Conditions: Chronic Scar Pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 16
Healthy volunteers: no

Brief summary:
The study is designed to determine whether a currently licensed version of botulinum toxin (Dysport®) is effective for the treatment of pain that has developed and/or persisted for months or years around the scar of a previous surgical site, and whether this condition could be suitable for the testing of similar new medicines. The study will compare three different doses of Dysport® to see if there is benefit and/or a best dose for treating persistent post-surgery scar pain.

Detailed description:

Arms:
arm 1: Crossover run-in part A - Subjects will be injected (Test 1) with either saline or local anaesthetic (lidocaine). One week later, they will be crossed over, injected with the other agent (Test 2). arm 2: Dysport dose 1 as a single-dose, intradermal injection. arm 3: Dysport dose 2 as a single-dose, intradermal injection. arm 4: Dysport dose 3 as a single-dose, intradermal injection. arm 5: Placebo single-dose, intradermal injection.

Interventions: intervention 1: Lidocaine intervention 2: Botulinum toxin type A intervention 3: Placebo intervention 4: Placebo
Intervention descriptions: intervention 1: 0.5 mL (2.5 mg) of lidocaine per injection point will be injected subcutaneously (maximum 10 injection points). intervention 2: 0.2 mL of one of three different doses of Dysport per injection point will be injected intradermally (maximum 10 injection points). intervention 3: Part A - 0.5 mL of sodium chloride solution 0.9% (saline solution) per injection point will be injected subcutaneously (maximum 10 injection points). intervention 4: Part B - 0.2 mL of sodium chloride solution 0.9% (saline solution) per injection point will be injected intradermally (maximum 10 injection points, 2,0 mL maximum).

Protocol document:
Prot_000.pdf: 
 
 
 
 
Study number D-FR-52120-244 - Protocol version 3.0 - Date: 04 December 2018 
Page 1 of 89 
 
STUDY PROTOCOL 
 
A double-blind, randomised, placebo controlled, proof-of-concept study 
in subjects with abdominal or thoracic chronic scar pain to assess 
the analgesic properties of intradermal doses of Dysport® 
 
Study Number D-FR-52120-244 
Protocol Version 3.0, dated 04 December 2018 
 
EUDRACT Number 2018-001703-37 
IND Serial Number Not applicable 
 
 
Sponsor: 
Ipsen Innovation SAS 
ZI de Courtaboeuf 
5 avenue du Canada 
91966 Les Ulis Cedex, France 
 
 
Serious Adverse Event Reporting: 
Fax: 
 
Email: 
 
 
 
Emergency Contact: 
 Ipsen Innovation SAS 
ZI de Courtaboeuf, 5 avenue du Canada, 91966 Les Ulis Cedex, France 
Phone: 
 
Mobile: 
(for emergencies) 
 
The person listed above is the qualified physician designated by the sponsor as the first point 
of contact for emergency situations. 
 
 
Persons supplied with this information must understand that it is strictly confidential. 
Information contained herein cannot be disclosed, submitted for publication or used for any purpose other 
than that contemplated herein without the sponsor’s prior written authorisation
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
Study number D-FR-52120-244 - Protocol version 3.0 - Date: 04 December 2018 
Page 2 of 89 
 
Sponsor Authorised Protocol Approver 
Name, Title: 
 
 
Sponsor Medical Monitor 
Qualified physician designated by the sponsor who is responsible for all study-site related 
medical decisions (if other than investigator). 
Name, Title: 
 
Address: 
IPSEN Biopharm Ltd, 102 Park Drive, Milton Park, Oxfordshire, OX14 4RY, 
England 
Phone: 
 
Mobile: 
 
Email: 
 
 
Sponsor Clinical Pharmacologist 
Name, Title: 
 
Address: 
Ipsen Innovation SAS, 5 avenue du Canada, 91966 Les Ulis Cedex, France 
Phone: 
 
Mobile: 
 
Email: 
 
 
Principal Investigator 
Name, Title: 
 
 
Address: 
St Pancras Clinical Research, 285-287 Gray’s Inn Road, London WC1X 8QD, 
England 
Phone: 
 
Mobile: 
 
Email: 
 
 
Project Management and Monitoring Office 
Address:  
Aepodia France SARL, ZI de Courtaboeuf, 3 avenue du Canada, 91940 Les Ulis, 
France 
Phone:  
 
Fax: 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


PPD
PPD
PPD
PPD


 
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Study number D-FR-52120-244 - Protocol version 3.0 - Date: 04 December 2018 
Page 4 of 89 
 
