administration 
A study flow chart for Stage 1 and Stage 2 is presented in Figure 2. 
 


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Figure 2 Study Flow Chart 
 
 
 
3.7.2.1 
Stage 1 
The maximum permitted dose in Stage 1 (double-blind and open-label periods) is 800 U. 
Double-Blind Period (Treatment Cycle 1) 
The starting dose for PVD2 Cohort 1 will be Dysport 100 U or placebo. It is anticipated that if 
there are no safety issues, then the predefined doses for PVD2 Cohorts 2 and 3 will be 300 U 
and 400 U, respectively, and doses for Cohorts 5, 7, 9 and 11 will be 500 U up to a maximum 
of 800 U by increments of 100 U, all with matching placebos. Subjects in PVD1 Cohorts 4, 6, 
8, 10 and 12 will receive the same dose as subjects in PVD2 Cohorts 3, 5, 7, 9 and 11.The 
DRC may recommend to reassess the previously used dose level based on the review of 
efficacy and safety data from the cohorts.  
Open-Label Period (Treatment Cycles 2-4) 
For a given subject, the Dysport dose for treatment cycles 2, 3 and 4 will be based on the 
investigator’s judgement (based on efficacy and safety).  
• 
Treatment cycle 2: the Dysport dose can either be the Dysport dose assessed in the 
previous treatment cycle (double-blind period) for the current cohort or the Dysport 
dose of the following cohort (provided it has been approved by the DRC).  
DB=double-blind, OL=open-label 


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• 
Treatment cycles 3 and 4: the Dysport dose can either be the dose assessed in the 
previous treatment cycle, a lower dose or the dose of the following cohort (provided it 
has been approved by the DRC).  
If any subject fulfils the retreatment criteria and needs a higher dose for treatment prior to the 
DRC having approved the next dose level, the subject can either accept the dose level 
currently on, or delay injection until the next dose level is approved by the DRC or withdraw 
from the study.  
A subject can receive up to a maximum of 4 treatment cycles with Dysport. The last treatment 
cycle should last at least 12 weeks and should not be initiated after Week 36.  
3.7.2.2 
Stage 2 
As for Stage 1, the maximum permitted dose in Stage 2 (double-blind and open-label periods) 
is 800 U. 
Double-Blind Period (Treatment Cycle 1) 
Depending upon the results from Stage 1 and the recommendation from the DRC, two doses 
of Dysport will be selected.  
• 
Dysport high dose (optimal highest safe and efficacious dose) selected from Stage 1 or 
• 
Dysport low dose selected based on safety and efficacy considerations observed in 
Stage 1 or 
• 
Placebo. 
Open-Label Period (Treatment Cycles 2-4) 
For a given subject, the Dysport dose for treatment cycles 2, 3 and 4 will be:  
• 
Treatment cycle 2: the Dysport dose will be the lowest of the two Dysport doses tested 
in the double-blind period of Stage 2.  
• 
Treatment cycles 3 and 4: as per the investigator’s judgement (based on efficacy and 
safety), the Dysport dose can be either the low or high dose tested during the 
double-blind period of Stage 2. 
A subject can receive up to a maximum of 4 treatment cycles with Dysport. The last treatment 
cycle should last at least 12 weeks and should not be initiated after Week 36.  
3.7.3 
Retreatment Criteria (Stage 1 and Stage 2) 
From Week 12 onwards (Stages 1 and 2), need for retreatment will be assessed at each visit. 
All subjects willing to continue in the study will be offered to receive Dysport (under an 
open-label design). 
Retreatment with Dysport will only be initiated if all of the following criteria are fulfilled 
(retreatment criteria): 
• 
At least 12 weeks have elapsed since the last treatment received.  
• 
Based on investigator’s judgement, this is in the best interest of the subject. 
• 
Subject is willing to be retreated. 
• 
The subject has not experienced any unacceptable AE as judged by the investigator. 
• 
Negative urine pregnancy test. 
• 
Negative drug screen test for illicit drugs.  
Details on dose administration for Stage 1 are provided in Sections 3.7.2.1 and for Stage 2 in 
Section 3.7.2.2. 


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3.8 
Study Duration 
This study will consist of a 14-day screening period (Stage 1 and Stage 2), a double-blind 
treatment period including treatment administration at Day 1 and a follow-up period of 36 to 
48 weeks (calculated from the dosing at Day 1). From Week 12 onwards of the double-blind 
period, the subject may enter an open-label treatment period and receive up to three additional 
treatment cycles with Dysport administered at least 12 weeks apart (a maximum of 
4 treatments including the one received in the double-blind period).  
Individual subject participation in this study will be for a maximum of 54 weeks (Stage 1 and 
Stage 2):  
• 
Screening: 2 weeks (plus 2 weeks window) 
• 
Follow-up: a maximum of 48 weeks follow-up plus 2 weeks window period for the 
EOS Visit depending on the number of treatments administered and the treatment 
intervals.  
The subject’s participation in the study will be considered to have ended 36 to 48 weeks after 
the first dose, but not before 12 weeks have elapsed after the last dose.  
The overall duration of the study, including Stage 1 and Stage 2 with a maximum allowed 
dose of 800 U, will be approximately 4 years. The study will be considered to have started 
when the first subject has provided signed informed consent. The study will be considered to 
have ended after the last subject has completed the EOS visit in the study. 
3.9 
Stopping Rules and Discontinuation Criteria 
A specific site or a given cohort can be discontinued or the entire study may be terminated if 
recommended by the DRC at any time during Stage 1 or if the sponsor judges it necessary for 
any reason any time during the study. In that case, all efforts should be made to perform the 
scheduled procedures and assessments for subjects who are still in the study until 12 weeks 
after the last dose. 
The study could be stopped or discontinued due to following reasons: 
• 
As per the DRC’s decision in Stage 1: 
- 
Any DLE identified as a safety concern (definition provided in Section 3.1.1.1); 
- 
Any clinically significant AE(s) identified as a safety concern (definition 
provided in Section 3.1.1.1); 
- 
For any other safety reason. 
• 
As per sponsor’s decision anytime during the study for reasons including: 
- 
Failure of the site staff to comply with the protocol or with the GCP guidelines; 
- 
AEs or SAEs leading to safety concerns (See Section 8.1.6); 
- 
Inadequate subject recruitment; 
- 
Other reasons (decisions made by the Regulatory Authorities or Ethics 
Committees or any other sponsor business decision). 
The subject withdrawal criteria as discussed in Section 4.4.  
3.10 
Source Data Recorded on the Case Report Form 
Data will be collected in the eCRF in compliance with FDA 21 CFR Part 11. As required by 
GCP, the sponsor assigned monitor will verify, by direct reference to the source documents, 
that the data required by the protocol are accurately reported on the eCRF.  


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The source documents must, as a minimum, contain a statement that the subject is included in 
a clinical study, the date that informed consent was obtained prior to participation in the 
study, the identity of the study, diagnosis and eligibility criteria, visit dates (with subject 
status), IMP administration, and any AEs and associated concomitant medication. 
As required by ICH GCP Section 6.4.9, if some items are recorded directly on the eCRF and 
are considered as source data, the identification of these data must be documented and agreed 
between the investigator and the sponsor. 
Definition for source data and source documents are given below: 
• 
Source Data: All original records and certified copies of original records of clinical 
findings, observations, or other activities necessary for the reconstruction and 
evaluation of the study. Source data are contained in source documents (original 
records or certified copies). 
• 
Source Documents: Original documents, data and records (e.g. hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or magnetic media, x rays, subject files, 
and records kept at the pharmacy, at the laboratories and at medicotechnical 
departments involved in the clinical study). 
The subject must have consented to their medical records being viewed by the sponsor’s 
authorised personnel, and by local, and possibly foreign, Competent Authorities (CAs). This 
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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Note: Lettered inclusion and exclusion criteria indicate an update or deletion following an 
amendment to the protocol (e.g. a=criterion amended once, b=criterion amended twice, 
c=criterion amended three times). 
4.1 
Inclusion Criteria 
All subjects must fulfil all the following criteria to be included in the study: 
(1a) Female subjects aged 18 years or above. 
(2) 
Willing to provide a written informed consent prior to any study related procedures. 
(3) 
Criterion 3 is removed by protocol amendment. 
(4) 
Are premenopausal, as evidenced by a serum follicle stimulating hormone (FSH) level 
of <35 mIU/mL as assessed at the Screening Visit. 
(5) 
Have a negative pregnancy test at screening. 
(6) 
Willing to practice a highly effective form of contraception method at the beginning of 
the study, for the duration of the study and for a minimum of 12 weeks following last 
administration of study drug. Highly effective methods of contraception are defined as 
methods of birth control which result in a low failure rate (i.e. less than 1% per year) 
when used consistently and correctly such as implants, injectables, combined oral 
contraceptives, intrauterine devices, or vasectomised partner. The double barrier 
method (condom and spermicide) may be considered an acceptable form of birth 
control if determined appropriate for the subject by the investigator. 
(7) 
Have vulvodynia with provoked vestibular pain for at least 6 months and for no more 
than 15 years. 
(8a) Have provoked pain at the posterior vestibule on a Q-tip test, with pain at positions 5, 6 
and 7 o’clock (must be bilateral pain) at the Screening Visit. 
(9a) Are able to tolerate the smallest dilator size (diameter 0.5 inches) at the Screening 
Visit, i.e. agree to the next successive dilator size to be tested for pain response (i.e. the 
two smallest sized dilators (#1 and 2) are to be tested).  
(10a) Pain score ≥5 on an 11-point NRS for the DMTS at the Baseline Visit. 
(11a) Willing to abstain from sex therapy (defined as a therapy primarily focused on the 
management of vulvar pain) for the duration of screening and up to at least Week 6 of 
the first treatment cycle.  
(12b) In Stage 1, Cohorts 1, 2, 3, 5, 7, 9 and 11 will include subjects with secondary 
vulvodynia (i.e. having a past history of pain-free intercourse or insertion of any object 
>1 cm diameter). In Stage 1, Cohorts 4, 6, 8, 10 and 12 will include subjects with 
primary vulvodynia (having life-long provoked vestibular pain). In Stage 2, subjects 
with either primary or secondary vulvodynia may be enrolled as approved by the DRC. 
(13) Willing and able to comply with study restrictions, able to attend the clinic for the 
required duration of assessments during the study period and willing to return to the 
clinic for the follow-up evaluation as specified in the protocol. 
(14) If the subject has received oral antidepressants, anxiolytics or anti-epileptics, then the 
dose of these medications should have been stable for at least 6 months prior to the 
Screening Visit and expected to remain stable throughout the first treatment cycle. 


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4.2 
Exclusion Criteria 
Subjects will not be included in the study if they meet any of the following exclusion criteria: 
(1a) Have provoked pain on a Q-tip test at the anterior vestibule (anywhere between 9 and 
3 o’clock or more anteriorly) at the Screening Visit.  
(2b) Able to tolerate the 6th (diameter 1¼ inches) dilator size (i.e. agree to the next 
successive dilator size to be tested for pain response) at the Baseline Visit (i.e. at least 
one of the two largest sized dilators (#7 and/or 8) is tested). 
(3a) Any non-provoked (i.e. spontaneous) vulvar pain in the past 6 months prior to the 
Screening Visit. Note: pain provoked by any vestibular pressure (including but not 
limited to sitting, bicycling or tight clothing) is considered provoked pain. 
(4a) Deep pain during intercourse in the past 6 months prior to the Screening Visit. 
(5a) Score of 4 or 5 on any of the 3 pain questions (questions #17, 18 or 19) of the mFSFI 
questionnaire. 
(6) 
Criterion 6 is removed by previous protocol amendment. 
(7a) Significant depressive disorder, e.g. having a score ≥20/27 on the Patient Health 
Questionnaire (PHQ-9) scale at the Baseline Visit. 
(8b) Genitourinary or gastrointestinal conditions/history including:  
- 
Skin disease at the vestibule such as lichen sclerosus, lichen planus, vaginal or 
vulvar atrophy, desquamative inflammatory vaginitis and allergic vulvitis. 
- 
Severe endometriosis (severe defined as requiring regular medications to manage 
the endometriosis symptoms).  
- 
Severe bladder and bowel symptoms e.g. diagnosed interstitial cystitis/Bladder 
Pain Syndrome, severe urinary incontinence, faecal incontinence, inflammatory 
bowel disease. 
- 
Genitourinary or rectal cancer. 
- 
Congenital urogenital abnormalities (e.g. vaginal septa, imperforate hymen, 
urethral diverticulum). 
- 
Pain in urethra (diagnosis based on subject’s interview and physical 
examination). 
- 
Symptomatic urogenital prolapse at physical examination. 
- 
History of traumatic or post radiotherapy vulvar lesions. 
- 
Pudendal neuralgia 
- 
Other conditions that in accordance to the investigator’s judgement may interfere 
with treatment or impact the study outcome. 
(9) 
Previous surgery/conditions including: 
- 
Hysterectomy 
- 
Vestibulectomy 
- 
Urologic surgery 
- 
Perianal surgery 
- 
Genital trauma or mutilation/cutting 
- 
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(10) Vaginal infections (bacterial vaginosis, presence of candidiasis or trichomoniasis) at 
Screening Visit. 
(11) Current infection at the injection site(s). 
(12) Unable to receive intramuscular injections. 
(13) History of hypersensitivity to Dysport or drugs with a similar structure or any excipient 
used in the formulation. 
(14) Clinically significant history of alcohol/drug abuse the last 24 weeks prior to screening 
or clinically significant alcohol/drug dependence within 2 years prior to screening. 
Exceptions include caffeine or nicotine abuse/dependence. 
(15a) Positive urine test for illicit drugs (drugs of abuse) at screening. In the event a subject 
tests positive for cannabinoids (tetrahydrocannabinol), the investigator will evaluate the 
subject’s ability to abstain from cannabis during the study. If in the investigator’s 
clinical judgement, the subject will abstain, the subject may be enrolled after 
consultation with the Medical Monitor. Note: at the discretion of the investigator, 
positive drug screens for prescribed medications will not be considered exclusionary. 
(16c) Has received any of the following: 
- 
Pelvic floor physical therapy initiated, stopped or modified (frequency or type of 
physical therapy) during the last 12 weeks prior to Baseline (physical therapy 
includes but is not limited to: internal/external myofascial release by 
physiotherapist, biofeedback, home pelvic floor exercises, self-taught exercises, 
use of vaginal dilators, etc.). 
- 
Sex therapy in the past 6 weeks prior to Baseline. 
- 
Previous treatment with any BTX for any indication within the last 1 year. 
- 
Treatment for vestibular pain, with hormonal creams, in the last 1 week prior to 
Screening unless continued at the same dosing regimen throughout the study. 
- 
Currently receiving treatment for stress or urge urinary incontinence. 
- 
Treatment with any of the following drugs that could affect neuromuscular 
function: curare-like nondepolarising agents, lincosamides, polymyxins, 
anticholinesterases, aminoglycoside antibiotics (topical use is permitted except at 
the vulvar vestibular region), tizanidine and baclofen, within the last 4 weeks 
prior to Baseline or during the study. 
- 
Injections of steroids in the vulva within the last 4 weeks prior to the Screening 
Visit or planned use during the study. 
- 
Treatment with an investigational drug within the last 4 weeks prior to Baseline 
or scheduled treatment with such a drug during the study period. 
- 
Is likely to require treatment during the study with drugs that are not permitted 
by the study protocol. 
(17) Any mental condition rendering the subject unable to understand the nature, scope and 
possible consequences of the study, and/or evidence of an uncooperative attitude, as 
judged by the investigator.  
(18) Abnormal baseline findings, any other medical condition(s) or laboratory findings that, 
in the opinion of the investigator, might jeopardise the subject’s safety or compromise 
compliance with the objectives and/or procedures of this protocol or preclude the 
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(19) Female subject who is pregnant or planning to become pregnant during the study or, is 
currently lactating (breastfeeding). 
4.3 
Rationale for Inclusion/Exclusion Criteria 
In order to establish the preliminary efficacy of Dysport in this dose escalation and dose 
expansion study, a subset of vulvodynia subjects suffering from provoked vestibular pain is 
selected. It is hypothesised that pelvic floor muscle hypertonicity underpins the posterior 
vestibular pain experienced and consequently, these subjects are likely to respond to treatment 
with Dysport. Hence, the inclusion and exclusion criteria for this study have been tailored to 
ensure enrolment of female subjects with a confirmed diagnosis of PVD based on the three 
established criteria as per Pukall 2007 [21]: self-report of superficially-located pain during 
sexual intercourse; a lack of physical findings (e.g. infections) to explain the pain or the 
persistence of pain after conditions believed to be related to the pain have been treated; and a 
positive response (i.e. pain) during the cotton-swab test. This will also help target a 
homogenous subject population and limit intersubject variability. 
4.4 
Subject Withdrawal Criteria and Procedures 
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each subject is free to withdraw from the study at any time. 
The investigator and/or sponsor can withdraw a subject at any time for any reason (e.g. 
protocol violation). 
The investigator also has the right to withdraw a subject from the study for reasons including: 
• 
If required by the DRC due to reasons described in Section 3.1.1.2 
• 
Any AE that jeopardises the safety of the subjects 
• 
Other reasons concerning the health or wellbeing of the subject 
• 
In the event of concurrent illness, based on the benefit risk for the subject as assessed 
by the investigator (see concomitant medications not permitted in Section 6.3) 
• 
Pregnancy (see Section 8.1.7) 
• 
Lack of cooperation in completing the study visits or schedules or study assessments 
• 
Study is stopped or discontinued (See Section 3.9 for further details) 
• 
Death (see Section 8.1.8) 
• 
Any other reason as judged by the investigator to be in the best interest of the subject. 
If a subject decides to withdraw from the study after administration of IMP, or should the 
investigator decide to withdraw the subject, all efforts will be made to complete and report the 
observations at least 12 weeks after the last dose or up to the time of withdrawal as thoroughly 
as possible. A complete assessment should be made and final evaluations be done at the time 
of the subject’s withdrawal as described in Section 5.2.4 with an explanation given of why the 
subject is withdrawing or being withdrawn from the study. 
 The reason for and date of withdrawal from the study must be recorded on the eCRF. If a 
subject withdraws consent, every attempt will be made to determine the reason. If the reason 
for withdrawal is an AE or a clinically significant laboratory test abnormality, monitoring will 
continue until the event has resolved or stabilised, until the subject is referred to the care of a 
local health care professional, or until a determination of a cause unrelated to the IMP or 
study procedure is made. The specific AE or test result(s) must be recorded on the eCRF. All 
evaluations should be performed, according to the protocol, on the last day the subject 
receives IMP, or as soon as possible thereafter.  


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5 
STUDY PROCEDURES 
5.1 
Study Schedule 
The schedule of procedures and assessments during the study for the double-blind treatment 
period is summarised in Table 2 and for the open-label treatment period in Table 3. 
Subjects enrolled prior to implementation of Version 3.0 (dated 04 November 2018), i.e. 
subjects included in Cohort 1, will continue to follow the study assessments and procedures as 
per the protocol Version 2.0 (dated 15 May 2018). 
If the COVID-19 pandemic prevents subjects from coming to the site, subjects can have their 
study visit assessments performed remotely as judged appropriate by the investigator; the 
medical monitor/sponsor must be informed before implementing this. In such a case, the 
investigator will perform a telemedicine visit and will make every effort, where applicable, to 
contact the subject’s general practitioner or equivalent to ensure all important medical 
information and safety event(s) occurring since the last visit are collected. Guidance on how 
to collect protocol-planned assessments will be provided to the investigator in a separate 
document. Such document will be filed in the Trial Master File (TMF). IECs/IRBs will be 
notified of the changes as applicable locally. Of note, as the adapted visit deviates from the 
regular protocol plan, the changes will be recorded as protocol deviations related to 
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The total volume of blood drawn for all evaluations throughout this study is approximately 
46 mL for each subject (Table 4).  
Table 4 
Blood Volume for Collection 
Purpose 
Maximum Blood Volume 
per Sample (mL) 
Maximum Number of 
Blood Samples 
Maximum Total Blood 
Volume (mL) 
Haematology  
3 
3 
9 
Serum Chemistry  
4 
3 
12 
FSH 
1 
1 
1 
Putative antibodies 
12 
2 
24 
Total volume for all tests 
46 
FSH=follicle stimulating hormone 
5.2 
Study Visits 
For the purpose of study visits and procedures, the duration of 1 month=4 weeks=28 days. For 
assessments done at the Screening Visit, but not repeated at the Baseline Visit, the Screening 
values will be considered as Baseline.  
Subjects are required to remain at the clinic for the required duration of study assessments and 
for at least 30 minutes after study drug administration. 
The priority order for performing the assessments is discussed in Section 6.6. 
If the COVID-19 pandemic prevents subjects from coming to the site, study assessments 
planned in the protocol will be limited to the ones possible remotely, denoted with an 
asterisk (*) in Table 2, Table 3, Section 5.2.2, Section 5.2.3 and Section 5.2.4; of note no 
study assessments should be performed remotely for the Screening, Baseline and EOS/EWD 
visits. Completion of questionnaires on the subjects’ own device will be performed provided 
that the site staff can access the ePRO system to record the visit date. 
5.2.1 
Procedures for Screening and Enrolment - Visit 1 (Day -14 (-14 days/ +3 days)) 
A signed and dated informed consent form will be obtained before screening procedures. 
After informed consent is obtained, subjects who are screened will be allocated a subject 
number. All screened subjects must be identifiable throughout the study. The investigator will 
maintain a list of subject numbers and names to enable records to be found at a later date if 
required. 
5.2.1.1 
Screening – Visit 1 - Day -14 (-14 days/ +3 days) 
The Screening Visit (Visit 1) will take place on Day -14 of the study. The visit window will 
be from Day -28 to Day -11. 
The following assessments will be performed: 
• 
Eligibility check (inclusion/exclusion criteria) 
• 
Demographic data (year of birth, age, sex, ethnicity, and race)  
• 
Medical history, including significant ongoing medical history, surgical history and 
vulvodynia history 
• 
Vital signs (supine or sitting blood pressure and heart rate) 
• 
Body height and weight 
• 
Physical examination 
• 
Blood sampling (nonfasting) for haematology, biochemistry, putative antibodies and 
FSH  


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• 
Urine pregnancy test  
• 
Urine test for illicit drugs 
• 
Vaginal culture/polymerase chain reaction for yeast, parasitic and bacterial infections 
• 
PCS 
• 
mFSFI (pain to be recorded at the visit, and 1 week prior to the Baseline Visit; other 
domains to be recorded only at the visit) 
• 
Relationship/partner status (to be recorded at the visit and then weekly during the 
screening period) 
• 
mVPAQ (pain and life interference to be recorded at the visit, and 1 week prior to the 
Baseline Visit; other subscales to be recorded only at the visit) 
• 
Intercourse details (to be recorded daily during the screening period) 
• 
Dilator size 6 insertion details (to be recorded weekly during the screening period) 
• 
PGI-S (to be recorded at the visit, and 1 week prior to the Baseline Visit) 
• 
Q-tip test 
• 
Dilator test 
• 
Record: 
- 
Prior and concomitant medications/therapies (including pain rescue medication) 
administered within 28 days before the Screening Visit 
- 
Prior pelvic floor physical therapy or sex therapy received in the past 2 years 
prior to the planned Baseline 
- 
Treatment for anterior vestibular pain 
- 
Prior treatment with any BTX within the last 1 year 
- 
Prior and concomitant nondrug therapies and surgical procedures administered 
within 28 days before the Screening Visit 
- 
Use of any experimental new drug or device within past 4 weeks prior to the 
planned Baseline. 
• 
Collection of AEs (since the signature of the informed consent) 
• 
Instructions on patient diary completion. 
Following confirmation of eligibility of the subject for the study and confirmation that the 
recruitment is still open in the cohort/group, subjects will be randomised and allocated to one 
of the dosing groups specified in Section 3.7.2. 
A subject can be rescreened once, if all eligibility criteria were met but the subject was not 
enrolled due to any of the following, and twice due to ANY of the following conditions if 
they had to stop the first screening period due to COVID-19:  
• 
Cohort recruitment being complete by the time the subject was eligible,  
• 
If the subject had a UTI or vaginal infection at first screening and has received 
adequate treatment leading to complete resolution of the infection,  
• 
If the subject failed screening due to a selection criterion that was removed from the 
previous version of the protocol. If the subject failed screening due to a selection 
criterion that was modified, she should have fulfilled the new criterion at the time of 
the first screening to be able to be rescreened. In these situations, the subject may only 
be rescreened once the new amended protocol has been approved by the IRB.  