SYNOPSIS 
Sponsor name 
Ipsen Innovation SAS 
Name of finished product 
Dysport® 
Name of active ingredient 
Clostridium botulinum toxin type A haemagglutinin complex (BTX-A-HAC) 
Title of the study 
A double-blind, randomised, placebo controlled, proof-of-concept study in 
subjects with abdominal or thoracic chronic scar pain to assess the analgesic 
properties of intradermal doses of Dysport® 
Sponsor study number 
D-FR-52120-244 
EUDRACT number 
2018-001703-37 
IND serial number 
Not applicable 
Phase of development 
Type of study 
Phase 2 
Proof-of-concept 
Number of planned centres 
One site in the United Kingdom (UK) 
Objectives 
Primary 
• 
To describe the pharmacodynamic analgesic profile (time of onset of 
meaningful analgesic effect, peak-effect, time to peak-effect, duration of 
effect) of intradermal doses of Dysport in subjects with abdominal or 
thoracic chronic scar pain. 
Secondary 
• 
To compare the efficacy of intradermal doses of Dysport to placebo. 
• 
To assess the safety and tolerability of a range of intradermal doses of 
Dysport. 
Exploratory 
• 
To explore improvement of quality of life (QoL) using SF-36 
questionnaire. 
• 
To explore concomitant use of rescue medication (analgesia). 
Study design 
The study will consist of two sequential parts, the first being to identify subjects 
who will potentially benefit from intradermal Dysport injection, ‘responders’, 
who will then progress to the second part, which is the double-blind study of the 
intradermal injection of Dysport or placebo:  
• 
Part A: A double-blind, randomised, initial two-period cross-over run-in 
part, extended screening period of placebo or local anesthetic (lidocaine), 
• 
Part B: A single-dose, double-blind, randomised, parallel part with one of 
the three different doses of Dysport or placebo. 
To ensure subjects will potentially benefit from intradermal injection of Dysport, 
they will be tested for responsiveness to local anaesthetic (lidocaine). 
In Part A, and upon consent and successful screening of medical eligibility, 
subjects will be injected (injection test 1) during a pre-randomisation run-in period 
in a double blind fashion with either saline or local anaesthetic (lidocaine) and 
assessed for pain perception up to 24 hours post-injection. One week later, they 
will be crossed over, injected with the other agent (injection test 2) and assessed 
for pain perception up to 24 hours post-injection. Pain intensity will be scored 
using a 11-point numerical rating scale (NRS) (from score 0 for “no pain” up to 
10 for “worst possible pain”). 
If subjects are assessed as responders, they will enter in Part B, and will be trained 
and provided with an Actiwatch® to enable them to record their spontaneous NRS 
scores. 
Before dosing on Day 1, the subjects will perform baseline assessments including: 
• 
diaryassessing allodynia, hyperalgesia and conditioned pain modulation, 
• 
Completion of a QoL questionnaire, 


 
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Study number D-FR-52120-244 - Protocol version 3.0 - Date: 04 December 2018 
Page 5 of 89 
 
• 
Safety assessments (physical examination, vital signs measurements, 
collection of adverse events (AEs) and recording of concomitant 
medication). 
Subjects will be dosed if considered as consistent in pain perception from the 
screening visit (i.e. variability < 2 for the average spontaneous NRS score 
pre-injection tests in Part A, pre-QST and pre-dosing, and clinically plausible as 
per investigator’s judgement). 
Subjects will then be assessed for pharmacodynamics and safety for up to 
16 weeks post-dose. 
Subjects will be discharged from the study after safety assessments (physical 
examination, vital signs) during an end of study (EoS) visit. 
Planned number of subjects 
Approximately 24 subjects are expected to be randomised in Part B into four arms, 
each with six subjects treated with either one dose of Dysport or placebo. 
Subjects who withdraw within the first six weeks after investigational medicinal 
product (IMP) dosing will be replaced. Replacement subjects will receive the 
same schedule and treatment as the subject they have replaced. 
Approximately 60 subjects are expected to enter the Part A to reach the targeted 
randomised subject number in Part B. 
Eligibility criteria 
Inclusion criteria 
(1a) 
Male and female subjects aged between 18 and 75 years inclusive at the 
time of giving informed consent. 
(2) 
Subjects suffering from an area of chronic pain post-abdominal or thoracic 
surgery, chronic abdominal or thoracic scar pain. 
(3) 
Longitudinal axis of the pain area of 10 cm long maximum (as mapped 
upon screening). 
(4) 
Subjects with moderate to severe pain, i.e. spontaneous NRS score of 4-8 
which has been stable for the previous month before screening. 
(5) 
Stable use of analgesics (or any medication impacting pain perception) 
during the month before screening and expected to be stable for the study 
duration. 
(6) 
Under stable medication regimen for other medication, i.e. during the 
month before screening. 
(7a) 
Time from surgery which caused the painful scar more than six months 
and less than ten years at screening. 
(8) 
No other distracting pain either chronic or acute. 
(9) 
Female subjects of childbearing potential must have a negative urine 
pregnancy test result and be willing to use reliable contraceptive measures 
throughout study participation. Reliable forms of contraception include 
but are not limited to hormonal contraceptives (e.g. oral, patch, injection), 
double-barrier (e.g. male condom plus spermicide, or female diaphragm 
plus spermicide), intrauterine device, male partner has had a vasectomy, 
total abstinence from intercourse with male partners (periodic abstinence 
is not acceptable). Female subjects meeting any of the following criteria 
are not considered to be of childbearing potential: postmenopausal 
(≥ 47 years of age and amenorrhoeic for at least 12 consecutive months), 
have been sterilised surgically (e.g. bilateral tubal ligation), have had a 
hysterectomy, have had a bilateral oophorectomy. 
(10) 
The subject’s primary care physician has provided evidence which can be 
used to confirm that within the last 12 months of dosing that there is 
nothing in their medical history that would preclude their enrolment into 
a clinical study. 
Exclusion criteria 
(1) 
Previous treatment with BTX (any serotype) during the past six months 
before screening. 


 
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Study number D-FR-52120-244 - Protocol version 3.0 - Date: 04 December 2018 
Page 6 of 89 
 
(2) 
History of hypersensitivity to any of the components of the Dysport 
formulation (which includes human serum albumin and lactose) or allergy 
to cow's milk protein. 
(3) 
Known hypersensitivity to lidocaine or other anaesthetics of the amide 
type, known hypersensitivity to hydroxybenzoates, complete heart block, 
hypovolaemia. 
(4) 
Any medical condition that may put the subject at risk with exposure to 
BTX, including diagnosed myasthenia gravis, Eaton-Lambert syndrome, 
amyotrophic lateral sclerosis, or any other disease that might interfere with 
neuromuscular function. 
(5) 
Opioid analgesic use at a Morphine Equivalent Dosage (MED) of >75mg 
per day. 
(6) 
Neuroma in the scar pain area, diagnosed per ultrasound. 
(7) 
Use of agents that could interfere with neuromuscular transmission, 
including calcium channel blockers, penicillamine, aminoglycosides, 
lincosamides, polymixins, magnesium sulphate, anticholinesterases, 
succinylcholine and quinidine. 
(8) 
Need of any prohibited medication. 
(9) 
Any abnormal laboratory value, physical examination, vital signs, or 
electrocardiogram (ECG) that, in the opinion of the investigator, is 
clinically significant and that would compromise the safety of the subject 
in the study. 
(10) 
Positive for hepatitis B antigen or hepatitis C virus ribonucleic acid, 
positive results for human immunodeficiency virus, or who receives 
diagnosis for acquired immunodeficiency syndrome. 
(11) 
Positive urine screen for drugs of abuse (except for cotinine and unless 
explained by the investigator for therapeutic use of medication) or any 
history of drug or alcohol abuse, misuse, physical or psychological 
dependence, mood changes, sleep disturbance and functional capacity 
which have an impact on pain perception. 
(12) 
Significant neurological or psychiatric disorders including mental 
instability (unrelated to the pain) that could interfere with pain 
assessments; other pre-existing pain syndromes, acute or chronic, that 
might impair the assessment of the scar pain. 
(13) 
Any medical history of significance and/or inadequately controlled such 
as cardiovascular (e.g. uncontrolled high blood pressure, high risk of 
cardiovascular events, severe heart failure), pulmonary (e.g.  uncontrolled 
asthma or emphysema), heamatologic, (e.g. coagulopathy/bleeding 
disorders), neurological (e.g. swallowing problems, blurred or double 
vision, trouble saying words clearly (dysarthria), hoarseness or change or 
loss of voice (dysphonia)), liver disease (e.g. severe hepatic impairment), 
kidney disease (e.g. impaired renal function in subjects taking diuretics, 
angiotensin converting enzyme (ACE)-inhibitors, or angiotensin II 
antagonists), endocrine, immunologic, dermatologic painful conditions or 
any other conditions that may compromise in the opinion of the 
investigator the ability of the subject to participate in the study. 
(14) 
If in the investigator’s opinion there are any factors that may confound the 
analysis of the study regarding efficacy and safety (e.g. NRS > 9). 
(15) 
Previous randomisation in this study. 
(16) 
Subjects who participated in a clinical research study involving a new 
chemical entity or an experimental drug within 30 days before screening. 
(17) 
Subjects who are incapable of complying with the protocol in the 
judgment of the investigator. 
Agent: 
Route, strength, regimen for 
Lidocaine hydrochloride 0.5% v/w solution for injection in 10-mL ampoules. 