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Rescreened subjects will sign a new informed consent form and a new subject number will be 
allocated. All screening assessments need to be repeated for the rescreened subject. 
Each investigator will maintain a record of all subjects screened (i.e. who signed the informed 
consent form) and enrolled (i.e. who was given a randomisation number) into the study. 
Records up to the time of premature termination should be completed. In the event that the 
subject was not receiving IMP, the primary reason will be recorded. 
5.2.2 
Procedures During Double-Blind Period – Treatment Cycle 1 (Stage 1 + Stage 2) 
5.2.2.1 
Baseline Visit (Day 1) 
The following procedures will be performed prior to the administration of study treatment: 
• 
Eligibility check (inclusion/exclusion criteria) 
• 
PGI-S (to be recorded 1 week prior to the visit and at the visit) 
• 
mFSFI (pain to be recorded 1 week prior to the visit and at the visit; other domains to 
be recorded only at the visit) 
• 
Relationship/partner status (to be recorded weekly from 2 weeks prior to the visit and at 
the visit) 
• 
mVPAQ (pain and life interference to be recorded 1 week prior to the visit and at the 
visit; other subscales to be recorded only at the visit) 
• 
PHQ-9 
• 
SF-36  
• 
Intercourse details (to be recorded daily from 2 weeks prior to the visit) 
• 
Dilator size 6 insertion details (to be recorded weekly from 2 weeks preceding the visit; 
assessment on the day of the visit should be avoided)  
• 
Dilator test 
• 
Measurement of pelvic floor muscle pressure (in all subjects in Stage 1 up to 400 U and 
in a subset of subjects in Stage 2 (i.e. in subjects who have never had a vaginal delivery 
(including attempted vaginal delivery), and at study sites that were provided a 
perineometer)) 
• 
Review of AEs 
• 
New or changed concomitant medications/nondrug therapies 
• 
Randomisation. 
Once these procedures have been performed, the study treatment will be injected as described 
in Section 6.2.2. 
Following injection, subjects will be observed at the study centre for at least 30 minutes. 
5.2.2.2 
Week 2 – Telephone Contact (Day 15 ±3 days) 
The following procedures will be performed at this telephonic contact: 
• 
Review of AEs 
• 
New or changed concomitant medications/nondrug therapies. 
5.2.2.3 
Week 6 Visit (Day 43 ±5 days) 
The following procedures will be performed: 
• 
PGI-S (to be recorded 1 week prior to the visit and at the visit)* 
• 
PGI-C (to be recorded 1 week prior to the visit and at the visit)* 


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• 
mFSFI (pain to be recorded 1 week prior to the visit and at the visit; other domains to 
be recorded only at the visit)* 
• 
Relationship/partner status (to be recorded weekly from 2 weeks prior to the visit and at 
the visit)* 
• 
mVPAQ (pain and life interference to be recorded 1 week prior to the visit and at the 
visit; other subscales to be recorded only at the visit)* 
• 
Intercourse details (to be recorded daily from 2 weeks prior to the visit)* 
• 
Dilator size 6 insertion details (to be recorded weekly from 2 weeks preceding the visit; 
assessment on the day of the visit should be avoided)*  
• 
Urine test for illicit drugs 
• 
Dilator test 
• 
Measurement of pelvic floor muscle pressure (in all subjects in Stage 1 up to 400 U and 
in a subset of subjects in Stage 2 (i.e. in subjects who have never had a vaginal delivery 
(included attempted vaginal delivery), and at study sites that were provided a 
perineometer to assess pelvic floor muscle pressure)) 
• 
CGI 
• 
Review of AEs* 
• 
New or changed concomitant medications/nondrug therapies* 
• 
Subject interviews (every effort should be made to conduct the interview within 
2 weeks of the subject’s Cycle 1-Week 6 visit in Stage 2). 
5.2.2.4 
Week 12 Visit (Day 85 +14 days) 
The following procedures will be performed: 
• 
mFSFI (pain to be recorded 1 week prior to the visit and at the visit; other domains to 
be recorded only at the visit)* 
• 
Relationship/partner status (to be recorded weekly from 2 weeks prior to the visit and at 
the visit)* 
• 
mVPAQ (pain and life interference to be recorded 1 week prior to the visit and at the 
visit: other subscales to be recorded only at the visit)* 
• 
PHQ-9* 
• 
SF-36* 
• 
PGI-S (to be recorded 1 week prior to the visit and at the visit)* 
• 
PGI-C (to be recorded 1 week prior to the visit and at the visit)* 
• 
Intercourse details (to be recorded daily from 2 weeks prior to the visit)* 
• 
Dilator size 6 insertion details (to be recorded weekly from 2 weeks preceding the visit; 
assessment on the day of the visit should be avoided)*  
• 
Blood sampling (nonfasting) for haematology and biochemistry**  
• 
Dilator test 
• 
Measurement of pelvic floor muscle pressure (in all subjects in Stage 1 up to 400 U and 
in a subject of subjects in Stage 2 (i.e. in subjects who have never had a vaginal 
delivery (included attempted vaginal delivery), and at study sites that were provided a 
perineometer to assess pelvic floor muscle pressure)) 
• 
CGI 


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• 
Review of AEs* 
• 
New or changed concomitant medications/nondrug therapies*. 
**In the event of a remote visit being required, blood sampling should be performed as soon 
as onsite visit resume and prior to the Week 18 Visit (as much as possible) and recorded as an 
unscheduled visit. 
Once these procedures have been performed, the need for retreatment will be assessed as 
described in Section 3.7.3: 
• 
Subjects eligible for retreatment will complete the remaining End of Cycle 1 
assessments and enter the treatment cycle 2 (open-label, see Section 5.2.3.1) on the 
same day or once the DRC has confirmed the dose of the next cohort; 
• 
Subjects not eligible for retreatment will perform an Additional Visit 6 weeks later (see 
Section 5.2.2.5).  
In the event of a remote visit being required, subjects should not receive re‐treatment with 
Dysport until onsite visits resume. 
5.2.2.5 
Weeks 18, 24, 30 and/or 36 – Additional Visits (Day 127, 169, 211 and/or 
253 ±14 days) 
The following procedures will be performed: 
• 
PGI-S (to be recorded 1 week prior to the visit and at the visit)* 
• 
PGI-C (to be recorded 1 week prior to the visit and at the visit)* 
• 
mFSFI (pain to be recorded 1 week prior to the visit and at the visit; other domains to 
be recorded only at the visit)* 
• 
Relationship/partner status (to be recorded weekly from 2 weeks prior to the visit and at 
the visit)* 
• 
mVPAQ pain and life interference subscales (to be recorded 1 week prior to the visit 
and at the visit)* 
• 
mVPAQ other subscales (at Week 24 and Week 36 only)* 
• 
PHQ-9 (at Week 36 only)* 
• 
SF-36 (at Week 36 only)* 
• 
Intercourse details (to be recorded daily from 2 weeks prior to the visit)* 
• 
Dilator size 6 insertion details (to be recorded weekly from 2 weeks preceding the visit; 
assessment on the day of the visit should be avoided)*  
• 
Dilator test 
• 
Measurement of pelvic floor muscle pressure (in all subjects in Stage 1 up to 400 U and 
in a subset of subjects in Stage 2 (i.e. in subjects who have never had a vaginal delivery 
(included attempted vaginal delivery), and at study sites that were provided a 
perineometer to assess pelvic floor muscle pressure)) 
• 
CGI 
• 
Review of AEs* 
• 
New or changed concomitant medications/nondrug therapies*. 
Once these procedures have been performed, the need for retreatment will be assessed as 
described in Section 3.7.3: 


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• 
Subjects eligible for retreatment will complete the remaining End of Cycle 1 
assessments and enter the treatment cycle 2 (open-label, see Section 5.2.3.1) on the 
same day or once the DRC has confirmed the dose of the next cohort; 
• 
Subjects not eligible for retreatment will perform an Additional Visit, every 6 weeks 
until they are eligible for retreatment or until they reach Week 36 visit. If eligible for 
retreatment at Week 36, subjects will perform the same assessments as described above 
for retreatment. If not eligible for retreatment at Week 36, subjects will perform the 
EOS Visit on the same day and complete the remaining EOS evaluations (see 
Section 5.2.4).  
In the event of a remote visit being required, subjects should not receive re‐treatment with 
Dysport until onsite visits resume. 
5.2.3 
Procedures During Open-Label Period – Treatment Cycles 2 to 4 
(Stage 1 + Stage 2) 
5.2.3.1 
Day 1 Visit (Treatment Visit) 
The following procedures will be performed prior to the administration of study treatment: 
• 
Urine pregnancy test 
• 
Urine test for illicit drugs 
• 
Review of AEs (only if the visit is not on the same day as the last visit of the previous 
cycle) 
• 
New or changed concomitant medications/nondrug therapies (only if Day 1 is not on 
the same day as the last visit of the previous cycle). 
If the visit occurs more than 2 weeks after the last visit of the previous treatment cycle, the 
following procedures will be done: 
• 
PGI-S (to be recorded 1 week prior to the visit and at the visit) 
• 
PGI-C (to be recorded 1 week prior to the visit and at the visit) 
• 
Relationship/partner status (to be recorded weekly from 2 weeks prior to the visit and at 
the visit) 
• 
Intercourse details (to be recorded daily from 2 weeks prior to the visit) 
• 
Dilator size 6 insertion details (to be recorded weekly from 2 weeks preceding the visit; 
assessment on the day of the visit should be avoided)  
• 
Dilator test 
• 
CGI. 
Once these procedures have been performed, the study treatment will be injected as described 
in Section 6.2.2. 
Following injection, subjects will be observed at the study centre for at least 30 minutes. 
5.2.3.2 
Week 2 – Telephone Contact (Day 15 ±3 days) 
The following procedures will be performed at this telephonic contact: 
• 
Review of AEs 
• 
New or changed concomitant medications/nondrug therapies. 
5.2.3.3 
Week 6 Visit (Day 43 ±5 days) 
The following procedures will be performed: 
• 
PGI-S (to be recorded 1 week prior to the visit and at the visit)* 


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• 
PGI-C (to be recorded 1 week prior to the visit and at the visit)* 
• 
Relationship/partner status (to be recorded weekly from 2 weeks prior to the visit and at 
the visit)* 
• 
Intercourse details (to be recorded daily from 2 weeks prior to the visit)* 
• 
Dilator size 6 insertion details (to be recorded weekly from 2 weeks preceding the visit; 
assessment on the day of the visit should be avoided)*  
• 
Urine test for illicit drugs 
• 
Dilator test 
• 
CGI 
• 
Review of AEs* 
• 
New or changed concomitant medications/nondrug therapies*. 
5.2.3.4 
Week 12 Visit (Day 85 ±14 days) 
The following procedures will be performed: 
• 
PGI-S (to be recorded 1 week prior to the visit and at the visit)* 
• 
PGI-C (to be recorded 1 week prior to the visit and at the visit)* 
• 
Relationship/partner status (to be recorded weekly from 2 weeks prior to the visit and at 
the visit)* 
• 
Intercourse details (to be recorded daily from 2 weeks prior to the visit)* 
• 
Dilator size 6 insertion details (to be recorded weekly from 2 weeks preceding the visit; 
assessment on the day of the visit should be avoided)* 
• 
Dilator test 
• 
CGI 
• 
Review of AEs* 
• 
New or changed concomitant medications/nondrug therapies*. 
Once these procedures have been performed: 
• 
If this visit occurs >36 weeks from Cycle 1 Day 1, subjects will perform the EOS Visit 
on the same day and complete the remaining EOS evaluations (see Section 5.2.4). 
• 
If this visit occurs ≤36 weeks from Cycle 1 Day 1, the need for retreatment will be 
assessed as described in Section 3.7.3: 
- 
Subjects eligible for retreatment will enter the next open-label treatment cycle 
(open-label, see Section 5.2.3.1) on the same day or once the DRC has confirmed 
the dose of the next cohort; 
- 
Subjects not eligible for retreatment will perform an Additional Visit 6 weeks 
later (see Section 5.2.3.5).  
In the event of a remote visit being required, subjects should not receive re‐treatment with 
Dysport until onsite visits resume. 
5.2.3.5 
Weeks 18 and/or 24 – Additional Visits (Day 127 or 169 ±14 days) 
The following procedures will be performed: 
• 
PGI-S (to be recorded 1 week prior to the visit and at the visit)* 
• 
PGI-C (to be recorded 1 week prior to the visit and at the visit)* 


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• 
Relationship/partner status (to be recorded weekly from 2 weeks prior to the visit and at 
the visit)* 
• 
Intercourse details (to be recorded daily from 2 weeks prior to the visit)* 
• 
Dilator size 6 insertion details (to be recorded weekly from 2 weeks preceding the visit; 
assessment on the day of the visit should be avoided)*  
• 
Dilator test 
• 
CGI 
• 
Review of AEs* 
• 
New or changed concomitant medications/nondrug therapies*. 
Once these procedures have been performed: 
• 
If this visit occurs >36 weeks from Cycle 1 Day 1, subjects will perform the EOS Visit 
on the same day and complete the remaining EOS evaluations (see Section 5.2.4). 
• 
If this visit occurs ≤36 weeks from Cycle 1 Day 1, the need for reinjection will be 
assessed as described in Section 3.7.3: 
- 
Subjects eligible for retreatment will enter the next open-label treatment cycle 
(open-label, see Section 5.2.3.1) on the same day or once the DRC has confirmed 
the dose of the next cohort; 
- 
Subjects not eligible for retreatment will perform a new Additional Visit, every 
6 weeks until they are eligible for retreatment (see Section 5.2.3.1), or until they 
reach Week 36 visit. If not eligible for retreatment at Week 36, subjects will 
perform the EOS Visit on the same day and complete the remaining EOS 
evaluations (see Section 5.2.4).  
In the event of a remote visit being required, subjects should not receive re‐treatment with 
Dysport until onsite visits resume. 
5.2.4 
End of Study Visit or Early Withdrawal Visit 
The procedures to be carried out at the EOS Visit or EWD Visit are identical. 
The following procedures will be performed at the EOS, or EWD visit (the procedures 
already performed on the same day at the previous study visit do not need to be repeated): 
• 
mFSFI (pain to be recorded 1 week prior to the visit and at the visit; other domains to 
be recorded only at the visit; only if the EOS/EWD visit occurs during the double-blind 
period) 
• 
mVPAQ (pain and life interference to be recorded 1 week prior to the visit and at the 
visit; other subscales to be recorded only at the visit; only if the EOS/EWD visit occurs 
during the double-blind period) 
• 
PHQ-9 only if the EOS/EWD visit occurs during the double-blind period 
• 
SF-36 (only if the EOS/EWD visit occurs during the double-blind period) 
• 
PGI-S (to be recorded 1 week prior to the visit and at the visit) 
• 
PGI-C (to be recorded 1 week prior to the visit and at the visit) 
• 
Relationship/partner status (to be recorded weekly from 2 weeks prior to the visit and at 
the visit) 
• 
Intercourse details (to be recorded daily from 2 weeks prior to the visit) 
• 
Dilator size 6 insertion details (to be recorded weekly from 2 weeks preceding the visit; 
assessment on the day of the visit should be avoided) 


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• 
Urine pregnancy test 
• 
Urine test for illicit drugs  
• 
Blood sampling (nonfasting) for haematology, biochemistry and putative antibodies  
• 
Dilator test 
• 
CGI 
• 
Review of AEs 
• 
New or changed concomitant medications/nondrug therapies. 
If the COVID-19 pandemic prevents subjects from coming to the site, EOS visits should be 
postponed until onsite visits resume. 
Subjects who attend the EOS Visit will be considered to have completed the study.  
Subjects with ongoing AEs or clinically significant laboratory test abnormalities (as 
determined by the investigator) will be monitored as described in Section 8.1.5 and 
Section 8.1.2.4, respectively. 


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6 
TREATMENT OF SUBJECTS 
6.1 
Investigational Medicinal Product Preparation Storage and Accountability 
6.1.1 
Investigational Medicinal Product Storage and Security 
The investigator, or an approved representative (e.g. pharmacist), will ensure that all IMP and 
any other study related material is stored in a secured area, under recommended temperature 
monitored storage conditions, in accordance with applicable regulatory requirements. 
The IMP Dysport and the matching placebo should be stored at the recommended temperature 
(between 2°C and 8°C).  
The IMP Dysport and the matching placebo must not be frozen and should be protected from 
light. 
6.1.2 
Investigational Medicinal Product Preparation 
The investigator, or an approved representative (e.g. pharmacist), will ensure that all IMP is 
reconstituted and dispensed by qualified staff members according to the procedure detailed in 
the study IMP instructions. 
6.1.3 
Investigational Medicinal Product Accountability 
All IMP is to be accounted for on the IMP accountability log agreed with the sponsor.  
Any reconstituted unused IMP has to be discarded in accordance with local regulations (e.g. 
inactivation with sodium hypochlorite or autoclave, etc.). All disposal ancillary materials (e.g. 
needles and syringes) must be discarded in suitable containers intended for incineration after 
use at the site. Used/partly used and unused supplies must be retained for verification and 
accountability by the sponsor or sponsor’s representative prior to destruction. If used/partly 
used vials must be destroyed after use at the site as per local regulations, labelled empty boxes 
must be retained for verification and accountability. Supplies will be destroyed preferably at 
the site; if not, returned to the interim storage facility for destruction.  
6.2 
Study Drugs Administered 
6.2.1 
Treatments Administered 
6.2.1.1 
Dysport 
Dysport will be provided in glass vials containing 300 U or 500 U (nominal) of BTX-A-HAC 
as white lyophilised powder for reconstitution (Table 5). 
Table 5 
Composition of Dysport  
Constituents 
Quantity 
Per 300 U Vial 
Per 500 U vial 
Active Substance 
Clostridium BTX-A-HAC 
300 U* 
500 U* 
Excipients 
Human serum albumin 
125 µg 
125 µg 
Lactose monohydrate 
2.5 mg 
2.5 mg 
BTX-A-HAC=botulinum toxin-A-haemagglutinin complex, U=units 
*One unit (U) is defined as the median lethal intraperitoneal dose in mice. 
The product does not contain any antimicrobial agent. 


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6.2.1.2 
Placebo 
Placebo will be provided in glass vials and will be undistinguishable from the active product. 
The placebo will contain only the excipients described in Dysport, without the addition of 
toxin, as a white lyophilised powder for reconstitution. There will be two matching placebo 
vials: one matching the 300 U Dysport vial, and one matching the 500 U Dysport vial 
(Table 6). The constituents in both placebo vials are identical: 
Table 6 
Composition of Matching Placebo  
Constituents 
Quantity 
Placebo 300 (Per Vial) 
Placebo 500 (Per Vial) 
Human serum albumin 
125 µg 
125 µg 
Lactose monohydrate 
2.5 mg 
2.5 mg 
The placebo product does not contain any antimicrobial agent. 
6.2.2 
Reconstitution and Administration Procedure 
The study treatment will be reconstituted at the investigational site with preservative free 
0.9% sodium chloride for injection.  
The study treatment will be prepared by the investigator/pharmacist/designated personnel 
according to the instruction leaflet allocated for that treatment. Study treatment kits will be 
designed 
to 
maintain 
the 
blind 
and 
the 
person 
reconstituting 
the 
treatment 
(investigator/pharmacist/delegated personnel) as well as the subject will remain blinded to the 
treatment during the double-blind period. 
The process of reconstitution will vary based on the period of the study (double-blind or 
open-label) and the dose to be injected. Detailed instructions on reconstitution will be 
provided in the instruction leaflet. 
A total of 2.5 mL of the reconstituted study treatment will be administered intramuscularly at 
five predefined needle insertion points (A, B, C, D, E) at 10 injection sites (5 mm (superficial) 
and 10 mm (deep) depths at each needle insertion point) across four pelvic floor muscles 
(pubococcygeus, bulbospongiosus, superficial transverse perineal muscle and deep transverse 
perineal muscle) in the vestibular region as described below; the injection diagram is included 
in Figure 3. Regardless of the study period or the treatment group to which the subject is 
allocated, the volume of 2.5 mL will be constant across all dose groups. 
 


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• 
Insertion point - 5 o’clock anterior to hymeneal ring (0.4 mL): #A 
- 
5 mm depth: 0.2 mL  left bulbospongiosus 
- 
10 mm depth: 0.2 mL  left pubococcygeus 
• 
Insertion point - 5 o’clock posterior to hymeneal ring (0.4 mL): #B 
- 
5 mm depth: 0.2 mL  left bulbospongiosus  
- 
10 mm depth: 0.2 mL  left pubococcygeus 
• 
Insertion point - 7 o’clock anterior to hymeneal ring (0.4 mL): #C 
- 
5 mm depth: 0.2 mL  right bulbospongiosus 
- 
10 mm depth: 0.2 mL  right pubococcygeus 
• 
Insertion point - 7 o’clock posterior to hymeneal ring (0.4 mL): #D 
- 
5 mm depth: 0.2 mL  right bulbospongiosus 
- 
10 mm depth: 0.2 mL  right pubococcygeus 
• 
Insertion point - 6 o’clock perineal body (0.9 mL): #E 
- 
5 mm depth: 0.45 mL  medial aspect of right/left superficial and deep 
transverse perineal 
- 
10 mm depth: 0.45 mL  medial aspect of right/left superficial and deep 
transverse perineal 
Further details on the injection procedures are described in the ‘Study Treatment 
Administration - Training Manual’ (included in the Study Manual). Training on injection 
procedures will be provided to each investigator performing IMP administration. 
Figure 3 Study Treatment – Sites of Administration 
 


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6.3 
Concomitant Medication/Therapy 
Any prior or concomitant medications and therapy given to a subject before screening (as 
described in the screening procedures in Section 5.2.1) or during the study will be indicated 
on the eCRF.  
The following concomitant medications/therapies are not permitted during this study (see also 
Section 4.2): 
• 
Sex therapy (defined as a therapy primarily focused on the management of vulvar pain) 
up to 6 weeks after the first treatment cycle of the double-blind period. Any sex therapy 
initiated after this, needs to be maintained at the same frequency/regimen throughout 
the study. 
• 
Any form of BTX for administration into any other part/site of the body. 
• 
Any experimental new drug or device. 
• 
Illicit drugs. 
• 
The following medications that affect neuromuscular transmission: curare-like 
nondepolarising agents, lincosamides, polymyxins, anticholinesterases, aminoglycoside 
antibiotics (topical use is permitted except at the vulvar vestibular region), tizanidine 
and baclofen, within the past 4 weeks prior to Baseline and during the study.  
• 
Injections of steroids in the vulva should have been stopped 4 weeks prior to the 
Screening Visit and are not allowed during the study.  
• 
Topical lidocaine, topical antidepressants, topical anti-epileptics and diazepam 
suppositories are not permitted during the study. Note: Immediately prior to and during 
study drug administration procedures, oral, topical (including lidocaine) or 
intravenous/injectable medications routinely used as standard of care for vaginal 
intramuscular injections are allowed.  
• 
Medications that affect bleeding disorders (antiplatelet agents and/or anticoagulants) 
that might interfere with local injections or medications that contraindicate 
intramuscular injection. 
The following concomitant medications/therapies are permitted during this study, but they 
must be monitored closely and, where applicable, their dose and dose regimen should remain 
constant as detailed below: 
• 
Concomitant pelvic floor physical therapy is permitted. Subjects should maintain the 
dose regimen constant from 12 weeks prior to Baseline and throughout the first 
treatment cycle. 
• 
Concomitant use of topical treatments for vestibular pain with topical hormonal creams 
are permitted if the subject has no residual anterior vestibule pain at screening and 
wants to continue on the same treatment regimen throughout the study to prevent 
recurrence of anterior vestibular pain. Note: Topical antidepressants are not permitted. 
• 
Concomitant use of oral antidepressants, anxiolytics or anti-epileptics is permitted as 
long as the dose has remained stable for at least 6 months prior to the Screening Visit. 
Subjects should try to maintain the dose regimen constant throughout the first treatment 
cycle. 
• 
Concomitant use of anticholinergic drugs (which may potentiate systemic 
anticholinergic effects) is permitted if the dosage has been stable for the 6 weeks prior 
to Baseline and is expected to remain at this stable dose throughout the study. 


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• 
If concomitantly taking other analgesics, the subjects should make their best effort to 
stop them at the Screening Visit. If stopping of analgesic intake is not possible or 
indicated, then the intake needs to be maintained at a constant dose throughout 
1st treatment cycle and all details need to be captured in the eCRF.  
• 
Pain rescue medication taken to prevent or treat provoked vestibular pain should be 
avoided. If needed, the subject will be allowed to take Nonsteroidal Anti-inflammatory 
Drugs (NSAIDS) or Acetaminophen at the recommended dose as per need (PRN). The 
subject should attempt to use the same pain rescue medication throughout the study. 
Subjects will record the dosage and count (number of pills taken) in the eDiary for the 
analgesic taken prior or after intercourse to prevent or treat vestibular pain 
(Section 7.4.2.5). However, the subject should refrain from taking any rescue 
medication within 24 hours of a study visit.  
During Stage 2, if required, the subject will be permitted to take from the following pain 
rescue medications listed in Table 7 at regular strength per approved labelling (recommended 
dose); these medications (i.e. Aspirin, Acetaminophen, Naproxen or Ibuprofen) are available 
over the counter (OTC). 
Table 7 
Permitted Pain Rescue Medications during Stage 2 
Rescue 
Medication 
Dose per Pill 
Permitted Frequency 
Maximum 
Allowed 
Total Daily 
Dose 
Acetaminophen 
 (regular strength) 
325 mg* 
2 pills every 4-6 hours only while the symptoms last 
4000 mg 
Aspirin 
 (regular strength) 
325 mg 
1-2 pills every 4 hours or 3 pills every 6 hours only while 
symptoms last 
4000 mg 
Ibuprofen 
200 mg 
1 pill every 4-6 hours only while symptoms last 
1200 mg 
Naproxen 
220 mg 
1 pill every 8-12 hours only while symptoms last 
660 mg 
mg=milligram. 
*medication may also be available at 500 mg strength in some regions. 
 
• 
Concomitant medications for other purposes are allowed at the investigator’s 
discretion. It is recommended that the dosage for these medications is kept constant 
throughout the study. Where medically appropriate, all concomitant medications being 
taken by a subject at entry into the study should continue at the same dose. 
6.4 
Lifestyle Restrictions/Recommendations 
Subjects will be requested to comply with the restriction criteria related to alcohol 
consumption and drugs of abuse, presented as exclusion criteria in Section 4.2. 
Subjects will be instructed to avoid vulvar irritants such as perfumes, deodorants, or soaps and 
will be encouraged to avoid modifying hygiene habits during the study. The subject should be 
instructed to wear only cotton underwear. 
6.5 
Procedures for Monitoring Subject Compliance 
The investigator will be responsible for monitoring subject compliance. Subjects can be 
withdrawn from the study at any time if the investigator or the sponsor determines that the 
subject is not in compliance with the study protocol. 


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Study Drug will be administered at the clinic by the investigator, thus, subject compliance 
with treatment is not expected to be an issue. Drug accountability records will be maintained 
by the investigator documenting that subject received allocated drug. 
6.6 
Priority Order on Study Procedures 
The following priority order should be followed in case study procedures are scheduled at the 
same time point: 
(1) 
The subject needs to complete the questionnaires at the site (PCS, mFSFI, PHQ-9, 
mVPAQ, SF-36) and subsequently complete the PGI-S and PGI-C assessments prior to 
seeing the investigator.  
(2) 
Interview and clinical examination by the investigator. 
(3) 
When doing the clinical examination, the investigator needs to conduct the dilator test 
prior to the measurement of pelvic floor muscles pressure. 
(4) 
For visits, other than the screening, CGI should be assessed by the investigator after all 
other clinical assessments have been performed. 


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7 
ASSESSMENT OF EFFICACY 
For the timing of assessments in this study, refer to the schedule for the double-blind 
treatment period in Table 2 and for the open-label treatment period in Table 8.  
7.1 
Primary Endpoint(s) and Evaluation(s) 
For Stage 1, the primary endpoint is safety between baseline and Cycle 1-Week 6. 
For Stage 2, the primary efficacy endpoint is the mean change from Baseline to Cycle 1-
Week 6 in the vaginal dilator induced pain as reported on an 11-point numeric rating scale 
(NRS) (using the dilator maximum tested size (DMTS) reported at Baseline). 
7.2 
Secondary Efficacy Endpoints and Evaluations 
Refer to Section 3.2.2 for secondary efficacy endpoints.  
Secondary efficacy endpoints and evaluations are summarised in Table 8. 
Table 8 
Secondary Efficacy Endpoints and Evaluations 
Measure 
Timepoint 
Variable 
Endpoint 
Vestibular pain using 
a vaginal dilator 
Screening, Baseline, Week 6, 
Week 12 and then every 
6 weeks until EOS - All TCs 
11-point NRS 
score for each 
dilator size that 
is tolerated by 
the subject 
Mean change from Baseline in 
the vaginal dilator induced pain 
(using the DMTS reported at 
baseline)  
Proportion of subjects who 
reported at least 30% decrease 
from Baseline in the vaginal 
dilator induced pain using 
DMTS at Baseline  
Proportion of subjects who 
reported at least 2-point 
decrease from Baseline in the 
vaginal dilator induced pain 
using DMTS at Baseline  
Proportion of subjects who 
reported at least 50% decrease 
in vaginal dilator induced pain 
using the DMTS at Baseline 
Maximum tested 
dilator size  
Screening, Baseline, Week 6, 
Week 12 and then every 
6 weeks until EOS - All TCs 
Dilator size 
Mean change from Baseline in 
the dilator size that provokes 
maximum tolerated pain 
Composite of 
vestibular pain 
induced by the dilator 
and the tolerability of 
the dilator size  
Screening, Baseline, Week 6, 
Week 12 and then every 
6 weeks until EOS - All TCs 
Composite score 
of 11-point NRS 
score and dilator 
size 
Mean change from Baseline in 
the composite score for vaginal 
dilator induced pain and dilator 
size. The composite score is the 
sum of all pain measurements 
across the full range of dilator 
sizes. In the construction of this 
endpoint, the pain score will be 
10 for any dilator size that is not 
tested because it is beyond 
tolerability. 
Frequency of 
intercourse and pain 
during intercourse [a] 
Screening, Baseline, Week 6, 
Week 12 and then every 
6 weeks until EOS - All TCs 
11-point NRS 
score 
Mean change from Baseline in 
the frequency of intercourse and 
pain during intercourse  


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Measure 
Timepoint 
Variable 
Endpoint 
Pain during insertion 
of vaginal dilator 
number 6 size [b] 
Screening, Baseline, Week 6, 
Week 12 and then every 
6 weeks until EOS - All TCs 
11-point NRS 
score 
Mean change from Baseline in 
pain during insertion  
Proportion of subjects having 
reported at least a 30% decrease 
in pain during insertion on the 
mean of the NRS values 
Proportion of subjects having 
reported at least a 50% decrease 
in pain during insertion on the 
mean of the NRS values 
Proportion of subjects having 
reported at least 2-point 
decrease in on the mean of the 
NRS values. 
Use of pain rescue 
medications [a] 
Throughout the study 
Type, dose, 
number of pills 
taken and 
frequency of 
pain rescue 
medications 
Use of pain rescue medication 
DB=double-blind, DTMS=dilator tested maximum size, EOS=end of study, EWD=early withdrawal, NRS=numeric rating 
scale, TCs=treatment cycles. 
a 
At the Screening Visit and then from 2 weeks prior to the next planned visit, subjects need to record daily if they 
had intercourse, the number of intercourse instances, corresponding pain during each intercourse instance on an 
11-point NRS and details of pain rescue medication if taken to prevent or treat vestibular pain.  
b 
From 2 weeks prior to the next planned visit, subjects need to rate weekly the level of the corresponding pain 
following insertion of vaginal dilator (number 6 size) on an 11-point NRS and details of associated pain medication 
if consumed. Assessment on the day of the visit should be avoided. 
 
7.3 
Exploratory Efficacy Endpoints and Evaluations 
Refer to Section 3.3 for exploratory efficacy endpoints.  
Exploratory efficacy endpoints and evaluations are summarised in Table 9. 


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Table 9 
Exploratory Efficacy Endpoints and Evaluations 
Measure 
Timepoint 
Variable 
Endpoint 
Vulvar pain and 
associated 
measures 
effecting life [a] 
Screening, Baseline, Week 6, 
Week 12, and then every 
6 weeks until End of TC 1 
(DB period only) 
mVPAQ pain 
and life 
interference 
subscales  
Mean change from Baseline in 
pain and life interference subscales 
Screening, Baseline, Week 6, 
Week 12, Week 24, End of 
TC 1 (DB period only) 
mVPAQ other 
subscale scores  
Mean change from Baseline in 
sexual function interference, self-
stimulation/ penetration 
interference, emotional response 
and cognitive response scores 
Sexual function 
[b] 
Screening, Baseline, Week 6, 
Week 12 and then every 6 
weeks until End of TC 1 (DB 
period only) 
mFSFI total 
score 
Mean change from Baseline in 
mFSFI total score 
Screening, Baseline, Week 6, 
Week 12 and then every 6 
weeks until End of TC 1 
(DB period only) 
mFSFI pain 
domain score  
Mean change from Baseline in 
pain domain score 
Screening, Baseline, Week 6, 
Week 12 and then every 6 
weeks until End of TC 1 
(DB period only) 
mFSFI other 
domain scores 
Mean change from Baseline in 
mFSFI other domain scores 
Pelvic floor 
muscle pressure 
Baseline, Week 6, Week 12 
and then every 6 weeks until 
End of TC 1 (DB period only) 
Resting vaginal 
pressure 
Mean change from Baseline in 
resting vaginal pressure of the 
pelvic floor muscle [c] 
Pelvic floor 
muscle pressure 
Baseline, Week 6, Week 12 
and then every 6 weeks until 
End of TC 1 (DB period only) 
Maximal 
squeeze 
pressure 
Mean change from Baseline in the 
maximal squeeze pressure of the 
pelvic floor muscle [c] 
Depression 
Baseline, Week 12, End of 
TC 1 (DB period only) 
PHQ-9 total 
score 
Mean change from Baseline in the 
PHQ-9 total score 
Quality of life 
 
Baseline, Week 12, End of 
TC 1 (DB period only)  
SF-36 total 
domain scores 
Mean change from Baseline in 
SF-36 scores  
Global impression 
of the treatment 
effect as 
measured by the 
investigator 
Week 6, Week 12 and then 
every 6 weeks until EOS – 
All TCs 
CGI score 
Mean score 
Patient Global 
impression of the 
severity of pain 
and change in 
pain as measured 
by the subject [d] 
Screening, Baseline, Week 6, 
Week 12 and then every 
6 weeks until EOS – All TCs 
PGI-S score 
Mean change from Baseline  
Week 6, Week 12 and then 
every 6 weeks until EOS – 
All TCs 
PGI-C score 
Mean score 
CGI=clinical global impression; DB=double-blind, EOS=end of study, EWD=early withdrawal, mFSFI=modified female 
sexual function index, mVPAQ=modified vulvar pain assessment questionnaire, PGI=patient global impression; 
PHQ-9=patient health questionnaire, SF-36=36-item short form survey, TCs=treatment cycles.  
a 
Subjects to complete the mVPAQ pain and life interference subscales at the Screening Visit, then 1 week prior to 
the next planned visit and at the visit; other mVPAQ subscales to be completed only at the visit. 
b 
Subjects to complete the mFSFI pain domain at the Screening Visit, then 1 week prior to the next planned visit and 
at the visit; other mFSFI domains to be completed only at the visit. 
c 
To be performed in all subjects in Stage 1 up to 400 U and in a subset of subjects in Stage 2 (i.e. in subjects who 
have never had a vaginal delivery (including an attempted vaginal delivery), and at study sites that were provided a 
perineometer to assess pelvic floor muscle pressure). 
d 
To be assessed at Screening Visit, then 1 week prior to the next planned visit and at the visit. PGI-C will be 
assessed Week 6 onwards only. 


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7.4 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data 
Methods for assessing efficacy data are described below. Timing of efficacy assessments are 
presented in Table 2 and Table 3, and discussed in Section 5.2. Procedures for recording 
efficacy data are discussed in Section 15.1, and methods of analyses are discussed in 
Section 11.4.3. The priority order for performing the assessments is discussed in Section 6.6. 
All efforts should be made to have the same investigator perform the clinical examinations for 
a given subject, at least for the Screening, Baseline, and Week 6 Visits of the first treatment 
cycle. 
The Sponsor will provide a device to complete the e-diary questionnaires in the study if 
requested by subjects or in situations in which the subject is not willing or able to use their 
own device. The device will be returned to the site at the completion of the subjects’ 
participation in the study. 
7.4.1 
Dilator Test (Vaginal Dilator Induced Pain) 
A set of 8 vaginal dilators of increasing diameter (#1 being the smallest and #8 being the 
largest) will be used to provoke pain to allow assessment of the vestibular pain intensity in 
each subject. At each visit, the investigator will insert the dilator between 3 to 4 cm depth in 
the vagina starting with the smallest sized dilator and progressively increasing the size of the 
dilator. No lubricant, other than water, may be used when inserting the dilator. In order to 
standardise the methodology each dilator should be inserted for a period of 5 to 10 seconds 
and the time period between the insertion of two dilators should be 30 seconds to 1 minute. 
Subjects will be required to rate the pain for each dilator size on an 11-point NRS (Figure 4) 
at each visit. Based on the subjective pain threshold, the largest sized dilator that the subject 
accepts/tolerates for the test (i.e. does not agree to the next successive dilator size to be 
tested), will be defined as the Dilator Maximum Tested Size (DMTS) that will be established 
at Baseline Visit. The dilator test will be used to assess the change from Baseline in the 
vaginal dilator induced pain as reported on a NRS (using the DMTS reported at baseline) as 
well as the dilator size that provokes maximum tolerated pain.  
Figure 4 Numeric Pain Rating Scale 
 
Subject interviews to assess the content relevance of the dilator test will be performed in 
Stage 2. Subjects from Stage 2 will be invited to complete the interview until the target 
sample of 20 subjects is achieved. Every effort should be made to conduct the interview 
within 2 weeks of the subject’s Cycle 1-Week 6 visit. 


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The subject interviews will be conducted by experienced interviewers trained in qualitative 
interview techniques. The details of the interview will be provided in the interview guide. 
7.4.2 
Patient Reported Questionnaires and Assessments 
In order to ensure accurate and unbiased subject questionnaire completion, the following 
guidelines should be adhered to: 
• 
The questionnaires should be completed by the subject (with the caregiver's assistance, 
if necessary), at the beginning of the site visit prior to having the interview with the 
investigator. 
• 
Study site personnel should not change responses on the questionnaires.  
An electronic Patient-Reported Outcome (ePRO) device will be used to complete the 
questionnaires (programmed in a predefined sequence) as well as to record data in the eDiary 
contributing towards completion of particular questionnaire subscales and efficacy endpoints. 
Timing of efficacy assessments are presented in Table 2 and Table 3. 
7.4.2.1 
Modified Vulvar Pain Assessment Questionnaire (mVPAQ)  
The Vulvar Pain Assessment Questionnaire (VPAQ) is a more recently developed, 
self-administered, 
multidimensional, 
vulvodynia 
specific 
questionnaire, 
including 
55 Likert-type questions and designed to capture 6 domains: pain severity, emotional 
response, 
cognitive 
response 
and 
interference 
with 
life, 
sexual 
function, 
self-stimulation/penetration [22]. The score for each question ranges from 0 to 4 and a mean 
score is computed for each domain.  
For the purpose of the study, the VPAQ subscales will be modified as: 
• 
mVPAQ pain subscale – The recall period will be over the past 1 week.  
• 
mVPAQ life interference subscale – The recall period will be over the past 1 week.  
• 
mVPAQ other subscales – The recall period will be over the past 1 month. 
• 
The sequence of questions for reporting distress (average/ worst) on the pain severity 
subscale were reversed. 
The mVPAQ questionnaire is included in Appendix 1. 
The data to be recorded by subjects in the eDiary contributing towards the completion of the 
questionnaire: 
• 
mVPAQ pain subscale – Assessed at Screening Visit, then 1 week prior to the next 
planned visit and at the visit. 
• 
mVPAQ life interference subscale – Assessed at Screening Visit, then 1 week prior to 
the next planned visit and at the visit. 
• 
mVPAQ other subscales – Assessed at the site during the visit (except Additional 
Visits at Week 18 and Week 30). 
7.4.2.2 
Assessment of Intercourse and Vaginal Dilator (Number 6 Size) Insertion Details 
From the Screening Visit (Day -14; i.e. during the screening period), and then 2 weeks 
(14 days) prior to the next planned visit, subjects will record on a daily basis in the eDiary 
(contributing to collection of data for the corresponding endpoint): 
• 
If they had intercourse and if yes, the number of intercourse instances in the previous 
24-hour period;  
• 
Rate the level of the corresponding pain during each intercourse instance on an 
11-point NRS; 


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• 
Details of pain rescue medication consumed for each intercourse instance (yes/no; if 
yes - type, dose, frequency, route, duration) to prevent or treat the vestibular pain. 
From 2 weeks prior to the next planned visit, all subjects are to rate in the eDiary once a week 
the level of the corresponding pain following insertion of the number 6 vaginal dilator into the 
vagina on an 11-point NRS and record details of associated pain medication if consumed. 
Assessment on the day of the visit should be avoided. 
7.4.2.3 
Modified Female Sexual Function Index (mFSFI) 
The FSFI is a validated self-reported multidimensional 19-item questionnaire for assessing 
the sexual function in women by evaluating six key domains of sexual function: desire, 
arousal, lubrication, orgasm, sexual satisfaction, and pain.  
A total score and domain scores will be calculated. Every item is assessed with a score from 0 
or 1 to 5, the total score being 2-36.  
For the purpose of the study, the recall periods for FSFI pain domain (Questions 17 to 19) will 
be modified as: 
• 
mFSFI pain domain – The recall period will be over the past 1 week.  
• 
mFSFI other domains – The recall period will be over the past 4 weeks. 
From Stage 2 onwards, Question 19 of the pain domain (measuring the level of pain ‘during’ 
and ‘following’ vaginal penetration with a 1-week recall period) will be split into two separate 
questions –  
• 
Question 19 – measuring the level of discomfort or pain during vaginal penetration. 
• 
Question 20 – measuring the level of discomfort or pain following vaginal penetration. 
The mFSFI questionnaire is included in Appendix 2. 
The data to be recorded by subjects in the eDiary contributing towards the completion of the 
questionnaire: 
• 
mFSFI pain domain – Assessed at Screening Visit, then 1 week prior to the next 
planned visit and at the visit. 
• 
mFSFI other domains – Assessed at the site during the visit. 
7.4.2.4 
Patient Global Impression (PGI) 
7.4.2.4.1 Patient Global Impression of Severity (PGI-S) of the Provoked Vulvar Pain  
An assessment of patient global impression of severity (PGI-S) of the pain will be conducted 
by the subject using a 4-point Likert scale (from 0: no pain to 3: severe pain). 
The PGI-S will be assessed by the subject by answering the following question: “How severe 
was your ‘provoked vulvar pain’ (pain specifically triggered by touching the vulvar area) over 
the past week?  
9 = not assessable due to lack of circumstances causing provoked pain  
0 = no pain 
1 = mild pain 
2 = moderate pain 
3 = severe pain.” 


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7.4.2.4.2 Patient Global Impression of Change (PGI-C) in the Provoked Vulvar Pain  
An assessment of global impression of change in pain will be conducted by the subject using 
a 7-point Likert scale (from -3: very much worse to +3: very much improved). 
The PGI-C will be assessed by the subject by answering the following question: “Compared 
to your provoked vulvar pain at Baseline i.e. prior to the study treatment initiation, your 
provoked vulvar pain is:  
+3 = very much improved  
+2 = much improved 
+1 = minimally improved 
 0 = no change from baseline 
-1 = minimally worse 
-2 = much worse  
-3 = very much worse.” 
7.4.2.5 
Use of Pain Rescue Medications  
As discussed in Section 7.4.2.2 subjects will record in the eDiary the details of pain 
medication taken to prevent or treat the pain during intercourse and/or dilator insertion.  
The type, dose and frequency of pain rescue medication intake will be analysed. 
7.4.2.6 
Patient Health Questionnaire (PHQ-9) 
The PHQ-9 is an easy-to-use, validated questionnaire to measure the severity of depression 
(Appendix 3). The response to treatment is scored for each of the nine DSM-IV (Diagnostic 
and Statistical Manual of Mental Disorders) criteria as "0" (not at all) to "3" (nearly every 
day) providing a total score being 0 to 27. Scores of 5, 10, 15, and 20 represent cut-off points 
for mild, moderate, moderately severe and severe depression, respectively. 
7.4.2.7 
36-Item Short Form Health Survey (SF-36) 
The SF-36 is a validated set of generic, coherent, and easily administered QoL measures 
(Appendix 4). These measures rely upon patient self-reporting and are now widely utilised by 
managed care organisations and by for routine monitoring and assessment of care outcomes in 
adult patients.  
The SF-36 has eight scaled scores; the scores are weighted sums of the questions in eight 
health concepts: physical functioning, bodily pain, role limitations due to physical health 
problems, role limitations due to personal or emotional problems, emotional well-being, 
social functioning, energy/fatigue, and general health perceptions.  
The total scores range from 0 to 100. Lower scores indicate a less favourable health state and 
higher scores a more favourable health state. 
7.4.2.8 
Pain Catastrophizing Scale (PCS) 
The PCS is a widely used, validated 13-item scale assessing the state of mind of subjects in 
pain through a comprehensive evaluation that encompassing the different perspectives on 
catastrophizing (Appendix 5). It is a self-administered questionnaire in which the subjects 
answer questions about how they feel and what they think about when they are in pain. Each 
item rated on a 5-point scale: 0 (not at all) to 4 (all the time). A total score, ranging from 0 to 
52 (sum of the 13 items) will be calculated. 


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7.4.3 
Investigator-Reported Assessments  
7.4.3.1 
Q-tip 
The Q-tip test, also known as the Cotton Swab test, is a widely used standard test to diagnose 
PVD, i.e. to assess the vestibular pain provoked by touch. A cotton swab/ cotton-tipped 
applicator will be used randomly to palpate all vulvar vestibular sites and the corresponding 
pain will be assessed [7, 25].  
The Q-tip test will be performed to screen the subjects but will not be an assessment of the 
efficacy of the study drug.  
7.4.3.2 
Clinical Global Impression (CGI)  
An assessment of global impression of treatment response will be conducted by the 
investigator using a 7-point Likert scale (from -3: very much worse to +3: very much 
improved). 
The CGI will be assessed by the investigator by answering the following question: ‘Compared 
to the subject’s condition at Baseline i.e. prior to the study treatment initiation, your subject’s 
condition is:  
+3 = very much improved;  
+2 = much improved;  
+1 = minimally improved; 
0 = no change from baseline; 
-1 = minimally worse;  
-2 = much worse;  
-3 = very much worse.” 
7.4.3.3 
Measurement of Pelvic Floor Muscle Pressure 
The resting vaginal pressure and maximal ‘squeeze’ pressure will be measured using a CE 
marked medical device in all subjects in Stage 1 up to 400 U and in a subset of subjects in 
Stage 2 who have never had vaginal delivery (included attempted vaginal delivery), and at 
study sites that were provided a perineometer. Three measures of resting vaginal pressure and 
three measures of maximal ‘squeeze’ vaginal pressure should be performed. The time period 
between each measure performed for either the resting or maximal ‘squeeze’ vaginal pressure 
should be 30 seconds to 1 minute. Each squeeze while performing the maximal ‘squeeze’ 
vaginal pressure should last for 5 seconds. 
Further instructions will be provided in the Study Manual. 


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8 
ASSESSMENT OF SAFETY 
8.1 
Adverse Events 
Adverse events will be monitored from the time that the subject gives informed consent and 
throughout the study until the end of study.  Information will be elicited by direct, nonleading 
questioning or by spontaneous reports. Further details for AE reporting can be found in 
Section 8.1.2. 
The investigator will be responsible for a clinical assessment of the study participants during 
the whole participation of the subjects in the study, from informed consent up to discharge 
from the study, and for the setup of a discharge plan if needed.  
The sponsor medical monitor and the GPS physician will monitor safety data throughout the 
course of the study. 
8.1.1 
Definition of an Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition 
can be symptoms (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g. laboratory findings, electrocardiogram). In clinical 
studies an AE can include an undesirable medical condition occurring at any time, including 
run in or washout periods, even if no IMP has been administered.  
This definition includes events occurring from the time of the subject giving informed consent 
until the end of the study (as defined in Section 3.8). 
8.1.2 
Categorisation of Adverse Events 
8.1.2.1 
Intensity Classification 
Adverse events will be classified as mild, moderate or severe according to the following 
criteria: 
• 
Mild: symptoms do not alter the subject’s normal functioning 
• 
Moderate: symptoms produce some degree of impairment to function, but are not 
hazardous, uncomfortable or embarrassing to the subject 
• 
Severe: symptoms definitely hazardous to wellbeing, significant impairment of 
function or incapacitation. 
8.1.2.2 
Causality Classification 
The relationship of an AE to IMP administration will be classified according to the following: 
• 
Related: reports including good reasons and sufficient information (e.g. plausible time 
sequence, dose response relationship, pharmacology, positive dechallenge and/or 
rechallenge) to assume a causal relationship with IMP administration in the sense that it 
is plausible, conceivable or likely. 
• 
Not 
related: 
reports 
including 
good 
reasons 
and 
sufficient 
information 
(e.g. implausible time sequence and/or attributable to concurrent disease or other drugs) 
to rule out a causal relationship with IMP administration. 
8.1.2.3 
Assessment of Expectedness 
The reference safety information for assessing expectedness of AEs/event in this study will be 
in the current IB. 