 
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Study number D-FR-52120-244 - Protocol version 3.0 - Date: 04 December 2018 
Page 7 of 89 
 
the pre-randomisation 
run-in period (Part A) 
0.5 mL (2.5 mg) of lidocaine per injection point will be injected subcutaneously 
(maximum 10 injection points). 
Placebo agent: 
Route, strength, regimen for 
the pre-randomisation 
run-in period (Part A) 
Sterile and preservative-free sodium chloride solution 0.9% v/w solution for 
injection (saline) 10-mL ampoules. 
0.5 mL of saline solution per injection point will be injected subcutaneously 
(maximum 10 injection points). 
Treatment: 
Route, strength, regimen for 
the randomised 
double-blind period 
(Part B) 
Dysport will be supplied as a white lyophilised powder in a vial containing 500 U 
of BTX-A-HAC. 
0.2 mL of 2.5, 10 or 20 U of Dysport per injection point will be injected 
intradermally (maximum 10 injection points, 200 U maximum). 
Placebo treatment: 
Route, strength, regimen for 
the randomised 
double-blind period 
(Part B) 
Placebo will be supplied as a white lyophilised powder in a vial containing the 
excipients from Dysport. 
0.2 mL of Dysport placebo per injection point will be injected intradermally 
(maximum 10 injection points). 
Criteria for evaluation 
(endpoints) for the 
randomised double-blind 
period 
Pharmacodynamics 
• 
Time to onset, i.e. time to decrease from baseline of two points in the 
spontaneous NRS score, 
• 
Peak-effect, i.e. maximal decrease from baseline in the spontaneous NRS 
score, 
• 
Time to peak-effect, i.e. time to reach the peak-effect, 
• 
Duration of effect, i.e. duration between time to onset and last timepoint 
with change from baseline in the spontaneous NRS score is ≥ two points, 
• 
Change from baseline in the spontaneous NRS score to each scheduled 
timepoint, 
• 
Change from baseline in the stimulus-evoked NRS score to each 
scheduled timepoint. 
Safety and tolerability 
• 
Monitoring of treatment emergent AEs (TEAEs) and concomitant 
medications, 
• 
Changes from baseline in physical examination findings (including 
examination of the scar at the injection sites) and vital signs recordings at 
each scheduled timepoint. 
Exploratory 
• 
Change from baseline in SF-36 scores at each scheduled timepoint, 
• 
Amount of rescue medication taken during the study, 
• 
Time to first intake of rescue medication. 
Statistical methodology 
This is an exploratory study to assess how Dysport might be of benefit in chronic 
pain. An appropriate sample size cannot be determined statistically as insufficient 
human data are available from previous clinical trials. Approximately 24 subjects 
(six subjects per treatment arm) will be randomised in the double-blind period 
(Part B). Subjects who withdraw within the first six weeks after IMP dosing for 
reasons other than lack of efficacy will be replaced. Only descriptive statistics will 
be provided. 