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8.1.2.4 
Laboratory Test Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the following 
apply:  
• 
They result in a change in IMP schedule of administration (change in dosage, delay in 
administration, IMP discontinuation), 
• 
They require intervention or a diagnosis evaluation to assess the risk to the subject, 
• 
They are considered as clinically significant by the investigator. 
8.1.2.5 
Abnormal Physical Examination Findings  
Clinically significant changes, in the judgement of the investigator, in physical examination 
findings (abnormalities) will be recorded as AEs.  
8.1.2.6 
Other Investigation Abnormal Findings 
Abnormal test findings as judged by the investigator as clinically significant 
(e.g. electrocardiogram changes, thyroid function disturbances) that result in a change in 
study drug dosage or administration schedule, or in discontinuation of the study drug, or 
require intervention or diagnostic evaluation to assess the risk to the subject, should be 
recorded as AEs.  
8.1.3 
Clinically Significant Adverse Events and Dose Limiting Events 
Definitions for identification of a clinically significant AE and a DLE for this study is 
provided in Section 3.1.1.1. 
Details of DRC meetings and the management of dose escalation of the cohorts by the DRC 
are provided in Section 3.1.1.2 
8.1.4 
Adverse Events of Special Interest 
The effects of Dysport and all BTX products may spread from the area of injection to produce 
symptoms consistent with the pharmacology of BTX. These symptoms have been reported 
hours to weeks after injection. Remote spread of toxin that affects swallowing and breathing 
can be life threatening, and there have been reports of death. The risk of symptoms is 
increased in subjects who have underlying conditions (e.g. disorders of the neuromuscular 
junction) that would predispose them to these symptoms. Dysport is contraindicated in 
individuals with known hypersensitivity to any BTX preparation or to any of the components 
in the formulation.  
Adverse events of special interest (AESIs) for Dysport in this study are defined as: 
• 
Any TEAE that suggest a possible remote spread of effect of the toxin or  
• 
Any TEAE related to urinary incontinence or faecal incontinence or  
• 
Any TEAE assessed as a potential hypersensitivity reaction,  
where there is a reasonable possibility of causal relationship with treatment with Dysport, 
regardless of the investigator reported causality. A list of Medical Dictionary for Regulatory 
Activities (MedDRA) preferred terms (PTs) that will be used to identify potential AESIs is 
provided in the statistical analysis plan (SAP). The list of PTs that is used by the sponsor to 
identify events suggestive of remote spread of toxin includes the terms compatible with the 
mechanism of action of BTX-A-HAC, is based on recommendations from the US Food and 
Drug Administration (US FDA) (Guidance for Industry: upper facial lines botulinum toxin 
products (Appendix A)) and the EU Committee for Medicinal Products for Human Use 
(CHMP) (Joint Assessment Report on definition of toxin spread). All AE PTs retrieved using 
this list of MedDRA PTs will be manually reviewed and medically evaluated by the sponsor 


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to determine to determine if there is a plausible possibility that they represent remote spread 
of toxin or suggestive of hypersensitivity reaction due to Dysport treatment. In order to 
perform the analysis, variables including alternate aetiology (medical history, concomitant 
medications, or diagnosis which could account for the symptoms), location of Dysport 
administration, and temporal relationship to IMP administration will be considered by the 
sponsor. 
8.1.5 
Recording and Follow-up of Adverse Events 
At each visit, the subject should be asked a nonleading question such as: “How have you felt 
since starting the new treatment/last dose/the last assessment?” 
All observed or volunteered AEs, regardless of treatment group or suspected causal 
relationship to IMP, will be recorded on the AE page(s) of the eCRF. Events involving drug 
reactions, accidents, illnesses with onset during the treatment phase of the study, or 
exacerbations of pre-existing illnesses should be recorded. 
Any AEs already recorded and designated as ‘continuing’ should be reviewed at each 
subsequent assessment. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a SAE 
requiring immediate notification to the sponsor or its designated representative. For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE (i.e. IMP or other illness). The investigator is required to assess causality and record that 
assessment on the eCRF. Follow-up of the AE, after the date of IMP discontinuation, is 
required if the AE or its sequelae persist. Follow-up is required until the event or its sequelae 
resolve or stabilise at a level acceptable to the investigator and the sponsor’s clinical monitor 
or his/her designated representative. 
8.1.6 
Reporting of Serious Adverse Events 
All SAEs (as defined below) regardless of treatment group or suspected relationship to IMP 
must be reported immediately (within 24 hours of the investigator’s knowledge of the event) 
using the fax number or email address specified at the beginning of this protocol. If the 
immediate report is submitted by telephone, this must be followed by detailed written reports 
using the SAE report form. 
A SAE is any AE that: 
(1) 
Results in death, 
(2) 
Is life threatening, that is any event that places the subject at immediate risk of death 
from the event as it occurred. It does not include an event that, had it occurred in a 
more severe form, might have caused death, 
(3) 
Results in in-patient hospitalisation or prolongation of existing hospitalisation, 
excluding admission for social or administrative reasons (see further), 
(4) 
Results in a persistent or significant disability/incapacity, where disability is a 
substantial disruption of a person's ability to conduct normal life functions, 
(5) 
Results in congenital anomaly/birth defect in the offspring of a subject who received 
the IMP, 
(6) 
Is an important medical event that may not result in death, be life threatening, or 
require hospitalisation when, based upon appropriate medical judgement, may 
jeopardise the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical events include 


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allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in in-patient hospitalisation, or the 
development of drug dependency or drug abuse. 
In addition to the above criteria, any additional AE that the investigator considers serious 
should be immediately reported to the sponsor and included in the corporate SAEs database 
system. This includes any suspected or confirmed coronavirus COVID-19 (SARS-CoV-2) 
infection (seriousness criteria should be “other medically significant” if no other seriousness 
criteria are present (e.g. hospitalisation)). 
• 
Hospitalisation is defined as any in-patient admission (even if less than 24 hours). For 
chronic or long term in-patients, in-patient admission also includes transfer within the 
hospital to an acute/intensive care in-patient unit. 
• 
Prolongation of hospitalisation is defined as any extension of an in-patient 
hospitalisation beyond the stay anticipated/required in relation to the original reason for 
the initial admission, as determined by the investigator or treating physician. For 
protocol-specified hospitalisation in clinical studies, prolongation is defined as any 
extension beyond the length of stay described in the protocol. Prolongation in the 
absence of a precipitating, treatment emergent, clinical AE (i.e. not associated with the 
development of a new AE or worsening of a pre-existing condition) may meet criteria 
for "seriousness" but is not an adverse experience and thus is not subject to immediate 
reporting to the sponsor.  
• 
Preplanned or elective treatments/surgical procedures should be asked for and 
documented in the subject’s screening records. Hospitalisation for a preplanned or 
elective treatment/surgical procedure should not be reported as an SAE unless there are 
complications or sequelae which meet the criteria for seriousness described above. 
Any SAE must be reported immediately (within 24 hours), using the fax number or e-mail 
address specified at the beginning of this protocol, independent of the circumstances or 
suspected cause, if it occurs or comes to the attention of the investigator at any time during 
the study period. 
Any AE/SAE with a suspected causal relationship to IMP administration occurring at any 
other time after completion of the study must be promptly reported. 
The following information is the minimum that must be provided to the sponsor within 24 
hours for each SAE: 
• 
Study number 
• 
Centre number 
• 
Subject number 
• 
AE 
• 
Causality 
• 
Investigator's name and contact details 
The additional information included in the SAE form must be provided to the sponsor or 
representative as soon as it is available. The investigator should always provide an assessment 
of causality for each event reported to the sponsor. Upon receipt of the initial report, the 
sponsor will ask for the investigator's causality assessment if it was not provided with the 
initial report. 


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The investigator should report a diagnosis or a syndrome rather than individual signs or 
symptoms. The investigator should also try to separate a primary AE considered as the 
foremost untoward medical occurrence from secondary AEs which occurred as complications. 
8.1.7 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP has 
interfered with a contraceptive method. If pregnancy occurs during the study, the outcome of 
the pregnancy will then need to be collected even if this occurs after the end of the study and 
the subject will not receive any further administration of the IMP.  
Information regarding pregnancies must be collected on the AE page of the eCRF and on the 
Standard Pregnancy Report Form, including pregnancies with normal progress and outcome. 
A Standard Pregnancy Report Form must be completed by the investigator and provided to 
the Sponsor’s Pharmacovigilance department within 24 hours of the knowledge of the 
pregnancy in any study subject. The sponsor will request further information from the 
investigator as to the course and outcome of the pregnancy using the Standard Pregnancy 
Outcome Report Form.  
The investigator must instruct all female subjects to inform them immediately should they 
become pregnant during the study. The investigator should counsel the subject, discuss the 
risks of continuing with the pregnancy and the possible effects on the foetus. Monitoring of 
the subject should continue until conclusion of the pregnancy, which may involve follow-up 
after the subject’s involvement in the study has ended. 
Pregnancies with a conception date during the study participation or within 12 weeks after 
subject’s last dose of IMP must also be reported to the investigator for onward reporting to the 
sponsor. 
8.1.8 
Deaths 
All AEs resulting in death either during the study period or within 12 weeks (84 days) after 
the last dose of IMP, must be reported as an SAE within 24 hours of the investigator’s 
knowledge of the event.  
The convention for recording death is as follows:  
• 
Adverse event term: lead cause of death (e.g. multiple organ failure, pneumonia, 
myocardial infarction), 
• 
Outcome: fatal. 
The only exception is if the cause of death is unknown (i.e. sudden or unexplained death), in 
which case the AE term may be “death” or “sudden death.” 
8.1.9 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events 
Discontinuation/withdrawal 
due 
to 
AEs 
should 
be 
distinguished 
from 
discontinuation/withdrawal due to insufficient response to the IMP (see Section 4.4). 
If the IMP is discontinued due to a SAE, it must be reported immediately to the sponsor’s 
designated representative (see Section 8.1.6). 
In all cases, the investigator must ensure the subject receives appropriate medical follow-up 
(see Section 8.1.5).  
In case of suspected or confirmed COVID-19 infection which is to be reported as an SAE 
(Section 8.1.6), the IMP administration may be temporarily postponed depending on the 
subject clinical presentation. In some cases, the investigator may request a subject be retested 
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8.1.10 
Reporting to Competent Authorities (CAs)/IECs/IRBs/Other Investigators 
The sponsor will ensure that processes are in place for submission of reports of Suspected 
Unexpected Serious Adverse Reactions occurring during the study to the CAs, IECs and other 
investigators concerned by the IMP. Reporting will be done in accordance with the applicable 
regulatory requirements. 
For study centres in the USA, Investigational New Drug Application Safety Reports will be 
submitted directly to the investigators. It is the investigators’ responsibility to notify their IRB 
in a timely manner. 
8.2 
Clinical Laboratory Tests 
Blood samples will be collected for the evaluation of haematology, serum chemistry, FSH, 
and putative antibodies. Full details regarding the clinical tests are provided in the Study 
Manual. 
A vaginal swab will be taken and analysed locally to detect possible infection.  
Urine samples will be collected for the evaluation of illicit drugs and pregnancy and analysed 
at the study site.  
The schedule of assessments is detailed in Section 5.1. 
The investigator will review the safety laboratory test results, document the review, and 
record any clinically relevant changes occurring or observed during the study in the AE 
section of the eCRF (see Section 8.1.2.4 for abnormal laboratory tests that should be recorded 
as AEs). 
All clinically relevant abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return to Baseline or to a level deemed acceptable by the 
investigator and the sponsor’s clinical monitor (or his/her designated representative) or until 
the abnormality is explained by an appropriate diagnosis.  
8.2.1 
Haematology 
Blood samples will be collected in a potassium ethylenediaminetetra-acetic acid tube to assess 
the following parameters: red blood cell count, haemoglobin, haematocrit, mean corpuscular 
volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, white 
blood cell count with differential (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils, and others) and platelet count. 
8.2.2 
Blood Biochemistry 
Blood samples will be collected in an activator gel tube to assess the following parameters: 
• 
urea, creatinine, total bilirubin, conjugated bilirubin 
• 
chloride, bicarbonate, sodium, potassium, calcium, inorganic phosphate 
• 
alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma 
glutamyl transferase 
• 
albumin, total protein, total cholesterol, triglycerides 
• 
glycated haemoglobin. 
8.2.3 
Pregnancy Test 
A human chorionic gonadotrophin urine test will be performed. Any subject becoming 
pregnant during the study will be withdrawn. All pregnancies that occur during the study are 
to be reported as described in Section 8.1.7. 


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8.2.4 
Drug of Abuse  
Urine drug screen (dipstick) will be performed to detect the presence of at least 
amphetamines, methamphetamines, cocaine, opiates and tetrahydrocannabinol. 
8.2.5 
Putative Antibody Testing 
Blood samples will be collected for the assay of putative antitoxin-A antibodies.  
After processing of the blood samples at the site, the resulting serum will be sent to the central 
laboratory for storage. Batch shipping to specific laboratories in charge of the analysis will be 
arranged by the central laboratory at appropriate intervals.  
All samples will be tested for the presence of binding antibodies with a validated assay. 
Samples found to be positive for the presence of binding antibodies will be analysed for the 
presence of neutralizing antibodies using another validated assay. 
Full details regarding the processing, labelling, storage and shipment processes for these 
samples are provided in the Study Manual. 
Tests results will be provided to the study site at the end of the study. 
8.2.6 
Vaginal Evaluation for Yeast and Bacterial Infection 
Vaginal swabs will be performed to screen the subjects but will not be an assessment of the 
safety of the study drug. 
Vaginal swabs will be performed and analysed for identification of pathogens (including 
Gardnerella vaginalis, Trichomonas vaginalis and Candida albicans). 
Test results need to be available during the screening period or prior to randomisation. 
8.3 
Physical Examination 
A physical examination will be done at Screening Visit. 
Any clinically significant physical examination findings (abnormalities) observed during the 
study will be reported as AEs. Any physical examination findings (abnormalities) persisting 
at the end of the study will be followed by the investigator until resolution or until reaching a 
clinically stable endpoint. 
8.4 
Local Tolerance  
Local tolerance will be part of the routine treatment assessment. 
Injection sites will be examined by a physician or medical staff at the visit, and assessed for 
characteristics such as tenderness, erythema, bleeding, swelling, rash, pain, itching, 
induration, haematoma, ulceration or necrosis. If present, these will be recorded on the AE 
page of the eCRF.  
8.5 
Vital Signs 
Vital signs including blood pressure and heart rate will be recorded at the Screening Visit 
after five minutes’ rest in a supine or sitting position.  
Body weight and height will also be recorded at Screening. 
Any clinically significant vital sign abnormalities observed during the study will be reported 
as AEs. 


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9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS 
Pharmacokinetics and pharmacodynamics are not assessed in this study. 


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10 
EXPLORATORY BIOMARKERS AND BIOBANKING 
Exploratory biomarker evaluation or biobanking are not being performed in this study. 
 


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11 
STATISTICS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a SAP, which will be dated and completed before the database lock of 
the intermediate analysis (described in Section 11.6). The SAP may modify the plans outlined 
in the protocol; however, any major modifications of the primary endpoint and/or its analysis 
will be reflected either in a protocol amendment or in a dedicated CSR section. 
Statistical evaluation will be performed using Statistical Analysis System (SAS)® (version 9.1 
or higher). 
The COVID-19 pandemic may have an impact on this trial and specific summaries will be 
provided in order to assess its impact. 
11.1 
Analyses Populations 
The following populations will be used during statistical analyses for Stage 1 and Stage 2: 
• 
Screened population: All subjects screened (i.e. who signed the informed consent). 
• 
Randomised population: All subjects randomised (i.e. who were randomly allocated 
to a treatment group). 
• 
Safety population: All randomised subjects who received at least one dose of IMP 
administration (including only partial administration). 
• 
modified Intent-to-Treat (mITT) population: All randomised subjects who received 
at least one IMP administration and had data for the primary endpoint at Baseline and 
Cycle 1-Week 6 visit (i.e. at least one pain score for one dilator size).  
• 
Per protocol (PP) population: All subjects in the mITT population for whom no 
major protocol deviations, which may interfere with the efficacy evaluation, occurred 
between Screening and Cycle 1-Week 6 included. 
11.1.1 
Populations Analysed 
In Stage 1, the primary analysis based on safety endpoints will be performed on the 
Safety population. Analyses of efficacy endpoints will be carried out on the mITT population. 
In Stage 2, the primary efficacy analysis based on efficacy endpoints will be performed on the 
mITT and PP population. Secondary analyses on efficacy endpoints will be carried on the 
mITT population. 
The analyses of safety data will be performed based on the safety population. 
11.1.2 
Reasons for Exclusion from the Analyses 
Any major protocol deviation (see Section 13.1.2 for definition) will be described. Subjects 
substantially affected directly or indirectly by COVID-19 will be flagged with a major 
protocol deviation.  
The final list of protocol deviations impacting the PP population will be reviewed prior to 
database lock, before unblinding of treatment groups for the intermediate and primary 
analysis (with the exception of DRC, which may/ may not request unblinding (see 
Section 3.1.1.2). The list may be updated, up to the point of database lock, to include any 
additional major protocol deviations impacting inclusion in the PP population. 


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11.2 
Sample Size Determination 
Stage 1:  
In Stage 1, the expected sample size is 10 evaluable subjects for PVD2 cohorts who will be 
randomised and treated in a 4:1 allocation ratio (Dysport or Placebo), and 8 evaluable subjects 
for PVD1 Cohort 4 treated in a 3:1 allocation ratio (Dysport or Placebo). 
After Cohort 3 (PVD2) and Cohort 4 (PVD1), the expected sample size is 10 evaluable 
subjects for additional PVD1 and PVD2 cohorts and treated in a 4:1 allocation ratio (Dysport 
or Placebo).  
Subject who discontinue prior to Week 6 for reasons unrelated to safety may be replaced at 
the discretion of the investigator and sponsor. As this is an exploratory stage, no formal power 
could be performed. However, with 8 active subjects per PVD2 dose cohort and if there are 
0 DLEs in a cohort, there is at least 80% probability that the true incidence of DLEs at the 
corresponding dose will not be greater than 18%. With 16 active subjects in PVD1 and PVD2 
dose cohorts and if there are 0 DLEs in a cohort, there is at least 80% probability that the true 
incidence of DLEs at the corresponding dose will not be greater than 9%. The ability to rule 
out smaller DLE rates with high confidence will come from observing additional subjects in 
Stage 2.  
Stage 2: 
The study sample size required to have at least 80% power to detect a 2-point improvement 
for an experimental drug arm relative to placebo on mean change from baseline to Week 6 in 
the vaginal dilator induced pain as reported on a numeric pain rating scale (using the DMTS) 
using a one-sided 0.10 level test (not corrected for multiplicity) is 21 evaluable subjects per 
arm (i.e. a total of 63 subjects). The following assumptions were used for the power 
statement:  
• 
Expected outcome on the mean change from baseline to Week 6 in the vaginal dilator 
induced pain as reported on a numeric pain rating scale in the placebo group = 2-point 
decrease (reference approximated by VAS per speculum in Bornstein, 2010 [26])  
• 
Expected outcome on the mean change from baseline to Week 6 in the vaginal dilator 
induced pain as reported on a numeric pain rating scale in a Dysport treated 
group = 4-point decrease  
• 
Expected common standard deviation of the mean change from baseline to Week 6 in 
the vaginal dilator induced pain as reported on a numeric pain rating scale = 3-points 
(approximated per VAS data in Table 2 in Davis 2013 [27]). 
Subject who discontinue prior to Week 6 for reasons unrelated to safety will be replaced at the 
discretion of the investigator and sponsor. 
At the end of Stage 2, if the true DLE rate is 6% or greater, there is at least 80% probability to 
observe at least 1 DLE in 29 subjects (8 in Stage 1 and 21 in Stage 2). Therefore, if there are 
no observed DLEs in both Stage 1 and Stage 2 at a dose level, then there is good confidence 
that the true DLE rate is no more than 6%. If the dose chosen in Stage 2 has been tested on 
two cohorts (PVD1 and PVD2) in Stage 1, at the end of Stage 2, if the true DLE rate is 5% or 
greater, there is at least 80% probability to observe at least one DLE in 37 subjects (16 in 
Stage 1 and 21 in Stage 2). Therefore, if there are no observed DLEs in both Stage 1 and 
Stage 2 at a dose level, then there is good confidence that the true DLE rate is no more than 
5%. If it is reasonable to assume that the relationship between toxicity and dose level is 
monotonic non-decreasing, then we may pool dose levels to obtain a higher degree of 
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Following the review of data available from Stage 1, the sample size may be formally 
recalculated for Stage 2 after the intermediate analysis. 
11.3 
Significance Testing and Estimations 
Stage 1: 
As this is a descriptive safety study, no formal statistical testing will be carried out. P-values, 
unadjusted for multiple comparisons, may be presented, but they will be regarded as 
descriptive.  
Stage 2: 
All statistical tests will be performed at a one-sided significance level of 10%. 
11.4 
Statistical/Analytical Methods 
Statistical analyses will be performed by an external CRO, managed by the sponsor’s 
biometry department. 
All analyses will be provided by stages. In addition, within each stage, the double-blind and 
open-label periods will be separately analysed. For doses that are selected for Stage 2, safety 
data may be pooled and summarised. 
11.4.1 
Demographic and Other Baseline Characteristics 
In order to evaluate balance of treatment groups, descriptive summary statistics (n, mean, 
standard deviation (SD), median, minimum, maximum) or frequency counts of demographic 
and baseline data (medical history, concomitant disease, etc.) will be presented by treatment 
group. 
In Stage 1, main demographic and baseline characteristics will be provided in patients 
recruited before and after the start of COVID-19 pandemic (i.e. before / after first patient 
randomised in Cohort 6) in order to identify a potential change in the general patients’ 
characteristics. 
11.4.2 
Subject Disposition and Withdrawals 
The numbers and percentages of subjects screened, randomised and included in the analysis 
populations will be tabulated. The reasons for subject exclusions from each of the populations 
will also be tabulated. In addition, the numbers of subjects who discontinued and completed at 
each of the study periods (double-blind treatment period and open-label period) will be 
tabulated. Primary reasons for discontinuation of study treatment will be tabulated. 
The impact of COVID-19 pandemic on the trial will be assessed through the summary of data 
collected in relation to COVID-19, i.e. disposition of patients including the proportion of 
patients impacted and withdrawn due to COVID-19 pandemic and number of patients with 
visits impacted by COVID-19 with the corresponding reason. Exposure to treatment will also 
be described before and after the start of COVID-19 pandemic (i.e. before/after first patient 
randomised in Cohort 6). 
11.4.3 
Efficacy Evaluation 
Stage 1: 
The primary objective and endpoint of the Stage 1 is the safety assessments.  
Descriptive statistics will be performed on the safety and efficacy endpoints. 


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Stage 2: 
The study will be considered successful if the superiority of at least 1 Dysport group relative 
to placebo could be demonstrated with regard to the primary efficacy endpoint.  
The primary efficacy endpoint is the change from baseline to Week 6 in the vaginal dilator 
induced pain as reported on an 11-point NRS (using the DMTS reported at baseline). 
An ANCOVA will be performed. The model will include the treatment group (2 Dysport 
doses and placebo) as factor, baseline pain and stratification variable (pain onset subtype 
(primary and secondary PVD)) as covariates. Subjects who are unable to reach the baseline 
maximum tested size at a postbaseline visit will have an imputed pain score of 10 at the 
maximum tested size for that visit. 
The primary efficacy results will be presented adjusted for covariates. The following 
estimates will be provided:  
• 
For each of the 3 treatment groups, the least squares means of change from baseline in 
vaginal dilator and 2-sided 95% confidence interval are presented. 
• 
For each of the 2 Dysport groups, the least squares means of the difference against 
placebo with a 2-sided simultaneous 80% confidence intervals will be presented. 
Non-parametrics tests may also be carried out to evaluate robustness of the results. 
Secondary efficacy endpoints will be analysed using an ANCOVA or a logistic regression 
according to the endpoints scale (categorical or continuous). The treatment group will be 
included as factor and the baseline and stratification variable as covariates in the model. 
Additional psychometric analyses will be conducted on the study data (Stage 1 and Stage 2) 
to validate the PROs used in the study. 
The scoring of patient reported questionnaires will be detailed in the SAP. For mVPAQ, the 
analysis of life interference subscale will be done with and without the item ‘ability to fall 
asleep’. The analysis of pain severity subscale will be done with and without the items 
‘unpleasantness’ and ‘distress’. The total mVPAQ will also be computed with and without 
these items. 
11.4.4 
Adjustment for Country/Centre Effect 
Descriptive analysis will be carried out to evaluate/describe any possible centre effect. 
11.4.5 
Handling of Withdrawals, Discontinuations or Missing Data  
As described in Section 11.2, for Stage 1 and Stage 2, subjects who discontinue prior to 
Week 6 for reasons unrelated to safety may be replaced at the discretion of the investigator 
and sponsor. 
Sensitivity analyses will be carried out to evaluate the impact of missing data where 
appropriate. 
11.4.6 
Data Analyses Timepoints 
11.4.6.1  Data Review Committee (End of Stage 1 - Cycle 1-Week 6) 
When all subjects in PVD2 cohorts in Stage 1 have reached Cycle 1-Week 6 visit, the DRC 
will review the unblinded efficacy and safety data to enable the selection of doses. 
Once all subjects in PVD1 cohorts have reached Cycle 1-Week 6 visit, the DRC will meet and 
based on unblinded review of all safety and efficacy data from the cohort, will recommend if 
further PVD1 cohort(s) are required or if PVD1 subjects should be removed from Stage 2. 