 
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Page 8 of 89 
 
TABLE OF CONTENTS 
 
RATIONALE FOR PROTOCOL AMENDMENT # 2 ...................................................... 12 
LIST OF DEFINITIONS AND ABBREVIATIONS........................................................... 15 
1 
BACKGROUND INFORMATION ............................................................................ 18 
1.1 
Introduction ................................................................................................................... 18 
1.2 
Name and Description of the Investigational Medicinal Product ............................ 19 
1.3 
Non-Clinical Data ......................................................................................................... 19 
1.4 
Clinical Data .................................................................................................................. 20 
1.5 
Rationale for the Study ................................................................................................. 20 
1.6 
Dosage Selection ............................................................................................................ 20 
1.7 
Population to be Studied .............................................................................................. 21 
1.8 
Known and Potential Risks to Human Subjects ........................................................ 21 
2 
STUDY OBJECTIVES ................................................................................................. 23 
2.1 
Primary Objective ......................................................................................................... 23 
2.2 
Secondary Objectives ................................................................................................... 23 
2.3 
Exploratory Objectives ................................................................................................. 23 
3 
INVESTIGATIONAL PLAN ...................................................................................... 24 
3.1 
Overall Study Design and Plan .................................................................................... 24 
3.2 
Study Endpoints ............................................................................................................ 25 
3.2.1 
Primary Endpoints ...................................................................................... 25 
3.2.2 
Secondary Endpoints .................................................................................. 25 
3.2.3 
Exploratory Endpoints ................................................................................ 25 
3.3 
Study Duration .............................................................................................................. 25 
3.4 
Randomisation and Blinding ....................................................................................... 26 
3.4.1 
Method of Randomisation .......................................................................... 26 
3.4.1.1 
Pre-randomisation Run-in Period (Part A) ................................................. 26 
3.4.1.2 
Randomised Double-blind Period (Part B) ................................................. 26 
3.4.2 
Blinding ....................................................................................................... 27 
3.4.3 
Code-break .................................................................................................. 27 
3.5 
Stopping Rules and Discontinuation Criteria ............................................................ 28 
3.6 
Source Data Recorded on the Case Report Form ...................................................... 28 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 29 
4.1 
Inclusion Criteria .......................................................................................................... 29 
4.2 
Exclusion Criteria ......................................................................................................... 29 
4.3 
Rationale for Specific Inclusion / Exclusion Criteria ................................................ 30 
4.4 
Withdrawal of Subjects ................................................................................................ 31 
5 
STUDY CONDUCT ...................................................................................................... 32 
5.1 
Study Schedule of Assessments .................................................................................... 32 
5.2 
Study Visits and Procedures ........................................................................................ 32 
5.2.1 
Screening ..................................................................................................... 32 


 
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5.2.1.1 
Informed Consent ......................................................................................... 32 
5.2.1.1 
Screening Procedures .................................................................................. 32 
5.2.2 
Pre-randomisation Run-in Period (Part A) ............................................... 32 
5.2.3 
Randomised Double-blind Period (Part B) ................................................ 33 
5.2.3.1 
Baseline visit ................................................................................................ 33 
5.2.3.2 
Randomised Period ...................................................................................... 33 
5.2.4 
Early Discontinuation or End of Study Visit ............................................. 34 
5.3 
Lifestyle Restrictions .................................................................................................... 34 
5.3.1 
Diet ............................................................................................................... 34 
5.3.2 
Alcohol ......................................................................................................... 34 
5.3.3 
Physical Activity .......................................................................................... 34 
5.3.4 
Prohibited Concomitant Medications and non Drugs Therapies ............. 34 
5.4 
Priority Order on Study Procedures ........................................................................... 35 
6 
TREATMENT OF SUBJECTS ................................................................................... 36 
6.1 
Study Drug(s) ................................................................................................................ 36 
6.1.1 
Dosage Form and Strength ......................................................................... 36 
6.1.1.1 
Agents for the Pre-randomisation Run-in Period (Part A) .......................... 36 
6.1.1.2 
IMP for the Randomised Double-blind Period (Part B) .............................. 36 
6.1.2 
Supplies ........................................................................................................ 36 
6.1.3 
Packaging and Labelling ............................................................................ 37 
6.1.4 
Storage ......................................................................................................... 37 
6.1.5 
Dispensing, Treatment and Administration Procedure ............................. 37 
6.1.6 
Accountability .............................................................................................. 38 
6.2 
Rescue Medication ........................................................................................................ 38 
6.3 
Concomitant Medications ............................................................................................ 39 
6.4 
Subject Compliance Monitoring .................................................................................. 39 
7 
SAFETY ASSESSMENTS ........................................................................................... 40 
7.1 
Adverse Events .............................................................................................................. 40 
7.1.1 
Definition of an Adverse Event .................................................................. 40 
7.1.2 
Adverse Events Categorisation, Recording, and Follow-up ...................... 40 
7.1.2.1 
Assessment of Expectedness ......................................................................... 41 
7.1.2.2 
Follow-Up of Adverse Events ...................................................................... 41 
7.1.2.3 
Reporting of Adverse Events ........................................................................ 41 
7.1.3 
Serious Adverse Event Assessment and Reporting to Sponsor ................. 41 
7.1.4 
Suspected Unexpected Serious Adverse Reactions .................................... 43 
7.1.5 
Pregnancy .................................................................................................... 43 
7.1.6 
Adverse Events of Special Interest ............................................................. 43 
7.1.7 
Deaths .......................................................................................................... 43 
7.1.8 
Reporting to Competent Authorities, IECs/IRBs and other Investigators 43 
7.2 
Specific Safety Assessments ......................................................................................... 44 
7.2.1 
Physical examinations ................................................................................ 44 


 
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7.2.2 
Vital Signs ................................................................................................... 44 
7.2.3 
Electrocardiograms ..................................................................................... 44 
7.2.4 
Clinical laboratory tests .............................................................................. 45 
7.2.4.1 
Blood Analyses ............................................................................................. 45 
7.2.4.2 
Urinalysis ..................................................................................................... 45 
7.2.4.3 
Pregnancy Test ............................................................................................. 45 
7.2.4.4 
Drug of Abuse .............................................................................................. 45 
7.2.5 
Scar Ultrasound .......................................................................................... 46 
8 
PHARMACOKINETIC ASSESSMENTS ................................................................. 47 
9 
PHARMACODYNAMIC ASSESSMENTS ............................................................... 48 
9.1 
Numerical Rating Scale ................................................................................................ 48 
9.1.1 
Spontaneous Average and Worst Pain NRS Score during the Screening 
Visit .............................................................................................................. 48 
9.1.2 
Spontaneous Current Pain NRS Score in Part A ...................................... 48 
9.1.3 
Spontaneous Average and Worst Pain NRS Score in Part B .................... 49 
9.2 
Stimulus-evoked NRS Score during Quantitative Sensory Testing ......................... 49 
9.2.1 
Light Touch ................................................................................................. 49 
9.2.2 
Pressure (Pressure Pain Threshold) .......................................................... 49 
9.2.3 
Temperature ................................................................................................ 50 
9.3 
Area of Pain ................................................................................................................... 50 
10 
EXPLORATORY ASSESSMENTS ............................................................................ 51 
10.1 Quality of Life questionnaire Short Form-36 ............................................................. 51 
10.2 Rescue Medication ........................................................................................................ 51 
11 
STATISTICAL ANALYSES ....................................................................................... 52 
11.1 Analyses Populations .................................................................................................... 52 
11.2 Sample Size Calculation ............................................................................................... 52 
11.3 Statistical Methods ........................................................................................................ 52 
11.3.1 
Safety Evaluation ........................................................................................ 52 
11.3.1.1 
Pre-randomisation Run-in Period (Part A) ................................................. 52 
11.3.1.2 
Randomised Double-blind Period (Part B) ................................................. 52 
11.3.2 
Pharmacokinetic Evaluation ...................................................................... 53 
11.3.3 
Pharmacodynamic/ Efficacy Evaluation ................................................... 53 
11.3.3.1 
Pre-Randomisation Run-in Period .............................................................. 53 
11.3.3.2 
Randomised Double-blind Period ................................................................ 53 
11.3.4 
Interim Analyses ......................................................................................... 55 
12 
DATA HANDLING AND RECORD KEEPING ....................................................... 56 
12.1 Data Collection .............................................................................................................. 56 
12.2 Data Reporting .............................................................................................................. 56 
12.3 Data Management ......................................................................................................... 56 
12.4 Record Keeping ............................................................................................................. 57 
13 
REGULATORY AND ETHICAL CONSIDERATIONS ......................................... 58 
13.1 Regulatory Considerations ........................................................................................... 58 