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11.4.6.2 Primary Analysis (End of Stage 2 Cycle 1-Week 12)  
A primary unblinded analyses will be performed. The cut-off date will be when all Stage 2 
subjects have completed the Cycle 1-Week 12 visit. Analyses will be performed on:  
• 
Subjects in Stage 1 – all safety and efficacy data available at the time of the data cut-off 
date. 
• 
Subjects in Stage 2 – all safety and efficacy data available up to Cycle 1-Week 12 visit. 
11.4.7 
Safety Evaluation 
All safety data will be included in the subject data listings. Analyses and summary tables will 
be based upon the safety population. 
All AEs will be coded according to the current version of MedDRA at the time of database 
lock and will be classified by MedDRA preferred term and system organ class. AE listings 
will be presented by subject, system organ class and preferred term. 
Incidence of all reported TEAEs and SAEs will be tabulated by treatment, group, dose and 
overall. In addition, summary tables will be presented by maximum intensity, drug 
relationship and TEAEs associated with premature withdrawal of study medication. 
A TEAE is defined as any AE that occurs during the active phase of the study if:  
• 
it was not present prior to receiving the first dose of IMP, or  
• 
it was present prior to receiving the first dose of IMP but the intensity increased during 
the active phase of the study. 
All TEAEs will be flagged in the AEs listings. 
Summary statistics (mean, median, SD and range as appropriate) by treatment group, dose 
and by overall will be presented for clinical laboratory tests at each assessment with change 
from Baseline. For laboratory data, abnormal values will be flagged in the data listings and a 
list of clinically significant abnormal values will be presented. Shift tables will be presented 
of the number and percentage of subjects with low, normal or high values and normal or 
abnormal exams. 
The number and percentage of subjects with the presence of BTX-A antibodies (neutralising) 
at Baseline will be presented. The number of seroconverters (subjects who have negative 
results at Baseline and have at least one positive result at any one post-treatment timepoint) 
for neutralising antibodies will be reported. 
11.5 
Subgroup Analyses 
Descriptive statistics for the primary efficacy endpoint and main baseline characteristics will 
be provided by pain onset subtype (primary and secondary PVD) for Stage 2 on the mITT 
population. In addition, overall adverse events summary as well as TEAEs and SAEs will be 
provided (by SOC and PT) by pain onset subtype. 
Other subgroup analyses may be planned according to clinical interest and detailed in the 
SAP. 
11.6 
Intermediate Analyses 
At the point when the DRC recommends moving to Stage 2 of the study, an intermediate 
unblinded analysis of data available from all double-blind periods of all cohorts in Stage 1 
will be performed when all subjects from the latest cohorts have completed their Cycle 1-
Week 12 visit (data cut-off date corresponding to the last Cycle 1-Week 12 visit date).  


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All AE data available at the time of the data cut-off date (including data from the double-blind 
cycle from all cohorts) will be analysed using descriptive statistics. A thorough description of 
TEAEs collected during the double-blind periods will be performed. 
Demographic and baseline characteristics, disposition, concomitant medications and treatment 
exposure will be described as well.  
All efficacy related secondary endpoints will be described using change from baseline and 
categorical analyses (as summarised in Section 7.2). In addition, descriptive statistics will also 
be provided for selected exploratory endpoints (mean PGI-C score, and mean changes from 
baseline in the following endpoints: PGI-S score, mVPAQ pain and life interference subscales 
scores, mFSFI total score and domain scores and PHQ-9 total score).  
A detailed description of this intermediate analysis will be provided in the SAP. 


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12 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
Authorised personnel from external CAs and sponsor authorised Quality Assurance personnel 
may carry out inspections and audits. The purpose of an audit is to ensure that ethical, 
regulatory and quality requirements are fulfilled in all studies performed by the sponsor. 
Auditors and inspectors must have direct access to study documents and site facilities as 
specified in Section 13.4, and to any other locations used for the purpose of the study in 
question (e.g. laboratories). 
In the event of the site being notified directly of a regulatory inspection, the investigator must 
notify the sponsor’s representative as soon as possible, to assist with preparations for the 
inspection. 


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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Protocol Amendments and Protocol Deviations   
13.1.1 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior 
written approval or favourable opinion of a written amendment by the IEC/IRB, except when 
necessary to eliminate immediate safety concerns to the subjects or when the change involves 
only logistics or administration. The principal investigator and the sponsor will sign the 
protocol amendment. 
13.1.2 
Protocol Deviations and Exceptions 
All protocol deviations will be identified and recorded by the sponsor or sponsor’s 
representative. 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. 
Major protocol deviations are a subset of protocol deviations that might significantly affect 
the completeness, accuracy, and/or reliability of the study data or that might significantly 
affect a subject’s rights, safety, or well-being. (For example, major protocol deviations might 
include enrolling subjects in violation of key eligibility criteria designed to ensure a specific 
subject population or failing to collect data necessary to interpret primary endpoints, as this 
may compromise the scientific value of the trial.) 
Generally, a protocol deviation qualifies as major if: 
(1) 
The deviation has harmed or posed a significant or substantive risk of harm to the 
research subject 
(2) 
The deviation compromises the scientific integrity of the data collected for the study 
(3) 
The deviation is a wilful or knowing breach of human subject protection regulations, 
policies, or procedures on the part of the investigator(s) 
(4) 
The deviation involves a serious or continuing noncompliance with any applicable 
human subject protection regulations, policies, or procedures 
(5) 
The deviation is inconsistent with Ipsen’s research, medical, and ethical principles. 
See also Section 11.1.2 for details on the impact of major protocol deviations on the inclusion 
of subjects in each analysis population. 
A minor protocol deviation is any change in the study design, study conduct and/or 
procedures that are not in accordance with the protocol and any study materials originally 
approved by the IEC/IRB but do not have a major impact on the subject’s rights, safety or 
wellbeing, or the completeness, accuracy and reliability of the study data. 
As a matter of policy, the sponsor will not grant exceptions to protocol specific entry criteria 
to allow subjects to enter a study. If under extraordinary circumstances such action is 
considered ethically, medically, and scientifically justified for a particular subject, prior 
approval from the sponsor and the responsible IRB/IEC, in accordance with the Standard 
Operating Procedure (SOP), is required before the subject will be allowed to enter the study. 
If study site personnel learn that a subject who did not meet protocol eligibility criteria was 
entered in a study (a protocol deviation), they must immediately inform the sponsor. Such 
subjects will be discontinued from the study, except in an exceptional instance following 
review and written approval by the sponsor, and if applicable according to the local regulatory 
requirement, the responsible IRB/IEC. 


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13.2 
Information to Study Personnel 
To ensure accurate, complete and reliable data, the sponsor or its representatives will provide 
instructional material to the study sites, as appropriate. A study initiation visit will be 
conducted prior to screening start to instruct the investigators and study coordinators. This 
session will give instruction on the protocol, the completion of the CRF and all study 
procedures. The investigator is responsible for giving information about the study to all staff 
members involved in the study or in any element of subject management, both before starting 
any study procedures and during the course of the study (e.g. when new staff become 
involved). The investigator must assure that all study staff members are qualified by 
education, experience, and training to perform their specific responsibilities. These study staff 
members must be listed on the study site authorisation form, which includes a clear 
description of each staff member’s responsibilities. This list must be updated throughout the 
study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including the 
investigator, and for ensuring their compliance with the protocol. Additional information will 
be made available during the study when new staff become involved in the study and as 
otherwise agreed upon with either the investigator or the study monitor. 
13.3 
Study Monitoring 
The investigator is responsible for the validity of all data collected at the site. 
The sponsor is responsible for monitoring these data to verify that the rights and wellbeing of 
subjects are protected, that study data are accurate (complete and verifiable to source data) 
and that the study is conducted in compliance with the protocol, GCP and regulatory 
requirements. 
Sponsor assigned monitors will conduct regular site visits. The investigator will allow direct 
access to all relevant files (for all subjects) and clinical study supplies (dispensing and storage 
areas) for the purpose of verifying entries made in the eCRF, and assist with the monitor’s 
activities, if requested. Adequate time and space for monitoring visits should be made 
available by the investigator. 
The site must complete the eCRFs on an ongoing basis to allow regular review by the study 
monitor, both remotely by the internet and during site visits.  
Whenever a subject name is revealed on a document required by the sponsor (e.g. laboratory 
print outs) the name must be blacked out permanently by the site personnel, and annotated 
with the subject number as identification. 
13.3.1 
Data Review Committee 
The DRC will be composed of sponsor representatives independent from the study team, 
including at least a representative from neurology therapeutic area department and a 
statistician, a non-sponsor physician expert in the treatment of vulvodynia and a CRO 
representative to assist in the logistics of the meetings. A DRC charter will be developed to 
define roles and responsibilities and the DRC meetings will take place as defined in the 
charter describing the operation of this committee.  
The Chair of the DRC will be responsible for communicating the committee’s 
recommendations to the study team who will immediately inform the investigators. 
The DRC charter will be available in the TMF. 
Refer to Section 3.1.1.2 for details of safety assessments to be done by the DRC. 


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13.4 
Investigator’s Regulatory Obligations 
All clinical work under this protocol will be conducted according to GCP rules. This includes 
that the study may be audited at any time by a quality assurance personnel designated by the 
sponsor, or by regulatory bodies. The investigator must adhere to the GCP principles in 
addition to any applicable local regulations. 
If requested, the investigator will provide the sponsor, applicable regulatory agencies, and 
applicable IEC/IRB with direct access to any original source documents. 
The investigator(s) should demonstrate due diligence in recruitment and screening of potential 
study subjects. The enrolment rate should be sufficient to complete the study as agreed with 
the sponsor. The sponsor should be notified of any projected delays, which may impact the 
completion of the study. 
13.5 
Audit and Inspection 
Authorised personnel from external CAs and the sponsor’s authorised Quality Assurance 
personnel may carry out inspections and audits (see Section 12). 
13.6 
Data Quality Assurance 
Monitored eCRFs shared between the investigational site and the assigned Data Management 
CRO, will be reviewed (data review) for completeness, consistency, legibility and protocol 
compliance. 
Reasons should be given on the relevant eCRF for any missing data and other protocol 
deviations. Any electronic queries and items not adequately explained will require additional 
electronic manual queries to be raised to the investigator by the monitor for 
clarification/correction. The investigator must ensure that queries are dealt with promptly. All 
data changes and clarifications can be viewed in the audit trail function of the eCRF. 


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14 
ETHICS 
14.1 
Compliance with Good Clinical Practice and Ethical Considerations 
This study will be conducted in compliance with IECs/IRBs, informed consent regulations, 
the Declaration of Helsinki, ICH GCP Guidelines (Section 1), FDA 21 CFR Part 11, 
Electronic Records, Electronic Signatures, and FDA, Guidance for Industry: Computerized 
Systems Used in Clinical Trials. 
In addition, this study will adhere to all local regulatory requirements.  
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject emergency study contact cards, 
subject recruitment procedures (e.g. advertisements), any written information to be provided 
to subjects and a statement from the IEC/IRB that they comply with GCP requirements. The 
IEC/IRB approval must identify the protocol version as well as the documents reviewed. 
After IEC/IRB approval, changes will require a formal amendment. Once the study has 
started, amendments should be made only in exceptional circumstances. Changes that do not 
affect subject safety or data integrity are classified as administrative changes and generally do 
not require ethical approval. If ethically relevant aspects are concerned, the IEC/IRB must be 
informed and, if necessary, approval sought prior to implementation. Ethical approval on 
administrative changes will be obtained if required by local/site IEC/IRB. 
14.2 
Informed Consent for Participation in the Study 
Prior to study entry, the investigator, or a person designated by the investigator, will explain 
the nature, purpose, benefits and risks of participation in the study to each subject, subject’s 
legally acceptable representative or impartial witness. Written informed consent must be 
obtained prior to the subject entering the study (before initiation of any study-related 
procedure and administration of the IMP). Sufficient time will be allowed to discuss any 
questions raised by the subject. 
The sponsor will provide a sample informed consent form. The final version controlled form 
must be agreed to by the sponsor, and the IEC/IRB and must contain all elements included in 
the sample form, in language readily understood by the subject. Each subject’s original 
consent form, personally signed and dated by the subject or by the subject’s legally acceptable 
representative, and by the person who conducted the informed consent discussion, will be 
retained by the investigator. The investigator will supply subjects with a copy of their signed 
informed consent. 
The consent form may need to be revised during the study should important new information 
become available that may be relevant to the safety of the subject or as a result of protocol 
amendments. In this instance approval should always be given by the IEC/IRB. It is the 
investigator’s responsibility to ensure that all subjects subsequently entered into the study and 
those currently in the study sign the amended form. This is documented in the same way as 
previously described. Subjects who have completed the study should be informed of any new 
information that may impact on their welfare/wellbeing. 
The investigator should, with the consent of the subject, inform the subject’s primary 
physician about their participation in the clinical study. 


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14.3 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards 
As required by local regulations, the sponsor’s Regulatory Affairs group will ensure all legal 
regulatory aspects are covered, and obtain approval of the appropriate regulatory bodies, prior 
to study initiation in regions where an approval is required. 
The following documents should be submitted to the relevant IEC/IRB for review and 
approval to conduct the study (this list may not be exhaustive): 
• 
Protocol/amendment(s) approved by the sponsor, 
• 
Currently applicable IB or package labelling, 
• 
Relevant investigator’s curriculum vitae, 
• 
Subject information and informed consent document(s) and form(s), 
• 
Subject emergency study contact cards, 
• 
Recruitment procedures/materials (advertisements), if any. 
The IEC(s)/IRB(s) will review all submission documents as required, and a written favourable 
opinion for the conduct of the study should be made available to the investigator before 
initiating the study. This document must be dated and clearly identify the version number(s) 
and date(s) of the documents submitted/reviewed and should include a statement from the 
IEC/IRB that they comply with GCP requirements. 
The study may begin at the investigative site(s) only after receiving this dated and signed 
documentation of the IEC/IRB approval or favourable opinion. 
During the study, any update to the following documents will be sent to the IEC/IRB either 
for information, or for review and approval, depending on how substantial the modifications 
are: (1) IB; (2) all protocol amendments and revised informed consent(s), if any. 
At the end of the study, the EC will be notified about the study completion. 
14.4 
Confidentiality Regarding Study Subjects 
The investigator must assure that the privacy of the subjects, including their personal identity 
and all personal medical information, will be maintained at all times. In eCRFs and other 
documents or image material submitted to the sponsor, subjects will be identified not by their 
names, but by their year of birth and an identification code (identification number). 
Personal medical information may be reviewed for the purpose of verifying data recorded on 
the eCRF. This review may be conducted by the study monitor, properly authorised persons 
on behalf of the sponsor, the quality assurance unit, or regulatory authorities. Personal 
medical information will always be treated as confidential. 


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15 
DATA HANDLING AND RECORD KEEPING 
15.1 
Data Recording of Study Data 
In compliance with GCP, the medical records/medical notes, etc., should be clearly marked 
and permit easy identification of a subject’s participation in the specified clinical study. 
The investigator must record all data relating to protocol procedures, IMP administration, 
laboratory data, safety data and efficacy ratings on the eCRFs provided for the study. The 
investigator, by completing the signature log, may formally designate authority to complete 
eCRFs to appropriately qualified staff having certified user access to the eCRF.  
Subject completed diaries and questionnaires will be electronic. The data will be entered by the 
subject directly into a separate EDC (ePRO) secured by individual and confidential access 
codes. Data will be accessible to the clinical site and sponsor in a read only mode.  
The investigator must, as a minimum, provide an electronic signature (e-signature) to each 
case report book to attest to the accuracy and completeness of all the data. If any changes are 
made to the eCRF, after a form has been locked and electronically signed, the investigator 
will be required to perform an additional e-signature authorising agreement with any new 
information or changes to the eCRF. 
All corrections on the eCRF will be automatically tracked and a reason for change is always 
required. In the eCRF, the audit trail function will allow the changes made to be viewed on 
each item entered. 
15.2 
Data Management 
Electronic Data Capture (EDC) will be utilised for collecting subject data (except subject 
reported questionnaires and diaries entered into an ePRO). Each site is required to have a 
computer and internet connection available for site entry of clinical data. All entries in the 
eCRF will be done under the electronic signature of the person performing the action. This 
electronic signature consists of an individual and confidential username and password 
combination. It is declared to be the legally binding equivalent of the handwritten signature. 
Only sponsor authorised users will have access to the eCRF as appropriate to their study 
responsibilities. Users must have successfully undergone software application training prior to 
entering data into the eCRF. 
Data management will be conducted by a CRO, directed by the sponsor’s Biometry group. All 
data management procedures will be completed in accordance with the sponsor and the 
contracted CRO SOPs. Prior to data being received in-house at the assigned CRO, they will be 
monitored at the investigator site (for further details please see Section 13.3 Study Monitoring). 
The CRF and other data documentation removed from the investigator site(s) will be tracked by 
the CRO and the monitor. 
The sponsor will ensure that an appropriate eCRF is developed to capture the data accurately, 
and suitable queries are raised to resolve any missing or inconsistent data. The investigator 
will receive their data, from the clinical study, in an electronic format (PDF files) which will 
be an exact copy of the eCRF and ePRO, and will include the full audit trail, for archiving 
purposes and future reference. 
Any queries generated during the data management process will also be tracked by the 
contracted Biometry CRO. It is the CRO’s study monitor’s responsibility to ensure that all 
queries are resolved by the relevant parties. 
The sponsor will also ensure that SAE data collected in the eCRF are consistent with 
information provided to the sponsor’s pharmacovigilance department (and vice versa).  


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The coding of an AE, medical history, surgical procedures and concomitant medication terms 
will be performed by a contracted CRO, directed by the sponsor’s Biometry Group, and 
reviewed and approved by the sponsor. Concomitant medications will be coded using 
WHODRUG and AEs/medical history terms will be coded using MedDRA. 
Complete data from enrolled subjects will be reported in the eCRFs and collected in the 
sponsor’s database. 
For screen failure subjects, at least the Unique Subject Identifier, the date of informed 
consent signature and the potential AEs which occurred during the screening phase will be 
reported in the eCRFs and collected in the sponsor’s database. Rescreened subjects will sign a 
new informed consent form and a new subject identification number will be allocated. 
15.3 
Record Archiving and Retention 
Prior to the start of the study, the monitor must ensure the archiving facilities are adequate 
and archiving/retention responsibilities of the investigator have been discussed.  
Study documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications 
in an ICH region (that is at least 15 years) or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the product. However, these documents should be 
retained for a longer period if required by the local applicable regulatory requirements or by 
an agreement with the sponsor. The investigator should take measures to prevent accidental or 
premature destruction of these documents. The final archiving arrangements will be confirmed 
by the monitor when closing out the site. The sponsor will inform the investigator, in writing, 
as to when these documents no longer need to be retained. 
If the principal investigator relocates or retires, or otherwise withdraws his/her responsibility 
for maintenance and retention of study documents, the sponsor must be notified (preferably in 
writing) so that adequate provision can be made for their future maintenance and retention. 


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16 
FINANCING AND INSURANCE 
16.1 
Contractual and Financial Details 
The investigator (and/or, as appropriate, the hospital administrative representative) and the 
sponsor will sign a clinical study agreement prior to the start of the study, outlining overall 
sponsor and investigator responsibilities in relation to the study. Financial remuneration will 
cover the cost per included subject, based on the calculated costs of performing the study 
assessments in accordance with the protocol, and the specified terms of payment will be 
described in the contract. The contract should describe whether costs for pharmacy, laboratory 
and other protocol required services are being paid directly or indirectly. 
Financial Disclosure Statements will need to be completed, as requested by FDA 21 CFR 
Part 54. 
16.2 
Insurance, Indemnity and Compensation 
The sponsor will provide Product Liability insurance for all subjects included in the clinical 
study. Where required, a hospital specific indemnity agreement will be used. 


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17 
REPORTING AND PUBLICATIONS OF RESULTS 
17.1 
Publication Policy 
The sponsor encourages acknowledgement of all individuals/organisations involved in the 
funding or conduct of the study, including medical writers or statisticians subject to the 
consent of each individual and entity concerned, including acknowledgement of the sponsor. 
The results of this study may be published or communicated to scientific meetings by the 
investigators involved in the study. For multicentre studies, a plan for scientific publication 
and presentation of the results may be agreed and implemented by the study investigators or a 
Steering Committee. The sponsor requires that reasonable opportunity be given to review the 
content and conclusions of any abstract, presentation, or paper before the material is 
submitted for publication or communicated. This condition also applies to any amendments 
that are subsequently requested by referees or journal editors. The sponsor will undertake to 
comment on the draft documents within the time period agreed in the contractual 
arrangements, including clinical trial agreements, governing the relationship between the 
sponsor and authors (or the author’s institution). Requested amendments will be incorporated 
by the author, provided they do not alter the scientific value of the material. 
If patentability would be adversely affected by publication, this will be delayed until (i) a 
patent application is filed for the content of the publication in accordance with applicable 
provisions of the clinical trial agreement concerned, (ii) the sponsor consents to the 
publication, or (iii) the time period as may be agreed in the contractual arrangements, 
including clinical trial agreements, governing the relationship between the sponsor and 
authors (or authors’ institution) after receipt of the proposed publication by the sponsor, 
whichever of (i), (ii) or (iii) occurs first. 
The author undertakes to reasonably consider the sponsor's request for delay to the proposed 
publication should the sponsor reasonably deem premature to publish the results obtained at 
the then stage of the study. 
17.2 
Clinical Study Report 
As indicated in Section 11.4.6, a primary analysis will be performed after all subjects in 
Stage 2 complete the Week 12 visit. An interim Clinical Study Report (CSR) may be 
prepared.  
A final CSR will be prepared where any subject has signed informed consent, regardless of 
whether the study is completed or prematurely terminated. Where appropriate an abbreviated 
report may be prepared. The CSR will be prepared according to the ICH guideline on 
structure and contents of CSRs and will comply with any applicable regulatory requirements, 
national laws in force and will be in English. 
 


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18 
REFERENCES 
1. 
Bornstein J, Goldstein AT, Stockdale CK et al. 2015 ISSVD, ISSWSH, and IPPS 
consensus terminology and classification of persistent vulvar pain and vulvodynia. J 
Low Genit Tract Dis. 2016;20(2):126-130. 
2. 
Nagandla K, Sivalingam N. Vulvodynia: integrating current knowledge into clinical 
practice. Review Royal College of Obstetricians and Gynaecologists 2014;16:259-267. 
3. 
Reed BD, Harlow SD, Sen A et al. Prevalence and demographic characteristics of 
vulvodynia in a population-based sample. Am J Obstet Gynecol. 2012;206(2):170e1-
e9. 
4. 
Harlow BL, Kunitz CG, Nguyen RHN et al. Prevalence of symptoms consistent with a 
diagnosis of vulvodynia: population-based estimates from 2 geographic regions. Am J 
Obstet Gynecol. 2014;210:40e1-8. 
5. 
Pukall CF, Goldstein AT, Bergeron S et al. Vulvodynia: definition, prevalence, impact, 
and pathophysiological factors. J Sex Med. 2016;13(3):291-304.  
6. 
Pelletier F, Girardin M, Humbert P et al. Long-term assessment of effectiveness and 
quality of life of OnabotulinumtoxinA injections in provoked vestibulodynia. J Eur 
Acad Dermatol Venereol. 2016;30(1):106-111. 
7. 
Goldstein AT, Pukall CF, Brown C et al. Vulvodynia: assessment and treatment. J Sex 
Med. 2016;13(4):572-590.  
8. 
Mandal D, Nunns D, Byrne M et al. Guidelines for the management of vulvodynia. Br 
J Dermatol 2010;162:1180–1185. 
9. 
Reissing ED, Brown C, Lord MJ et al. Pelvic floor muscle functioning in women with 
vulvar vestibulitis syndrome. Journal of Psychosomatic Obstetrics & Gynecology 
2005;26(2):107-113. 
10. 
Pelletier F, Parratte B, Penz S et al. Efficacy of high doses of botulinum toxin A for 
treating provoked vestibulodynia. Br J Dermatol. 2011 Mar;164(3):617-622. 
11. 
Bohm-Starke N, Hilliges M, Falconer C et al. Neurochemical characterization of the 
vestibular nerves in women with vulvar vestibulitis syndrome. Gynecol Obstet Invest. 
1999;48: 270–275. 
12. 
Morrissey D, El-Khawand D, Ginzburg N et al.  Botulinum toxin A injections into 
pelvic floor muscles under electromyographic guidance for women with refractory 
high-tone pelvic floor dysfunction: a 6-month prospective pilot study. Female Pelvic 
Med Reconstr Surg. 2015;21(5):277-282. 
13. 
Dykstra DD, Presthus J. Botulinum toxin type A for the treatment of provoked 
vestibulodynia: an open-label, pilot study. J Reprod Med. 2006;51(6):467-470. 
14. 
Ghazizadeh S, Nikzad M. Botulinum toxin in the treatment of refractory vaginismus. 
Obstet Gynecol. 2004;104:922–925. 
15. 
Bertolasi L, Emma F, Jee Yun C. Botulinum Neurotoxin Type A injections for 
vaginismus secondary to Vulvar Vestibulitis Syndrome. Obstetrics & gynecology. 
2009;114(5):1008-1016. 
16. 
Abbott JA, Jarvis SK, Lyons SD et al. Botulinum toxin type A for chronic pain and 
pelvic floor spasm in women a randomized controlled trial. Obstetrics & Gynaecology 
2006:108(4):915-923. 