 
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13.2 Ethical Review Considerations .................................................................................... 58 
13.3 Subject Information Sheet and Consent ..................................................................... 58 
13.4 Final Report Signature ................................................................................................. 59 
14 
INSURANCE AND FINANCE .................................................................................... 60 
14.1 Insurance ....................................................................................................................... 60 
14.2 Financial Agreement ..................................................................................................... 60 
15 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 61 
15.1 Protocol Amendments and Protocol Deviations and Exceptions ............................. 61 
15.1.1 
Protocol Amendments ................................................................................. 61 
15.1.2 
Protocol Deviations and Exceptions........................................................... 61 
15.1.3 
Information to Study Personnel ................................................................. 62 
15.2 Monitoring ..................................................................................................................... 62 
15.3 Investigator’s Regulatory Obligations ........................................................................ 63 
15.3.1 
Audit and Inspection ................................................................................... 63 
15.3.2 
Data Quality Assurance .............................................................................. 63 
16 
PUBLICATION POLICY ............................................................................................ 64 
17 
REFERENCES .............................................................................................................. 65 
18 
ATTACHMENTS ......................................................................................................... 68 
18.1 Attachment 1 – Study Schedule of Assessments ........................................................ 68 
18.2 Attachment 2 – Blood Sampling Summary ................................................................ 71 
18.3 Attachment 3 – Clinical Laboratory Tests ................................................................. 72 
18.4 Attachment 4 – Quantitative Sensory Testing ........................................................... 74 
18.5 Attachment 5 – Criteria to be evaluated for each subject ......................................... 78 
18.6 Attachment 6 – Protocol Amendment #2 Summary .................................................. 79 
 
 
LIST OF TABLES 
Table 1 
Part A Pre-randomisation Run-in Numbers ..................................................... 26 
Table 2 
Part B Randomisation Numbers ........................................................................ 27 
Table 3 
Primary Objective - Analysis of Primary Endpoints ....................................... 53 
Table 4 
Secondary Objectives - Analysis of Secondary Endpoints .............................. 54 
Table 5 
Exploratory Endpoints - Analysis of Exploratory Endpoints ......................... 55 
 
LIST OF FIGURES 
Figure 1 
Injection Paradigm .............................................................................................. 21 
Figure 2 
Study Design ........................................................................................................ 25 
Figure 3 
Administration Scheme ....................................................................................... 38 
Figure 4 
Numerical Rating Scale ....................................................................................... 48 
 


 
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RATIONALE FOR PROTOCOL AMENDMENT # 2 
 
The overall changes and rationale for the changes made to this protocol are as follows: 
• 
A maximum age of the subject for inclusion to the study was increased to 75 years old. 
The following inclusion criterion is updated accordingly ‘Male and female subjects 
aged between 18 and 75 years inclusive at the time of giving informed consent’. 
Raising the upper age limit of subjects to 75 years would enhance the value of the study, 
given the frequency of surgery in the older age group, particularly the frequency of post-
surgical neuralgia after incisional cancer surgery for chest and abdominal tumours.  
The sponsor has an extensive experience with Dysport for different indications, for more 
than 25 years postmarketing experience, with continuous monitoring of safety data via 
signal detection activities in approved indications: both aesthetic and spasticity and 
other therapeutic indications with various routes of administration, including 
intramuscular, subcutaneous, and intradermal. The safety profile due to the route of 
administration is not different in terms of localised reactions between various age 
groups. The current labelling for Dysport contains the following recommendations for 
treating physicians for elderly patients (≥ 65 years):  Clinical experience with Dysport 
has not identified differences in response between the elderly and younger adult 
patients. In general, elderly patients should be observed to evaluate their tolerability of 
Dysport, due to the greater frequency of concomitant disease and other drug therapy. 
Considering the well-established safety profile of Dysport and the Sponsor’s assessment 
of the proposed changes, the overall risk benefit of the study remains favourable. 
 
• 
The time from surgery which caused the painful scar for inclusion to the study was 
extended to ten years. ‘Time from surgery which caused the painful scar more than 
six months and less than ten years at screening’. 
Extension of the duration from five to ten years is considered acceptable providing the 
pain is clearly associated with previous abdominal or thoracic surgery, and the subject 
can consistently define and rate the pain area in an objective and plausible manner. It 
is now held that painful conditions with clear aetiology related to diagnosed tissue 
damage/disease remain reversible with effective treatment. This is distinct from cases 
where there may be significant psycho-social factors (e.g. acquired mental health 
issues; ongoing litigation, severe ‘illness behaviour’ etc), widespread bodily pain.  The 
pain associated with the wound or scar is classically in a small well defined area, with 
the subject able to consistently reproduce the mapped area. Indeed this is a 
requirement for screening and subsequent visits. It is our contention that the reliability 
of these criteria is crucial, while the duration of such pain is at most a minor factor. 
 
• 
Two parts of the QST test (punctate hyperalgesia, vibration disappearance) won’t be 
performed for the following reasons: 
1. Punctate hyperalgesia – This test uses a painful stimulus (Neurotips) which has to 
be applied to an already painful area. As this test would not be repeated at Week 6 
and Week 12 after treatment, we consider not to perform it at baseline in subjects 
already experiencing moderate to severe pain at the level of their scar. 
2. Vibration disappearance - This test using a tuning fork requests a bony prominence 
closest to the test site. In the context of this study where location of the painful area 
might vary (abdominal, thoracic scar), the corresponding bony prominence might 
differ from one subject to another and introduce variability in the conduct of the 


 
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procedure. As this test would not be repeated at Week 6 and Week 12 after treatment, 
Sponsor considers not to perform it at baseline. 
 