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17. 
Peterson C, Giraldi A, Lundvall L et al. Botulinum toxin Type A—a novel treatment 
for provoked vestibulodynia? Results from a randomized, placebo controlled, double 
blinded study. J Sex Med 2009;6:2523–2537. 
18. 
Shafik A and El-Sibai O. Vaginismus: results of treatment with botulin toxin. Journal 
of Obstetrics and Gynaecology 2000;20(3):300-302. 
19. 
Yoon H, Chung WS. Botulinum Toxin A for the management of vulvodynia. 
International Journal of impotence Research 2007; 19:84-87. 
20. 
Jeon Y, Kim Y, Yoon H et al. A retrospective study of the management of vulvodynia. 
Korean J Urol. 2013;54(1):48-52. 
21. 
Pukall CF, Young RA, Roberts MJ et al. The vulvalgesiometer as a device to measure 
genital pressure-pain threshold. Physiol. Meas. 2007:28;1543–1550. 
22. 
Dargie E, Holden RR, Pukall CF. The Vulvar Pain Assessment Questionnaire 
inventory. Pain 2016; 157(12):2672-2686. 
23. 
Rosen R, Brown C, Heiman J et al. The Female Sexual Function Index (FSFI): 
a multidimensional self-report instrument for the assessment of female sexual function. 
J Sex Marital Ther. 2000;26(2):191-208. 
24. 
Wiegel M, Meston C, Rosen R. The Female Sexual Function Index (FSFI): 
cross-validation and development of clinical cutoff scores. J Sex Marital Ther. 
2005;31(1):1-20. 
25. 
Aerts L, Bergeron S, Pukall CF et al. Provoked Vestibulodynia: does pain intensity 
correlate with sexual dysfunction and dissatisfaction?. J Sex Med 2016; 1-8. 
26. 
Bornstein J, Tuma R, Farajun Y et al. Topical nifedipine for the treatment of localized 
provoked vulvodynia: a placebo-controlled study. J Pain. 2010;11(12):1403-1409. 
27. 
Davis SNP, Bergeron S, Binik YM et al. Women with provoked vestibulodynia 
experience clinically significant reductions in pain regardless of treatment: Results 
from a 2-year follow-up study. J Sex Med 2013;10:3080–3087. 
 


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19 
LIST OF APPENDICES 
Appendix 1 mVPAQ (Version 1.2) ........................................................................ 105 
Appendix 2 mFSFI (Version 1.3) ........................................................................... 108 
Appendix 3 PHQ-9 ................................................................................................. 114 
Appendix 4 SF-36 ................................................................................................... 115 
Appendix 5 PCS ..................................................................................................... 121 
Appendix 6 Protocol Amendment: Version 2.0 (15 May 2018) ............................ 122 
Appendix 7 Protocol Amendment: Version 3.0 (04 November 2018) ................... 129 
Appendix 8 Protocol Amendment: Version 4.0 (08 April 2019) ........................... 156 
Appendix 9 Protocol Amendment Version 5.0 (23 January 2020) ........................ 170 
Appendix 10 Protocol Amendment Version 6.0 (08 October 2020) ...................... 197 


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Appendix 1 mVPAQ (Version 1.2) 
 


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Appendix 5 PCS 
 




































































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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
D-FR-52120-236 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Protocol Version 3.0: 04 November 2018 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON(S) FOR CHANGES 
 
The protocol was updated to add more flexibility in the duration of 
the screening period, to make the screening period consistent 
between Stage 1 and Stage 2, remove the upper age limit of subjects, 
clarify the timing of assessments performed as part of 
inclusion/exclusion criteria, revise the scoring requirement of the 
mFSFI questionnaire exclusion criterion, remove the PCS exclusion 
criterion, clarify the concomitant medications exclusion criterion, 
update the rescreening criteria, specify the PGI-S secondary endpoint 
as mean change from baseline, modify the mITT population to be 
consistent with the SAP, and correct any inconsistencies. 
Additionally, in response to the FDA agency feedback:  
• 
The recall periods for some subscales/domains of patient 
reported outcomes were modified and questionnaires 
updated (mFSFI and mVPAQ) which were appended to the 
protocol 
• 
The schedule of assessments was updated with regards to the 
frequency and timing of collection of some parameters to 
align with the recommendations 
• 
Subject interviews to assess the content relevance of the 
dilator test (primary endpoint) were added.  
 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
STATISTICAL ANALYSIS PLAN 
(SAP) UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 




























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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
D-FR-52120-236 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Protocol Version 4.0: 08 April 2019 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON(S) FOR CHANGES 
 
The protocol was updated to:  
• 
Include an additional Cohort 4 in Stage 1 enrolling 8 subjects 
with primary vulvodynia (PVD1 subjects) in parallel to the 
Cohort 3 enrolling subjects with secondary vulvodynia 
(PVD2 subjects), thus impacting the overall sample size. 
• 
Further clarify the inclusion and exclusion criteria to facilitate 
subject recruitment. 
• 
Further clarify the concomitant medications exclusion 
criterion. 
• 
Update the name of the sponsor’s Chemistry, Manufacturing 
and Control Supply Chain department. 
• 
Update the definition used to define the mITT and 
PP populations. 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
STATISTICAL ANALYSIS PLAN 
(SAP) UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 






















































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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
D-FR-52120-236 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Protocol Version 5.0: 23 January 2020 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON(S) FOR CHANGES 
 
The protocol was updated to:  
• 
Include additional cohorts up to a maximum of 800 U 
• 
Clarify assessment for pelvic floor muscles pressure 
• 
Update the sample size determination criteria 
• 
Clarify inclusion/exclusion criteria related to vaginal delivery 
and medical history 
• 
Update the names of sponsor representatives 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
STATISTICAL ANALYSIS PLAN 
(SAP) UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 






















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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
D-FR-52120-236 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Protocol Version 6.0: 08 October 2020 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON(S) FOR CHANGES 
 
The protocol was updated to:  
• 
Reflect that during Stage 2, two optimally safe and effective 
doses of Dysport will be further investigated; the option of testing 
one Dysport dose during Stage 2 was removed. 
• 
Clarify that the role of the DRC was to make recommendation on 
dose escalation, dose de-escalation, progression from Stage 1 to 
Stage 2 or study termination decisions in Stage 1. 
• 
Clarify in inclusion criteria 12b, the specific cohorts that enrolled 
subjects with primary vulvodynia versus secondary vulvodynia. 
• 
Shift the evaluation of CGI-C and PGI-C from secondary 
objectives/efficacy parameters to exploratory objectives/efficacy 
parameters. 
• 
Add guidance on COVID-19 infection to be reported as an SAE, 
and its impact on IMP administration. 
• 
Add a provision for the subjects to have their study visit 
assessments performed remotely, if they are unable to attend the 
site visit due to the COVID-19 pandemic. 
• 
Add permitted pain rescue medication during Stage 2. 
• 
Add further clarification in the statistical section on the: 
 Doses being evaluated in Stage 2,  
 COVID-19 specific analyses,  
 
Intermediate analyses to be performed at the point when the 
DRC recommends moving to Stage 2 and 
 
Potential sample size recalculation for Stage 2 following the 
intermediate analysis. 
• 
Update the mFSFI questionnaire to version 1.3. 
 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
STATISTICAL ANALYSIS PLAN 
(SAP) UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 
 

SAP_001.pdf: 
  
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STATISTICAL AND ANALYSIS PLAN 
 
PROTOCOL NUMBER: D-FR-52120-236 
 
PROTOCOL TITLE: A PHASE II, MULTICENTRE, DOUBLE-BLIND, RANDOMISED, 
PLACEBO-CONTROLLED, DOSE ESCALATION AND DOSE FINDING STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF DYSPORT IN VULVODYNIA 
PATIENTS 
 
PROTOCOL VERSION AND DATE: 6.0 – 08 OCTOBER 2020 
 
 
SAP Version 
Date 
Final Version 1.0 
11 February 2021 
 






  
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TABLE OF CONTENTS 
1 
INFORMATION TAKEN FROM THE PROTOCOL ............................................... 8 
1.1 
Study objectives ............................................................................................................... 8 
1.1.1 
Primary objective ........................................................................................... 8 
1.1.2 
Secondary objectives ..................................................................................... 8 
1.1.3 
Exploratory objectives ................................................................................... 8 
1.2 
Study design ..................................................................................................................... 9 
1.3 
Methods and procedures ................................................................................................ 9 
1.3.1 
Schedule of assessments ............................................................................... 9 
1.3.2 
Planned sample size ...................................................................................... 9 
1.3.3 
Method of Randomisation ............................................................................ 9 
1.3.4 
Validation scale study D-FR-52120-252 .................................................... 10 
1.3.5 
Data review Committee and planned Analyses .......................................... 10 
2 
SUBJECT POPULATIONS (ANALYSIS SETS) ...................................................... 10 
3 
STATISTICAL METHODS ........................................................................................ 11 
3.1 
Statistical analysis strategy .......................................................................................... 11 
3.1.1 
Multiplicity .................................................................................................. 13 
3.1.2 
Significance testing and estimation ............................................................ 13 
3.1.3 
Withdrawal visit and end of study visit ....................................................... 13 
3.2 
Subject disposition and population ............................................................................. 13 
3.3 
Protocol Deviations ....................................................................................................... 13 
3.4 
Demographic and Baseline characteristics ................................................................. 14 
3.5 
Medical and surgical history ........................................................................................ 14 
3.6 
Prior and concomitant therapies ................................................................................. 14 
3.7 
Subject compliance ....................................................................................................... 15 
3.8 
Efficacy analysis ............................................................................................................ 15 
3.8.1 
Primary efficacy analysis ............................................................................ 16 
3.8.2 
Secondary efficacy analyses ....................................................................... 16 
3.8.3 
Exploratory efficacy analyses ..................................................................... 21 
3.9 
Safety .............................................................................................................................. 24 
3.9.1 
Extent of exposure ...................................................................................... 24 
3.9.2 
Adverse events ............................................................................................. 25 
3.9.3 
Laboratory data ........................................................................................... 27 
3.9.4 
Vital signs .................................................................................................... 28 
3.9.5 
Physical examination .................................................................................. 28 
3.9.6 
Antibodies .................................................................................................... 28 
3.10 Missing data and other data issues .............................................................................. 29 
3.10.1 
Missing data ................................................................................................ 29 
3.10.2 
Missing or incomplete dates ....................................................................... 29 


  
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3.11 Derived data .................................................................................................................. 30 
3.12 Rules and data formats ................................................................................................. 31 
3.13 Pooling of Centres ......................................................................................................... 31 
3.14 Covariates and analysis of subgroups ......................................................................... 31 
3.15 COVID-19 impact ......................................................................................................... 32 
4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS . 33 
4.1 
Software ......................................................................................................................... 33 
4.2 
Validation programs ..................................................................................................... 33 
4.3 
Restitution of the programs ......................................................................................... 33 
5 
CHANGES FROM PROTOCOL ................................................................................ 33 
5.1.1 
Schedule of assessments ............................................................................. 33 
5.1.2 
Data Analyses Timepoints .......................................................................... 33 
5.1.3 
COVID-19 Pandemic Start Date ................................................................ 33 
5.1.4 
Per Protocol (PP) population ..................................................................... 33 
6 
REFERENCES .............................................................................................................. 34 
7 
APPENDICES ............................................................................................................... 35 
7.1 
Appendix 1: List of PCSA criteria .............................................................................. 35 
 


  
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA: 
Anti-drug Antibodies 
AE: 
Adverse Event 
AESI 
AEs of special interest 
ALP: 
Alkaline phosphatase 
ALT: 
Alanine aminotransferase 
AST: 
Aspartate aminotransferase 
ATC: 
Anatomic Therapeutic Class 
ANOVA: 
Analysis of Variance 
ANCOVA: 
Analysis of Covariance 
CGI: 
Clinical Global Impression 
BMI: 
Body Mass Index 
BTX 
Botulinum Toxin 
BTX-A: 
Botulinum toxin-A 
CRF: 
Case Report Form 
CRO: 
Clinical Research Organisation 
DB: 
Double-Blind 
DLE: 
Dose limiting event 
DRC: 
Data Review Committee 
DMTS: 
Dilator maximum tested size 
e: 
Electronic 
EOS: 
End of study 
ICH: 
International Council for Harmonisation  
IMP: 
Investigational Medicinal Product 
MedDRA: 
Medical Dictionary for Regulatory Activities 
mFSFI: 
modified Female Sexual Function Index 
mITT: 
modified Intent-To-Treat 
mVPAQ: 
modified Vulvar Pain Assessment Questionnaire 
NRS: 
Numeric Rating Scale 
OL: 
Open-Label 
PCSA: 
Potentially Clinically Significant Abnormalities 
PGI: 
Patient Global Impression 
PGI-C: 
Patient Global Impression of change in pain 
PGI-S: 
Patient Global Impression of severity of the pain  
PHQ-9: 
Patient Health Questionnaire-9 


  
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PP: 
Per Protocol 
PV: 
Pharmacovigilance 
PVD: 
Provoked vestibulodynia 
PVD1: 
Primary PVD subjects 
PVD2: 
Secondary PVD subjects 
SAP: 
Statistical and Analysis Plan  
SAE: 
Serious Adverse Event 
SAS®: 
Statistical Analysis System® 
SI: 
Standard International 
SDTM: 
Study Data Tabulation Model 
SOP: 
Standard Operating Procedure 
TEAE: 
Treatment Emergent Adverse Event 
WHO: 
World Health Organization 
 


  
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1 
INFORMATION TAKEN FROM THE PROTOCOL 
1.1 
Study objectives 
1.1.1 
Primary objective 
Stage 1 
The primary objective of the study is to assess the safety of increasing doses of 
Dysport in vulvodynia subjects with provoked vestibulodynia (PVD).  
Stage 2 
The primary objective of the study was to assess the efficacy of Dysport compared to 
placebo in vulvodynia subjects with PVD. However, the study was terminated before 
Stage 2 begins (please refer to Section 1.3.5). 
1.1.2 
Secondary objectives 
The secondary objectives of the study are as follows: 
Stage 1 
• 
To assess the efficacy of increasing doses of Dysport compared to placebo in 
vulvodynia subjects with PVD 
• 
To determine the doses of Dysport to be administered in Stage 2 
• 
To assess the sensitivity of the endpoints used in Stage 1 
Stage 2 
• 
To define the optimal doses of Dysport with an acceptable benefit/risk profile 
for the treatment of vulvodynia with PVD  
• 
To assess effect of Dysport on: 
- Vulvar pain  
- Use of pain rescue medication (type, dose and frequency) 
• 
To determine if primary and secondary PVD subjects benefit from Dysport 
administration 
• 
To assess the time to retreatment 
• 
To assess the safety of Dysport 
1.1.3 
Exploratory objectives 
The exploratory objectives of the study are as follows: 
• 
To assess effect of Dysport on: 
- Clinical Global Impression (CGI) of the treatment effect (assessed by the 
investigator)  
- Patient Global Impression of severity of the pain (PGI-S) and Patient Global 
Impression of change in pain (PGI-C) 
• 
Emotional response, cognitive response and associated life interference as 
assessed on modified Vulvar Pain Assessment Questionnaire (mVPAQ) 
subscales  
• 
Sexual function  
• 
To assess the efficacy of Dysport on the pelvic floor muscles pressure  
• 
To assess the efficacy of Dysport on depression  
• 
To assess the efficacy of Dysport on the quality of life 


  
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1.2 
Study design 
This is a Phase II multicentre, double-blind (DB), randomized, placebo-controlled, 
dose finding study to define the optimal doses of Dysport and evaluate its efficacy 
and safety compared to placebo in vulvodynia patients with PVD. Study treatment 
was injected at 5 needle insertion points at 10 injection sites in the vestibular area. 
The study consisted of a dose escalation stage (Stage 1) and a dose expansion stage 
(Stage 2). The purpose of the dose escalation was to determine the Dysport doses to 
be further investigated in Stage 2. Both Stage 1 and Stage 2 consisted of a DB period 
(treatment cycle 1; Dysport or placebo) followed by an open-label (OL) treatment 
period (treatment cycles 2 to 4; all subjects receive Dysport).  
However, the study was terminated before Stage 2 begins (please refer to Section 
1.3.5). 
 
1.3 
Methods and procedures 
1.3.1 
Schedule of assessments 
The schedule of procedures and assessments during the study is presented in section 
5.1 of the protocol. 
1.3.2 
Planned sample size 
In Stage 1, the expected sample size was 10 evaluable subjects for PVD2 (secondary 
PVD subjects, i.e. having a past history of pain free intercourse or insertion of any 
object >1 cm diameter) cohort to be randomized and treated in a 4:1 allocation ratio 
(Dysport or Placebo) and 8 evaluable subjects for PVD1 (primary PVD subjects, i.e. 
having life-long PVD) cohort 4 treated in a 3:1 allocation ratio (Dysport or Placebo). 
After Cohort 3 (PVD2) and Cohort 4 (PVD1), the expected sample size was 10 
evaluable subjects for additional PVD1 and PVD2 cohorts and treated in a 4:1 
allocation ratio (Dysport or Placebo). 
Subjects who discontinue prior to Week 6 for reasons unrelated to safety may be 
replaced at the discretion of the investigator and sponsor. As this is an exploratory 
stage, no formal power was performed. However, with 8 active subjects per PVD2 
dose cohort and if there are 0 dose limiting events (DLEs) in a cohort, there is at least 
80% probability that the true incidence of DLEs at the corresponding dose will not be 
greater than 18%. With 16 active subjects in PVD1 and PVD2 dose cohorts and if 
there are 0 DLEs in a cohort, there is at least 80% probability that the true incidence 
of DLEs at the corresponding dose will not be greater than 9%.  
 
1.3.3 
Method of Randomisation  
In stage 1, for the PVD2 cohorts, subjects were randomised with a 4:1 (Dysport: 
placebo) ratio. For the first PVD1 cohort, subjects were randomised with a 3:1 
(Dysport: placebo) ratio for Dysport 400 U and then for further PVD1 cohorts, 
subjects were randomised at 4:1 for Dysport 500 U and up to a maximum of 800 U. 
In an event, when the last subject in a cohort was being randomised, if an additional 
subject had been screened, this subject may be accepted in the cohort and be 
randomised. 
 


  
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1.3.4 
Validation scale study D-FR-52120-252 
The psychometric properties of the dilator-induced pain Numeric Rating Scale (NRS), 
dilator size 6 insertion pain NRS, pain on intercourse NRS, mVPAQ, and modified 
Female Sexual Function Index (mFSFI) were to be evaluated using data collected 
from all subjects randomized in Stage 1 and Stage 2. The planned analyses of these 
data are described in the Psychometric Analysis Plan of validation study D-FR-
52120-252. However, these analyses were cancelled following the decision to 
prematurely terminate the study. 
1.3.5 
Data review Committee and planned Analyses  
Data Review Committee  
A DRC has been established to make recommendations for dose escalation and dose 
de-escalation or study termination decisions in Stage 1. It was planned that (a) if no 
subject reports a clinically significant AE (defined in the protocol section 3.1.1.1) in 
a cohort, the DRC will meet once all PVD2 and PVD1 evaluable subjects of a dose 
level have reached Week 6 to review the unblinded efficacy and safety data and decide 
the dose for the next cohort or proceed to Stage 2; (b) If any subject reports a clinically 
significant AE, then further enrolment into the cohort as well as retreatment in open 
label cycles at the current dose will be suspended and an ad hoc DRC meeting will be 
scheduled to review the data and make a recommendation with regards to further 
conduct of the cohort and of Stage 1.  
Details related to DRC membership, responsibilities, procedures, role and remit are 
described in the DRC charter. 
 
Early Study Termination Decision 
Following the DRC meeting organized to review safety and efficacy data of cohorts 
1 to 6 on the 16 OCT 2020, the DRC sent the following recommendation:  
"No safety concerns noted in review of all available data. Efficacy cannot be assessed 
due to the small sample size of cohorts. The DRC would recommend that Stage 1 is 
not used to make an efficacy assessment, therefore there is no justification to increase 
the dose, nor to move to Stage 2."  
Ipsen subsequently decided to close the study early and to run the final analysis based 
on available Stage 1 data. Subjects in the study are followed until 12 weeks after the 
last dose as described in the protocol section 3.9.  
 
Final Analysis 
The final analysis will be carried out once all subjects from cohorts 1 to 6 have 
completed end of study evaluation, after the database lock. All unblinded safety and 
efficacy data available at the time of the database lock will be analysed. 
 
No control of the overall type I error rate is planned as only exploratory descriptive 
statistics are planned. 
 
2 
SUBJECT POPULATIONS (ANALYSIS SETS) 
Screened population 
The screened population is all subjects screened (i.e. who signed the informed 
consent). 


  
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Randomized population 
Randomized population is all subjects randomized (i.e. who were randomly allocated 
to a treatment group). 
modified Intent-To-Treat population 
The modified Intent-to-Treat (mITT) population is all randomized subjects who 
received at least one IMP administration and had data for the vaginal dilator induced 
pain as reported on an 11-point NRS [using the Dilator Maximum Tested Size 
(DMTS) reported at Baseline] at Baseline and Cycle 1-Week 6 visit (i.e. at least one 
pain score for one dilator size, which enables an imputed pain score of 10 at DMTS 
if needed). 
The mITT population will be analyzed using subjects as randomized. 
Active Treatment Population 
The Active Treatment Population is all randomized subjects who received at least one 
dose of Dysport (including only partial administration) during the DB and/or OL 
period. 
Safety 
The safety population is all randomized subjects who received at least one dose of 
IMP administration (including only partial administration). 
The safety population will be analyzed using subjects as treated (i.e. according to 
actual treatment received). 
 
3 
STATISTICAL METHODS 
3.1 
Statistical analysis strategy 
The statistical analyses will be performed in accordance with the ICH E9 guideline 
and will be based on the pooled data from the individual study sites, unless otherwise 
stated. 
Medpace will perform the statistical analysis of the efficacy, safety, and antibodies 
data. 
Overall, the analysis strategy is to evaluate safety and efficacy of Dysport compared 
to Placebo after single administration (DB period), and to evaluate efficacy and safety 
over repeated Dysport treatments, using analyses by Active Treatment Cycle. 
Listings will be presented by subject for DB and OL periods together while the tables 
associated with the DB period will be separated from the tables assessing repeat 
treatment with Dysport. 
Only descriptive statistics of Stage 1 data will be provided.  
Double-Blind Period (Stage 1 Cycle 1) Analyses 
For the analysis of the DB period, tables will be displayed using the following 
treatment group (DB treatment group) labels, in the following order: 
• 
Placebo: placebo groups from all cohorts will be pooled, including for mVPAQ 
pain, mVPAQ life interference and mFSFI pain domain of cohort 1 despite the 
change in recall period and time of assessments (see protocol version 3.0). 
• 
Dysport 
- 
Groups by dose (Dysport 100U, 300U, 400U, 500U, etc.) 
- 
All Dysport 


  
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Note: Cohort 1 (100U), 2 (300U), 3 (400U) and 5 (500U) included PVD2 subjects 
only. Cohort 4 (400U) and 6 (500U) included PVD1 subjects only. 
Repeat treatment: Active Treatment Analyses 
To assess efficacy and safety data over repeat treatments, data will be analysed using 
the Active Treatment Cycle approach as described in Figure 1 below. These analyses 
will be performed on the Active Treatment population:  
x for subjects treated with Dysport in the DB period, the first cycle in the DB 
period will be the first Active Treatment Cycle.  
x for subjects treated with placebo in the DB period, the first cycle in the OL 
period will be the first Active Treatment Cycle.  
Figure 1 Active Treatment Cycle Analysis 
 
Three types of summary tables will be produced: 
x Summary by number of active treatment cycles: these tables will present the 
long-term efficacy and safety data with all doses combined, and will display 
subjects with at least 1 (2, 3 and 4) active treatment cycles.  
x Summary by dose received at each active treatment cycle: to evaluate the 
safety of each dose at a given cycle.  
x Summary over the whole trial (restricted to Week 6 and 12 from DB and from 
first OL period) by the randomised treatment group (DB treatment group) may 
be provided for some efficacy analyses. 
 
The type of summary table(s) used for each endpoint are described in sections 3.8 
and 3.9.  
 
 
Descriptive Statistics 
All raw and derived variables will be listed and described using summary statistics. 
For categorical variables, summary statistics will be displayed by frequency counts 
and percentages by category. The missing category will be presented if there is at least 
one missing data in a treatment group. Except otherwise specified, subjects with 
missing data will be included in the calculation of percentages. For quantitative 


  
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variables, summary statistics will be displayed using descriptive statistics by number 
of observations, mean, standard deviation (SD), median, minimum and maximum.  
 
3.1.1 
Multiplicity 
No multiple testing will be performed. 
3.1.2 
Significance testing and estimation 
As this is a descriptive safety study, no formal statistical testing will be carried out 
based on Stage 1 data. 
3.1.3 
Withdrawal visit and end of study visit 
Subjects who have withdrawn early from the study have their last assessment (during 
early withdrawn visit) mapped as visit 90 in the Study Data Tabulation Model 
(SDTM). By convention, for these subjects, the visit number will be reassigned to the 
next empty visit number for analysis (i.e. if a subject has only Visit 1, 2, 3 and 90 
entered in the database, the visit number 90 will be reassigned to visit number 4). End 
of study visits will be described separately as “End of Study (Cycle X)”. 
 
3.2 
Subject disposition and population 
The following disposition summaries and listings will be provided: 
x Number and percentages of randomized subjects per country and site by DB 
treatment group. 
x Number and percentages of subjects screened, screen failed and reason for 
screen failure, randomized, treated, completed, withdrawn and reason for 
withdrawal by DB treatment group. 
x Listing of date of visit. 
x Listing of screen failure subjects. 
x Listing of withdrawn subjects (on the randomised population). 
 
The following population summaries and listings will be provided: 
x Number and percentage of subjects in each analysis population with reasons 
for exclusion from each population, for the DB treatment group and overall, 
based on all randomized subjects. 
x Listing of randomization details. 
x Listing of subjects who don’t meet eligibility criteria (violated inclusion 
criteria, fulfilled exclusion criteria).  
x Listing of subjects including flag for each analysis population and reason 
for exclusion from each population. 
 
3.3 
Protocol Deviations 
A list of major protocol deviations and any action taken have been defined in the 
Protocol Deviation Plan. Subjects with major protocol deviations will be determined 
before database lock and unblinding of the study. A final review will be done during 
the blind data review and documented in the protocol deviation listing. Confirmation 
of major deviations related to treatment and dose will be done after unblinding.   
Number and percentage of subjects with major protocol deviations will be 
summarized by deviation category for all randomized subjects. A Listing of major 


  
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protocol deviations will also be provided. COVID-19 related protocol deviations will 
be flagged.  
3.4 
Demographic and Baseline characteristics 
All demographic and Baseline characteristics (including the Pain Catastrophizing 
Scale total score) will be listed by treatment group, and subject for the randomised 
population. The Pain Catastrophizing Scale total score is calculated as the sum of the 
13 items, ranging from 0 to 52. 
Summary statistics will be provided for demographic and Baseline characteristics, by 
DB treatment group, for the Randomized, and mITT populations. 
Q-tip test results will be listed for all screened subjects. 
No statistical comparison of the treatment groups will be provided.  
3.5 
Medical and surgical history 
Medical and surgical history, non-drug therapies and surgical procedures will be 
coded using the latest version of MedDRA at the time of the database lock. 
Listings will present the primary system organ class, preferred term and verbatim text. 
The listings will be sorted by DB treatment group, subject, primary system organ 
class, preferred term and verbatim text.  
A frequency table of the number and percentage of subjects will be provided for all 
medical and surgical history by primary system organ class and preferred term. The 
table will be presented by DB treatment group for the randomised population. 
 
3.6 
Prior and concomitant therapies 
Prior and concomitant therapies will be coded using WHO-Drug Dictionary, the latest 
version at the time of database lock. The therapeutic class will correspond to the 
second level of ATC code. 
 
Medication, non-drug therapies, physiotherapies, sex therapies and surgical 
procedures start and stop dates will be compared to the date of the first IMP 
administration to allow classification as either Prior (P) only or Concomitant (PC, C): 
 
Prior (P) 
Start and stop dates prior to the date of the first IMP 
administration. 
Prior and 
Concomitant (PC) 
Start date before the date of the first IMP administration 
and stop date on or after the date of the first IMP 
administration. 
Concomitant (C) 
Start date on or after the date of first IMP administration. 
 
Summary tables on prior medications/non-drug therapies/surgical procedures will 
include “P” only, summary tables on concomitant medications/non-drug 
therapies/surgical procedures will include “C” and “PC”.  
 
A treatment will be considered concomitant to a cycle if the start date was on or before 
the IMP administration for the cycle and the stop date was on or after the IMP 
administration for the cycle. A treatment can be concomitant under more than one 
treatment cycle, but it will be considered as concomitant only once in the overall 
period. 
 


  
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The following summaries will be provided: 
- 
number and percentage of subjects with prior medication (category P) by 
ATC class and Preferred Name (PN, ATC level 2),  
- 
number and percentage of subjects with concomitant medication (categories 
PC, C) by ATC class and PN (ATC level 2),  
- 
number and percentage of subjects with prior non-drug therapy (category P) 
by SOC and PT, 
- 
number and percentage of subjects with concomitant non-drug therapy 
(categories PC, C) by SOC and PT, 
- 
number and percentage of subjects with prior pelvic floor physical 
therapy (category P) by SOC and PT, 
- 
number and percentage of subjects with concomitant pelvic floor physical 
therapy (PC, C) by SOC and PT, 
- 
number and percentage of subjects with prior sex therapy (category P) by 
SOC and PT, 
- 
number and percentage of subjects with concomitant sex therapy (categories 
PC, C) by SOC and PT, 
- 
number and percentage of subjects with concomitant surgical procedures by 
primary SOC and PT. 
All these tables will be presented during the DB period by DB treatment group for the 
randomized population. In addition, tables related to concomitant medications/ 
therapies/ surgical procedures will be presented during Active Treatment period all 
doses combined by Active Treatment Cycle and overall, for the Active Treatment 
population. 
Listings will be provided for all the summaries listed above with the therapeutic class, 
preferred term/name and verbatim text. The level of concomitance will also be 
presented (P, PC, C).  
A listing of prohibited concomitant medications and a listing of pain rescue 
medications will also be provided. 
The listings will be sorted by DB treatment group, subject, chronological start date, 
primary system organ class/therapeutic class, preferred term/name and verbatim 
name.  
 
3.7 
Subject compliance 
A listing will be presented for drug administration (volume administered, specified 
difficulties during drug administration, injection sites, date) at all treatment cycles by 
DB treatment group and subject. 
 
3.8 
Efficacy analysis 
The efficacy endpoints will be summarized using the analysis strategy in Section 3.1. 
Descriptive statistics will be provided for: 
x the DB period, by DB treatment group for the mITT population.  
x the Active Treatment Cycle, on the Active Treatment population: by number 
of active treatment cycles (all doses combined and/or by dose). The mITT 
population will be the primary population for analysis of efficacy data. Week 
6 and Week 12 will be the timepoints of primary interest.  
 


  
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3.8.1 
Primary efficacy analysis 
Not applicable as the primary objective of Stage 1 is related to safety. 
 
3.8.2 
Secondary efficacy analyses 
 
Vestibular pain using a vaginal dilator 
A set of 8 vaginal dilators of increasing diameter (#1 being the smallest and #8 being 
the largest) will be used to provoke pain to allow assessment of the vestibular pain 
intensity in each subject. Subjects will be required to rate the pain for each dilator size 
on an 11-point NRS at each visit. Pain score will be entered by the investigator (or 
delegated site staff) in the eCRF.  
Based on the subjective pain threshold, the largest sized dilator that the subject accepts 
to test, will be defined as the Dilator Maximum Tested Size (DMTS) that will be 
established at the Baseline Visit. The dilator test will be used to assess the change 
from Baseline in the vaginal dilator induced pain as reported on an NRS (using the 
DMTS reported at baseline) as well as the dilator size that provokes maximum pain. 
If a dilator size is not tested due to pain intensity, the pain will be scored at 10. If the 
test is not done due to other reasons, then the pain score will be considered as missing. 
Endpoints and corresponding analyses are described in Table 1. 
 
Table 1 
Dilator Induced Pain - Endpoints and Corresponding Analyses 
Endpoint 
Analyses 
Mean 
change 
from 
Baseline to each post-
treatment visit in the 
vaginal dilator induced 
pain as reported on the 
11-point NRS[1] 
Convention: 
According to the mITT Population definition, there will 
be no missing data for Week 6. For Week 12, the missing 
values will be kept as missing.  
 
- descriptive statistics: actual values and change from 
baseline values will be presented at all timepoints (over 
the double-blind and open-label periods). A plot of 
mean changes over time from baseline in pain scores 
will be provided by treatment group for DB period. 
 
Active Treatment Cycle:  
- A summary by number of active treatment cycles.  
- A plot of mean changes over time from baseline in 
pain scores will be provided by randomized treatment 
group for Week 6 and Week 12 over both of the DB and 
first OL period. 
 
Proportion of subjects 
who reported at least a 
50% 
decrease 
in 
vaginal dilator induced 
pain as reported on the 
11-point NRS[1] at 
each 
post-treatment 
Convention: 
According to the mITT Population definition, there will 
be no missing data for Week 6. For Week 12, the missing 
values will be kept as missing.  
 
- descriptive statistics will be presented at all timepoints.  
 


  
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visit (repeat for 30% 
decrease) 
Active Treatment Cycle:  
- A summary by number of active treatment cycles will 
be used. 
Proportion of subjects 
who reported at least 2-
point decrease from 
baseline 
in 
vaginal 
dilator pain as reported 
on the 11-point NRS[1] 
at each post-treatment 
visit 
Mean 
change 
from 
Baseline to each post-
treatment visit in the 
dilator 
size 
that 
provokes 
maximum 
tolerated pain 
- descriptive statistics: actual values and change from 
baseline values will be presented at all timepoints.  
- Number and percentage of each size will be provided 
at all timepoints. 
 
Active Treatment Cycle:  
- A summary by number of active treatment cycles will 
be used. 
 
Mean change from 
Baseline to each post-
treatment visit in the 
composite score for 
the vaginal dilator 
induced pain and 
dilator size 
 
Composite score derivation: 
The composite score for the vaginal dilator induced pain 
and dilator size is the sum of all pain measurements 
across the full range of dilator sizes. In the construction 
of this endpoint, the pain score will be 10 for any dilator 
size that is beyond the DMTS. As described in section 
3.10.1, there should be at least 6 pain scores (recorded by 
the investigator) to calculate the composite score. When 
there is a dilator size score missing, pain score will be 
imputed by the average of the previous (smaller dilator 
size) and the following (larger dilator size) valid values. 
For example, if the pain score for dilator size 4 is missing, 
then it will be imputed by the average of the pains scores 
for dilator size 3 and size 5 when both of them are 
available. 
 
- descriptive statistics: actual values and change from 
baseline values will be presented at all timepoints.  
 
Active Treatment Cycle:  
- A summary by number of active treatment cycles will 
be used.  
[1] Using DTMS at baseline. 
 
Pain during insertion of vaginal dilator number 6 size 
Cohort 1: once a week during the Screening period (Day -14 to Day 1), and once a 
week during the month (28 days) prior to the next planned visit, all subjects are to 
rate pain following insertion of the number 6 vaginal dilator (11-point NRS) and to 
record details of associated pain medication if consumed. Data are recorded in the 
patient’s eDiary. 


  
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Cohort 2 onwards: once a week during the 2 weeks preceding the next planned visit, 
all subjects are to rate pain following insertion of the number 6 vaginal dilator (11-
point NRS) and to record details of associated pain medication if consumed. Data are 
recorded in the patient’s eDiary. 
Endpoints and corresponding analyses are described in Table 2. 
 
Table 2 
Dilator #6 - Endpoints and Corresponding Analyses 
Endpoint 
Analyses 
Mean 
change 
from 
Baseline to each post-
treatment visit in pain 
during 
insertion 
of 
vaginal dilator number 
6 size as reported on 
the 11-point NRS 
 
Convention: 
Average of the values over the last 2 weeks preceding the 
visit. The average will be missing if and only if the two 
pain scores are both missing. This rule will be applicable 
for all cohorts including cohort 1. 
 
- descriptive statistics: actual values and change from 
baseline values will be presented at all timepoints.  
 
 
Active Treatment Cycle:  
- A summary by number of active treatment cycles will 
be used. 
Proportion of subjects 
who reported at least a 
50% decrease in pain 
during insertion of 
vaginal dilator number 
6 size as reported on 
the 11-point NRS at 
each post-treatment 
visit (repeat for 30% 
decrease) 
Convention: 
Average of the values over the last 2 weeks preceding 
the visit. The average will be missing if and only if the 
two pain scores are both missing. This rule will be 
applicable for all cohorts including cohort 1. 
 
- descriptive statistics will be presented at all timepoints.  
 
 
Active Treatment Cycle:  
- A summary by number of active treatment cycles will 
be used. 
Proportion of subjects 
who reported at least 
2-point decrease from 
baseline at each post-
treatment visit 
Proportion of subjects 
taking pain rescue 
medication associated 
with insertion of 
- descriptive statistics: number and percentage of subjects 
using pain rescue medication within the 2 weeks period 
preceding each visit, in subjects with non-missing pain 
score value in the corresponding period. 
 


  
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vaginal dilator number 
6 size. 
Active Treatment Cycle:  
- A summary by number of active treatment cycles will 
be used. 
 
Subjects having taken pain rescue medication associated 
with insertion of vaginal dilator will be listed, along with 
period, medication (primary system organ class, 
preferred term and verbatim text), name, number of pills, 
dosage of each pill, route, date, taken before/after the 
dilator insertion and pain during the dilator insertion in 
the corresponding week. 
 
 
Frequency of intercourse and pain during intercourse 
Cohort 1: Each day during the Screening period (Day -14 to Day 1), and during the 
month (28 days) preceding the next planned visit, subjects are to record in the eDiary 
if they had intercourse, the number of intercourse instances, corresponding pain 
during each intercourse instance (using an 11-point NRS) and details of pain rescue 
medication, if taken, to prevent or treat vestibular pain. 
Cohort 2 onwards: Each day during the Screening period and during the 2-week 
period preceding the next planned visit, subjects are to record if they had intercourse, 
the number of intercourse instances, corresponding pain during each intercourse 
instance on an 11-point NRS and details of pain rescue medication, if taken, to prevent 
or treat vestibular pain.  
Intercourse diary entry with no intercourse in the previous 24 hours and pain score 
entered as 0 will be considered as no intercourse in the previous 24 hours. Entry with 
no intercourse in the previous 24 hours and pain score different from 0 will be 
considered as an intercourse entry with the entered pain score. 
Endpoints and corresponding analyses are described in Table 3. 
 
Table 3 
Intercourse -  Endpoints and Corresponding Analyses 
Endpoint 
Analyses 
Mean 
change 
from 
baseline to each post-
treatment visit in the 
pain during intercourse 
as reported on the 11-
point NRS 
 
Conventions: 
Analysis of pain will be done on the subjects who had 
intercourse in the corresponding period. 
 
Average pain score over the week preceding the visit: 
The weekly average will be calculated as the average of 
the score over the last week (7 days) prior to the visit, for 
all cohorts (including cohort 1).  The weekly average will 
be calculated if at least 1 pain score has been recorded 
over the considered week.  
 
Average pain score over the 2 weeks preceding the visit: 
The 2-week average will be calculated as the average of 
the score over the last 2 weeks (14 days) prior to the visit, 
for all cohorts (including cohort 1). The 2-week average 
will be calculated if at least 1 pain score has been 
recorded in the considered 2-week period. 


  
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- descriptive statistics: actual values and change from 
baseline values will be presented at all timepoints.  
In the same table, number of subjects with or without 
partner at each timepoint will be also presented. 
 
 
Active Treatment Cycle:  
- A summary by number of active treatment cycles will 
be used. 
Mean 
change 
from 
baseline to each post-
treatment visit in the 
number of intercourse 
instances in subjects 
with partners 
Conventions: 
Analysis will be done on the subjects who have a partner 
at baseline and at the specific visit (DB Week 6, or Week 
12). 
Number of intercourse instances over the week preceding 
the visit 
The number of intercourse instances over the week 
preceding the visit will be calculated as the total number 
of intercourse instances over 7 days prior to the visit. 
There should be at least 1 eDiary input recorded in the 
week for calculating the number of intercourse instances 
over the period, otherwise it will be considered missing. 
 
Number of intercourse instances over the 2 weeks 
preceding the visit 
The number of intercourse instances over the 2 weeks 
preceding the visit will be calculated as the total recorded 
number of intercourse instances over 14 days prior to the 
visit. There should be at least 1 eDiary input recorded in 
the period for calculating the number of intercourse 
instances over the period, otherwise it will be considered 
missing. 
 
- descriptive statistics: actual values and change from 
baseline values will be presented at all timepoints.  
 
Active treatment cycle:  
- A summary by number of active treatment cycles will 
be used.  
 
Proportion of subjects 
having taken pain 
rescue medication 
associated with 
intercourse 
- descriptive statistics: number and percentage of subjects 
using pain rescue medication within the 1-week/2-week 
period preceding each visit, in subjects with non-missing 
pain score value in the corresponding period.  
 
Active Treatment Cycle:  
- A summary by number of active treatment cycles will 
be used. 
 


  
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Subjects having taken pain rescue medication associated 
with intercourse will be listed, along with period, 
medication (primary system organ class, preferred term 
and verbatim text), name, number of pills, dosage of each 
pill, route, date, taken before/after the intercourse 
instance and pain during the intercourse in the 
corresponding week. 
 
 
 
3.8.3 
Exploratory efficacy analyses  
 
Clinical Global Impression (CGI) and Patient Global Impression (PGI) 
 
Endpoints and corresponding analyses are described in Error! Reference source not 
found.. 
CGI was assessed by the investigator using a 7-point Likert scale during the visit. 
PGI-S and PGI-C: Subjects were to assess PGI-S and PGI-C in the eDiary one week 
prior to the next planned visit and at the visit. The outcome for the visit will be 
calculated as the average of a) the average of the entries on the date of the visit (in 
case of several entries on the day of the visit) and b) the average of the entries within 
the week prior to the visit (in case of several entries). 
Table 4 
CGI and PGI - Endpoints and Corresponding Analyses 
Endpoint 
Analyses 
Mean score of CGI 
- descriptive statistics will be presented at all timepoints. 
 
Active treatment cycle:  
- A summary by number of active treatment cycles will be 
used. 
Mean change from 
baseline 
to 
each 
post-treatment visit 
in the PGI-S  
 
- descriptive statistics: actual values and change from 
baseline values will be presented at all timepoints.  
 
Active treatment cycle:  
- A summary by number of active treatment cycles will be 
used. 
Mean PGI-C at each 
post-treatment visit  
- descriptive statistics will be presented at all timepoints. 
 
Active treatment cycle:  
- A summary by number of active treatment cycles will be 
used. 
 
 
mVPAQ and mFSFI 
 
Endpoints and corresponding analyses are described in Table 5.  
mVPAQ questionnaire is provided in protocol Appendix 1. It contains 6 subscales: 
pain severity, emotional response, cognitive response, life interference, sexual 


  
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function interference, self-stimulation/penetration interference. The subscale score is 
the average of the item scores under the subscale.  
For mVPAQ, the analysis of life interference subscale will be done with and without 
the item ‘ability to fall asleep’. The analysis of pain severity subscale will be done 
with and without the items ‘unpleasantness’ and ‘distress’. All these items will be 
included/excluded together when calculating subscale score.  
For mVPAQ pain subscale, life interference subscale and mFSFI pain domain: 
Subjects were to record in the e-diary the data related to the completion of these 
questionnaires in the eDiary one week prior to the next planned visit and at the visit. 
The subscale scores for the visit will be calculated as the average of a) the average of 
the subscale scores entered on the date of the visit and b) the average of the subscale 
scores entered within the week prior to the visit.For other mVPAQ subscales and 
mFSFI domains, data were recorded by the subject at the site during the visit.  
 
Table 5 
mVPAQ and mFSFI -  Endpoints and Corresponding Analyses 
Scales 
Endpoints 
Analyses/ Conventions 
Modified Vulvar 
Pain Assessment 
Questionnaire 
(mVPAQ) – Pain 
severity subscale 
 
Change from 
baseline in each 
question and 
subscale score 
The score for each question ranges 
from 0 to 4 and a mean score is 
computed. 
- descriptive statistics: actual values 
and change from baseline values will 
be presented at all timepoints.  
 
Modified Vulvar 
Pain Assessment 
Questionnaire 
(mVPAQ) – Life 
interference 
subscale 
 
Change from 
baseline in each 
question and 
subscale score 
The score for each question ranges 
from 0 to 4 and a mean score is 
computed. 
- descriptive statistics: actual values 
and change from baseline values will 
be presented at all timepoints.  
 
Modified Vulvar 
Pain Assessment 
Questionnaire 
(mVPAQ) – other 
subscales 
 
Change from 
baseline in each 
subscale score 
The score for each question ranges 
from 0 to 4 and a mean score is 
computed. 
- descriptive statistics: actual values 
and change from baseline values will 
be presented at all timepoints.  
 
modified Female 
Sexual Function 
Index (mFSFI) – 
pain domain 
 
Change from 
baseline in each 
question and total 
score 
See Table 6 for domain and total score 
calculation. 
- descriptive statistics: actual values 
and change from baseline values will 
be presented at all timepoints. 
 
Modified Female 
Sexual Function 
Index (mFSFI) – 
other domains 
 
Change from 
baseline total 
score in each 
domain 
See Table 6 for domain and total score 
calculation. 
- descriptive statistics: actual values 
and change from baseline values will 
be presented at all timepoints. 
 


  
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modified Female 
Sexual Function 
Index (mFSFI) – 
all domains 
 
Change from 
baseline in mFSFI 
total score. 
See Table 6 for domain and total score 
calculation. 
- descriptive statistics: actual values 
and change from baseline values will 
be presented at all timepoints.  
 
Pelvic floor 
muscles pressure – 
Resting and 
Squeezing 
Mean change from 
baseline in the 
pelvic floor 
muscles pressure 
for the 2 
conditions: 
- Resting vaginal 
pressure 
- Maximal 
’squeeze’ 
pressure, 
and the difference 
between the 2 
conditions 
(squeeze minus 
rest condition) 
 
Conventions: 
The mean of the 3 measurements will 
be used. The mean will be missing if 
and only if the 3 measurements are 
missing. 
An assessment will be invalidated if 
the measurement is not accurate as 
specified by the investigator or if 
subject had a vaginal delivery. 
Difference of the mean between 
Squeeze and rest conditions will be 
calculated. 
 
- descriptive statistics: actual values 
and change from baseline values will 
be presented at all timepoints.  
 
Patient Health 
Questionnaire 
(PHQ-9) 
 
Change from 
baseline in the 
PHQ-9 total score 
See Appendix 3 from protocol for 
total score definition. PHQ-9 
questionnaire comprises 9 items, each 
of which is scored 0 to 3, providing a 
0 to 27 total score. (If several entries 
are available on the date of visit, the 
average of the total score will be used) 
 
- descriptive statistics: actual values 
and change from baseline values will 
be presented at all timepoints.  
 
36-Item Short 
Form Health 
Survey (SF-36) 
 
 
Change from 
baseline in all 8 
domains scores, 
and the 2 
components 
(physical and 
mental) 
The eight dimensions of SF-36 and the 
Physical and Mental component will 
be derived by OPTUM. 
 
- descriptive statistics: actual values 
and change from baseline values will 
be presented at all timepoints.  
 
 


  
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Table 6. mFSFI Score Calculation 
 
Note: The individual domain scores and full scale (overall) score of the FSFI can be derived 
from the computational formula outlined in the table above (Rosen etc 2000). For individual 
domain scores, add the scores of the individual items that comprise the domain and multiply 
the sum by the domain factor. Add the six domain scores to obtain the full-scale score. It 
should be noted that within the individual domains, a domain score of zero indicates that the 
subject reported having no sexual activity during the recall period. 
 
3.9 
Safety 
For the DB period, summary tables by DB treatment group will be provided on the 
Safety population. 
For the Active Treatment Cycle, summary tables by number of active treatment cycles 
will be provided on the Active Treatment population. Additionally, a summary table 
will be also provided by dose received at each active treatment cycle on the Active 
Treatment population. 
 
The summary tables will follow the strategy specified in Section 3.1.  
 
3.9.1 
Extent of exposure  
 
To describe the duration of exposure, three durations of exposure will be calculated. 
- 
Duration of study treatment exposure will be defined in weeks as: 
 (The date of last visit attended – treatment cycle 1 injection date + 1) / 7. 
- 
Duration of treatment cycle will be defined in days as: 
For subjects who are retreated at the end of the cycle, the duration of treatment 
cycle is calculated as (date of retreatment) - (treatment injection date). 
For subjects who are not retreated at the end of the cycle, the duration of treatment 
cycle is calculated as (last attended visit date of the treatment cycle) – (treatment 
injection date) + 1. 
- 
Duration of Active Treatment exposure will be defined in weeks as: 
 (The date of last visit attended – first Dysport injection date + 1) / 7. 
 
The following summary tables will be provided: 
x Description of study treatment exposure by DB treatment group + overall 
subjects on the safety population for DB period and overall subjects for the 
whole active treatment periods. 
Study treatment exposure will be described both as a quantitative and 
qualitative variable.  


  
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x Description of duration of treatment cycle, for each treatment cycle, dose 
received of each treatment cycle and overall subjects from the safety 
population. 
x Description of duration of treatment cycle, by dose received at the cycle and 
all doses combined on the active treatment population. 
Active Treatment exposure will be described both as a quantitative and 
qualitative variable for each period of exposure. 
x A summary table with the total number of subjects who received 1, 2 or 3 
active treatment cycles and the total number of subjects who received at least 
1, 2 or 3 active treatment cycles, all doses combined on Active treatment 
population and by DB treatment group + overall subjects. 
 
To describe the doses received, the following summary tables will be provided: 
x Description of the actual dose received in each cycle by DB treatment group 
and overall subjects from the safety population. 
The number and percentage of subjects receiving the actual dose will be 
provided. 
x Description of the actual dose at each active treatment cycle, by treatment 
received for the active treatment cycle and overall subjects from the safety 
population. 
The number and percentage of subjects receiving the actual dose will be 
provided for each active cycle. 
x A listing of exposure data will also be provided. 
 
3.9.2 
Adverse events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) latest version (23.0 or later) and presented by MedDRA preferred term 
and system organ class. 
AEs will be classified as treatment-emergent AEs (TEAEs) according to the rules 
below: 
• 
Events with start date (and time) on or after the date (and time) of first IMP 
administration.  
• 
Events whose severity worsens on or after the date (and time) of first IMP 
administration. 
A TEAE that occurs under a particular treatment cycle and worsens in intensity under 
a different treatment cycle will be considered as treatment emergent under the two 
treatment cycles. In the event of another occurrence of a TEAE with a change in 
intensity under a different treatment cycle, the subject will also be counted in that 
different treatment cycle. A given AE will be assigned to the dose received prior to 
the onset of the AE in the designated treatment cycle.  
An overall summary table of all adverse events will be presented (as described in 
Section 3.9) and include the following: 
• 
Subjects with any TEAEs, 
• 
Subjects with any TEAEs by maximum intensity, 
• 
Subjects with any TEAEs related to IMP, 
• 
Subjects with any TEAEs related to IMP by maximum intensity, 
• 
Subjects with any TEAEs leading to drug withdrawal,  
• 
Subjects with any SAEs, 


  
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• 
Subjects with any TEAEs leading to death, 
• 
Subjects with any SAEs related to IMP, 
• 
Subjects with any TEAEs of special interest (AESIs). 
This summary table will be also be provided by dose received at each active treatment 
cycle. 
All TEAEs will be summarized with the number and percentage of subjects with 
adverse events classified by primary system organ class and preferred term. The 
number of occurrences of a TEAE will also be presented. This summary table will 
also be provided by dose received at each active treatment cycle. 
 
Summary tables will also be presented by SOC and PT for SAEs, TEAEs by intensity, 
TEAEs by causality, and non-serious TEAEs with at least 2 subjects. TEAEs will also 
be summarized by decreasing overall PT frequency 
If the intensity or causality is missing for a TEAE, it will be considered as missing in 
the summary tables. In the event of multiple TEAE being reported by the same subject 
within the same SOC/PT, the maximum intensity (severe > moderate > mild > 
missing) and the most serious causality (related > not related > missing) will be 
chosen. 
Listings will be presented and sorted by DB treatment group, subject ID, start date of 
AE, primary system organ class, preferred term and verbatim text for all adverse 
events recorded during the study. Other information collected, such as end date and 
outcome of AE, will be provided in the listings. 
Listings of SAE, adverse events leading to discontinuation from the study, clinically 
significant events, adverse events leading to drug withdrawal and death will also be 
presented. 
TEAEs will be identified in the adverse events listings. Pre-treatment AEs and 
clinically significant AEs will also be flagged in the AE listings. 
 
Adverse Events of Special Interest (AESIs) 
Adverse events of special interest (AESIs) for Dysport in this study are defined as: 
• 
Any TEAE that suggests a possible remote spread of effect of the toxin, or 
• 
Any TEAE related to urinary incontinence or faecal incontinence, or 
• 
Any TEAE assessed as a potential hypersensitivity reaction, 
where there is a reasonable possibility of causal relationship with treatment with 
Dysport, regardless of the investigator reported causality. 
The method described below is used for identification and analysis of events that may 
be qualified as TEAEs that suggest a possible remote spread of effect of the toxin, 
events related to incontinence or faecal incontinence or events suggestive of 
hypersensitivity like reactions. 
TEAEs due to possible remote spread of the effects of Dysport will be identified using 
the list of MedDRA preferred terms (PTs) compatible with the mechanism of action 
of BTX-A and based on the recommendations from the Committee for Medicinal 
Products for Human Use (CHMP) and the Food and Drug Administration (FDA). 
TEAEs potentially representing hypersensitivity reactions will be identified using the 
Standardised MedDRA Query (SMQ) (narrow search query) for hypersensitivity 
reactions. TEAEs that are possibly related to urinary incontinence or faecal 
incontinence will also be identified using the list of MedDRA preferred terms.  
The list of MedDRA preferred terms used to identify any potential AESI is provided 
in AESIs MeDDra.xlsx. 


  
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All TEAEs identified using the search strategy described above will be medically 
evaluated during the study before the database lock and unblinding, by the sponsor to 
identify events which could possibly represent “remote spread of effect of toxin”, or 
which are suggestive of “related to urinary incontinence or faecal incontinence” or 
“hypersensitivity reactions” due to study treatment administration. Events will be 
disregarded as an AESI if they are confounded by the presence of alternative clinical 
aetiologies (medical history, concomitant medication or diagnosis which could 
account for the symptoms); if they are considered to be local effects instead of distant 
spread, as judged by the site of injection; the time period between the last study 
treatment administration and event onset is not in accordance with the expected 
mechanism of action; or due to insufficient information/evidence to make an 
assessment. 
In the summary data tabulations and listings, only the final list of AESIs confirmed 
by the sponsor as “a possible remote spread event”, “hypersensitivity reactions” or 
“urinary incontinence and faecal incontinence” will be taken into account.  
Besides the AESI listing, a summary table of AESI will be presented by SOC and PT 
(as described in Section 3.9) and include the following: 
• 
Subjects with any AESI suggesting a possible remote spread of effect of the 
toxin, 
• 
Subjects with any AESI related to urinary incontinence or faecal incontinence,  
• 
Subjects with any AESI assessed as a potential hypersensitivity reaction. 
 
3.9.3 
Laboratory data 
All laboratory data will be presented in the units of International System of Units (SI).   
 
The following summaries will be provided: 
• 
A summary of the actual and change from baseline in each laboratory parameter 
by treatment group and timepoint,   
• 
A summary of the number and percentage of subjects experiencing Potentially 
Clinically Significant Abnormalities (PCSA). PCSA criteria for laboratory 
parameters are defined in appendix 2, 
For PCSA table, the denominator should be the number of subjects with both a 
baseline and a post-baseline assessment at a given timepoint. 
 
In addition, the following listings will be provided: 
• 
A listing of all laboratory data. Out-of-reference-range values will be flagged as 
high (H), low (L), clinically significant [C]. Any unscheduled laboratory 
assessments will be flagged as such in the listings. 
• 
Laboratory reference ranges, 
• 
A listing will present all values of the parameter for a subject with at least a 
clinically significant abnormal value for hematology and biochemistry. 
• 
A listing of PCSA. All data for a laboratory parameter will be displayed for a 
subject having at least one post-baseline PCSA (with flag indicating PCSA). 
• 
A listing will present the urine drug screening and urine pregnancy test. 
• 
A listing will be provided for subjects with abnormal result of drug abuse test. 


  
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Any clinically significant laboratory result abnormalities observed during the study 
will be reported as AEs. 
3.9.4 
Vital signs 
Vital signs were recorded at the Screening Visit. A listing of vital sign data by 
treatment group, with unscheduled vital signs flagged. 
Any clinically significant vital sign abnormalities observed during the study will be 
reported as AEs.  
3.9.5 
Physical examination 
Physical examination was done at the Screening Visit. Date of exam and overall 
assessment will be listed and sorted by DB treatment group, and subject ID, with 
unscheduled physical examination flagged. 
Any clinically significant physical examination finding observed during the study will 
be reported as AEs. 
3.9.6 
Antibodies 
The following definitions will be considered: 
• 
Seroconverters are subjects with ADA titer ≤1 for antibody at baseline and 
ADA titer > 1 post-treatment.  
• 
Seroreverters are subjects which ADA titer > 1 at baseline and ADA titer <= 
1 post-treatment.  
• 
Treatment boosted ADA are subjects with ADA titer > 1 at baseline that were 
boosted to a higher-level following IMP administration (the ADA titer is 
greater than 100 times the baseline titer). 
• 
Incidence is defined as the proportion of seroconverters or treatment-boosted 
subjects.  
 
The following conventions will be considered: 
- Percentage of seroconverters and incidence should be calculated using the number 
of subjects with a baseline and at least one ADA assessment post-treatment. 
- Percentages of seroreverters and Treatment boosted ADA should be calculated using 
the number of subjects with ADA titer > 1 at baseline and at least one ADA 
assessment post-treatment. 
 
The following summaries of ADA data will be provided:  
• 
An overall summary of ADA status for binding and neutralizing with: 
- 
number and percentage of baseline results with titer > 1, 
- 
quartiles of the titer range, 
- 
number of seroreverters, 
- 
number of treatment-boosted, 
- 
number and percentage of seroconverters, 
- 
incidence. 
 
A shift table from baseline to EOS/EW visit with the number and percentage of 
subjects separately for binding and neutralising ADA will be provided. 
 
The following listings should be provided: 


  
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• 
A listing of any ADA data, including baseline BTX status (if the subject has 
previously received any treatment with BTX), and the status and titer for 
binding ADA and titer for neutralizing ADA,  
• 
An overall ADA status of each subject, 
• 
A listing for all subjects with binding ADA results with titer > 1 post baseline. 
This listing will include the combined information about baseline BTX status, 
primary efficacy results and TEAEs, 
• 
A listing for all subjects with neutralizing ADA results with titer > 1 post 
baseline. This listing will include the combined information about baseline 
BTX status, primary efficacy results and TEAEs, 
 
3.10 
Missing data and other data issues 
3.10.1 
Missing data 
For vestibular pain using a vaginal dilator, if a dilator size is not tested due to pain 
intensity, the pain will be scored at 10. If the test is not done due to other reasons, 
then the pain score will be considered as missing.  
When calculating the composite score for the vaginal dilator induced pain and dilator 
size, there should be at least 6 pain scores (recorded by the investigator) to calculate 
the composite score. When missing, pain score will be imputed by the average of the 
previous (smaller dilator size) and the following (larger dilator size) valid values. For 
example, if the pain score for dilator size 4 is missing, then it will be imputed by the 
average of the pains scores for dilator size 3 and size 5 when both of them are 
available. 
For mVPAQ, Pain Severity should have at least 4 (out of 6) valid inputs; Emotional 
Response should have at least 10 (out of 15) valid inputs; Cognitive Response should 
have at least 5 (out of 8) valid inputs; Life Interference should have at least 7 (out of 
11) valid inputs; Sexual Function Interference should have at least 7 (out of 10) valid 
inputs; Self-Stimulation/Penetration Interference should have at least 3 (out of 5) 
valid inputs. The not applicable “N/A” entries are considered as valid inputs. 
For mFSFI, Desire domain should have at least 2 (out of 2) valid inputs; Arousal and 
Lubrication domains should have at least 3 (out of 4) valid inputs; Orgasm, 
satisfaction and Pain domains should have at least 2 (out of 3) valid inputs. There 
should be at least 4 (out of 6) non missing domain scores to calculate the total score. 
For PHQ-9, there should be at least 6 (out of 9) valid inputs to calculate the total score.  
When calculating scores/subscale scores from questionnaires (e.g, mVPAQ mFSFI, 
and PHQ-9), the missing item value will be ignored, and the scores computed will be 
scaled to have the same possible maximum score as for the whole questionnaire (by 
dividing the possible maximum score based on questions with non-missing values 
and multiplying the possible maximum score for the whole questionnaire). 
 
3.10.2 
Missing or incomplete dates 
In all listings, missing or incomplete dates should be left as they have been recorded. 
However, for calculation / sorting / assignation based on dates, the following methods 
will be used: 
The most conservative approach will be systematically considered (i.e. if the onset 
date of an AE/concomitant medication is missing / incomplete, it is assumed to have 
occurred during the study treatment phase (i.e. a TEAE for AEs) except if the partial 
onset date or other data [stop date, …] indicates differently). 


  
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• 
A missing/incomplete date of medical history or disease diagnosis will be 
assumed to have occurred before any study treatment, 
• 
A medication with partial start and stop dates will be considered as concomitant 
treatment, except if the partial dates indicate differently, 
• 
If an AE or SAE onset date is partial or missing, the event will be allocated to 
the first treatment where onset could have occurred (taking into account date and 
time stopped), 
• 
If the start date of a medication is partial or missing, the medication will be 
assigned to the most recent treatment received on or before the medication start 
date (taking into account date stopped). 
Where this is possible, the derivations based on a partial date will be presented as 
superior inequalities (i.e.: for an AE started in FEB2004 after the administration 
performed on 31JAN2004, the days since last dose will be “≥2”, similarly the duration 
of ongoing AEs or medication will be “≥xx” according to the start and last visit dates). 
 
If the date of diagnosis for provoked vestibulodynia is partial, the duration of 
provoked vestibulodynia will be calculated as follow: 1) If only day is missing, only 
month and year will be used in calculation. 2) If month is missing, only year will be 
used in calculation. 3) No imputation should be done at the data level.  
3.11 
Derived data 
The derived data are variables which are calculated from the raw data in the eCRF 
and not included in the database.  
The following derived data will be calculated and included in the listings: 
(1) 
Age  
Subject age (years) will be derived as (screening year – birth year). 
(2) 
BMI  
BMI (kg/m2) will be derived as Weight (kg)/[Height(cm)/100]2. 
(3) 
Changes from Baseline  
Changes from Baseline will be calculated as a difference from Baseline (e.g. 
assessment at the visit – assessment at Baseline). 
(4) 
Adverse event duration 
The AE duration = AE end date - AE start date + 1. If the start and end dates of the 
adverse event are identical then “<1” day will be presented, otherwise, it will be 
calculated as (end date - start date)+1 and presented in days. If the recorded end date 
is CONT. (for continuing), the end date will be listed as “ongoing” and the duration 
will be approximated as “≥(last attended visit date – start date)+1” day(s). If the start 
date or the end date are partial the duration will be presented as a superior inequality 
“≥xx” day(s) [i.e.: ≥2 where start date=31JAN2004 and end date=FEB2004 or start 
date=JAN2004 and end date=01FEB2004].  
(5) 
Concomitant therapy duration 
The duration of concomitant treatments/physiotherapy etc. will be calculated as (end 
date - start date) +1.   If the recorded end date is CONT. (for continuing) then the end 
date will be listed as “ongoing” and the duration will be approximated as “≥(last 
attended visit date – start date)+1” day(s). If the start date or the end date are partial, 
the duration will be presented as an inequality “≥xx” day(s) [i.e.: ≥2 where start 
date=31JAN2004 and end date=FEB2004 or start date=JAN2004 and end 
date=01FEB2004] but if both are partial or one is missing the duration will not be 
presented. 
(6) 
Study day 


  
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Study day will be defined as ‘-1’ for the day prior to first study drug administration 
and as ‘1’ for the day of first study drug administration (i.e. day 0 does not exist).  
(7) 
Study Baseline 
Baseline is defined as the last value, or the derived value specified for the parameter, 
available prior to the first study IMP treatment administration (i.e. prior to the DB 
period). Baseline for the active dysport cycle analysis will be the same as Baseline 
for the DB period, i.e., Baseline of the first study cycle. 
(8) 
Treatment cycle day 
For events within the ith cycle, the treatment cycle day = date of event - (date of (i)th 
injection) +1.  
 
3.12 
Rules and data formats 
Data will be presented using an appropriate number of decimal places (i.e. the number 
of decimal places used does not imply undue precision).  Raw data will be presented 
to the number of decimal places collected, and derived data will be presented to an 
appropriate number of decimal places. The appropriate number of decimal places will 
be determined by general practice, mathematical rationale or scientific rationale (e.g. 
age should be presented in whole numbers).  
Mean, median, standard deviation and standard errors of the mean (SE) values will 
be reported to one decimal place greater than the raw/derived data that they 
summarize. Minimum and maximum values will be reported with the same precision 
as the raw data. 
Percentages will be reported to one decimal place and 0% will not be presented. 
Percentages will be calculated using a denominator of all subjects in a specified 
population. The denominator will be specified in a footnote to the tables for 
clarification if necessary.  
Percentiles (e.g., 25%, 75%) should be presented to one decimal place more than the 
raw/derived data. 
Lower and upper confidence interval values should be presented to one decimal place 
more than the raw/derived data (i.e., to the same number of decimal places as the 
mean). 
P-values will be reported to four decimal places (e.g.: p=0.0037), after rounding. P-
values which are less than 0.0001 will be presented as ‘<0.0001’. 
All values below or above a limit of detection (e.g. <0.1 or >100) will be listed as 
such.  
All text fields must be left justified and numeric or numeric with some text 
specification (e.g.: not done, unknown, <4.5, …) must be decimal justified. Dates will 
be presented in the format [ddmmmyyyy] and times in the format [hh:mm]. 
3.13 
Pooling of Centres 
A subgroup analysis on individual or groups of centres will not be performed. 
3.14 
Covariates and analysis of subgroups 
The following statistical analyses by pain onset subtype (randomization stratification 
factor) will be done: 
x Demographics and baseline characteristics will be summarized by pain onset 
subtype, in the mITT population. 
x Descriptive statistics for the change from Baseline to Week 6 and Week 12 in 
the vaginal dilator induced pain as reported on an 11-point NRS (using the 


  
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DMTS reported at Baseline) will be provided by pain onset subtype (primary 
and secondary PVD) on the mITT population for DB period.  
x Descriptive statistics for the change from Baseline to Week 6 and Week 12 in 
the dilator size that provokes maximum tolerated pain will be provided by 
pain onset subtype (primary and secondary PVD) on the mITT population for 
DB period.  
x An overall adverse events summary will be done; TEAEs and SAEs will be 
described by SOC and PT for DB period (please refer to Section 3.9 for more 
details on the summary strategy).  
3.15 
COVID-19 impact  
The e-CRF was amended in order to collect data related to COVID-19 impact. These 
will be summarized as described thereafter. 
 
Disposition 
To assess the impact of COVID-19 pandemic on the trial, the following summaries 
will be provided: 
x Proportion of subjects impacted and withdrawn due to COVID-19 
pandemic.  
o the reasons of discontinuation related to COVID-19 will be 
presented separately. 
o the number of subjects exposed as well as impacted or infected will 
also be presented. 
x Number of subjects with visits impacted by COVID-19 with the 
corresponding reason. 
o the number of subjects per visit as well as the number of subjects 
with a missing visit per timepoint. 
o the number of visits impacted due to COVID-19 with the reasons 
will be presented to assess the impact of COVID-19. 
 
Demographic and Baseline characteristics 
Summary statistics will be provided for demographic and Baseline characteristics, by 
DB treatment group in subjects recruited (based on informed consent date) before and 
after (inclusive) the start of COVID-19 pandemic [i.e. 27-Jan-2020 based on date 
when the Public health emergency was declared by Health and Human Services] in 
order to identify a potential change in the general subject’s characteristics. 
 
Exposure 
To assess the impact of COVID-19 pandemic on the trial, the time elapsed between 
injections will be described for injections done before and after the start of COVID-
19 pandemic (27-Jan-2020), which will be presented by cycle and one subject will be 
counted once per cycle and period. Any cycle that ongoing on 27-Jan-2020 or after 
27-Jan-2020 will be considered as cycle after the start of COVID-19 pandemic. 
 
 


  
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4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS 
4.1 
Software 
All tables, listings and figures will be produced and statistical analysis performed 
using SAS version 9.4.   
4.2 
Validation programs 
Medpace will provide a Validation Plan to Ipsen identifying the methods of 
validation.  
Copies of the internal QC forms produced for the validation process and Medpace’s 
sign-off forms will be provided to the sponsor to support the validation. 
4.3 
Restitution of the programs 
All programs (including Macros and analysis datasets) producing the tables, listings 
and statistical output along with associated logs should be given to the sponsor when 
the tables, listings, figures and statistical analysis has been finalised. 
 
5 
CHANGES FROM PROTOCOL 
5.1.1 
Schedule of assessments 
The descriptive analysis to evaluate/describe any possible centre effect in protocol 
(section 11.4.4) is removed due to the small sample size. 
5.1.2 
Data Analyses Timepoints 
The intermediate and primary analyses will not be performed. All analyses related to 
Stage 2 will not be performed since the study was terminated before Stage 2 begins. 
Please refer to Section 1.3.5 for more details. 
5.1.3 
COVID-19 Pandemic Start Date 
The date 27-Jan-2020, when public health emergency was declared by Health and 
Human Services in the US, is used instead of the date specified in the protocol (i.e., 
when first subject randomised in Cohort 6) in order to describe any possible impact 
of COVID-19 pandemic on subjects followed-up in all cohorts, including during the 
open-label cycles. 
5.1.4 
Per Protocol (PP) population 
No Per Protocol population will be defined as it was planned for the analysis of Stage 
2 and the study was terminated before Stage 2 begins. Stage 1 efficacy analyses 
consist in descriptive only on the mITT population. 
 


  
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6 
REFERENCES 
1. 
Rosen, C. Brown, J. Heiman, S. Leiblum, C. Meston, R. Shabsigh, D. 
Ferguson, R. D'Agostino, R. The Female Sexual Function Index (FSFI): a 
multidimensional self-report instrument for the assessment of female sexual 
function. Journal of sex & marital therapy 2000; 26(2): 191-208. 
 
 


  
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7 
APPENDICES 
7.1 
Appendix 1: List of PCSA criteria 
 
PCSA for blood chemistry parameters: 
Parameter 
PCSA 
ALT/SGPT 
≥ 3 x ULN U/L 
AST/SGOT 
≥ 3 x ULN U/L 
GGT 
≥ 3 x ULN U/L 
ALP (Alkaline Phosphatase) 
≥ 1.5 x ULN U/L or ≥ 3 x ULN U/L 
Creatinine 
≥ 150 μmol/L (Adults) 
Blood Urea Nitrogen 
> 10 mmol/L 
Chloride 
≤ 90 mmol/L 
≥ 115 mmol/L 
Calcium 
<1.75 mmol/L 
>3 mmol/L 
Sodium 
<130 mmol/L 
> 150 mmol/L 
Potassium 
<2.5 mmol/L 
>6 mmol/L 
Total cholesterol 
> 6.22 mmol/L 
Triglycerides 
> 2.26 mmol/L 
HbA1c 
> 8% 
Albumin 
≤ 25 g/L 
Direct bilirubin 
> 2 ULN μmol/L 
Total bilirubin 
> 2 ULN μmol/L 
Phosphate 
< 0.75 mmol/L 
> 1.8 mmol/L 
Total protein 
< 40 g/L 
 


  
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PCSA for haematology parameters: 
Parameter 
PCSA 
White blood cell 
≤ 2.8 10^9/L 
≥ 16 10^9/L 
Red blood cell 
< 3 10^12/L 
> 6 10^12/L 
Hematocrit 
≤ 0.32 and 0.03 decrease from baseline L/L (female) 
≤ 0.37 and 0.03 decrease from baseline L/L (male) 
Lymphocytes 
< 0.3 10^9/L 
> 11.0 10^9/L 
Neutrophils 
< 1 10^9/L 
> 13 10^9/L 
Monocytes 
> 2.3 10^9/L 
Basophils 
> 10^9/L 
Eosinophils 
> 10^9/L 
Hemoglobin 
≤ 95 g/l (female) 
≤ 115 g/l (male) 
Platelet count 
<75.1 10^9/L 
≥ 700 10^9/L