QST at baseline will thus consists of the same series of tests (i.e. using light touch, 
pressure and temperature stimuli only) as those to be conducted at Week 6 and Week 
12. This series of tests will consist of: 
- 
Baseline assessments (NRS score) 
- 
Sensory threshold 
- 
Pain perception threshold 
- 
Static mechanical allodynia 
- 
Dynamic mechanical allodynia 
- 
Temporal summation 
- 
Pressure pain threshold 
- 
Conditioned pain modulation 
- 
Temperature threshold 
 
All modifications are presented in the Attachment 6. 
 
PROTOCOL HISTORY 
Protocol version 
Rationale for amendment 
V1.0, 25-MAY-2018 
Not applicable, initial version 
V2.0, 13-AUGUST-2018 
Amendment #1 
• Upon request of the Ethics Committee, and to ensure 
patient beneficence, the following statement is added to 
section 5.2.4 ‘The principal investigator will inform the 
family doctor and pain clinic (if applicable) with details of 
participation in the clinical study and any relevant 
information which may help the treating physician in the 
management of their patient’. 
• Upon request of the Ethics Committee, and to clarify how 
participants would be monitored through each stage of the 
study, the following statement is added to section 5.1 
‘Subjects will be monitored throughout the study with 
review of their pain scores at both telephone and physical 
visits to site. In addition, the subjects can contact the site at 
any time and if required an unscheduled visit can be 
performed to assess the subject and their participation in the 
study’. 
• As advised by the Medicines and Healthcare products 
Regulatory Agency (MHRA), the following criterion ‘The 
subject’s primary care physician has provided evidence 
which can be used to confirm that within the last 12 months 
of dosing that there is nothing in their medical history that 
would preclude their enrolment into a clinical study’ is 
added to the list of inclusion criteria and removed from the 
list of exclusion ones. 
• The following inclusion criterion ‘Under stable 
medication regimen for other medication, i.e. during the 


 
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month before screening’ was listed in section 4.1 of the 
protocol, but was missing in the synopsis. The list of 
inclusion criteria in the synopsis is updated accordingly. 
• A maximum opioid dosage use is defined for inclusion to 
the study. The following exclusion criterion is added 
accordingly ‘Opioid analgesic use at a Morphine Equivalent 
Dosage (MED) of >75 mg per day’. 
• The list of medications that should not start during the 
study is also updated. ‘High doses of opioids i.e. equivalent 
to morphine (oral) 100 mg/day, or equivalent as defined in 
the British national formulary ’ is replaced by ‘Opioids’. 
  
  
  
 
V3.0, 04-DECEMBER-2018 
Amendment #2 
See rationale for protocol amendment #2 (above) 
 


 
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LIST OF DEFINITIONS AND ABBREVIATIONS 
 
DEFINITIONS 
Wording Definition  
Audit 
Systematic and independent examination of the study-related 
activities and documents to determine whether the evaluated study-
related activities were conducted, and the data were recorded, 
analysed, and accurately reported according to the protocol, sponsor’s 
standard operating procedures, good clinical practices, and the 
applicable regulatory requirement(s). 
Compliance 
Adherence to all the study-related requirements, good clinical 
practices requirements and the applicable regulatory requirements. 
Double-blinding 
Procedure to which usually the subject(s), investigator(s), monitor(s), 
and in some cases, selected sponsor personnel, are being unaware of 
the treatment assignment(s). 
End of Study 
Date of the last visit or last scheduled procedure shown in the study 
schedule for the last active subject in the study. 
Enrol / Randomise 
Act of assigning a subject to a treatment. Subjects who are enrolled in 
the study are those who have been assigned to a treatment. 
Enter / Consent 
Act of obtaining informed consent for participation in a clinical study 
from subjects deemed- or potentially eligible to participate in the 
clinical study. Subjects entered into a study are those who sign the 
informed consent document directly. 
Ethics Committee 
Board or committee (institutional, regional, or national) composed of 
medical professional and non-medical members whose responsibility 
is to verify that the safety, welfare, and human rights of the subjects 
participating in a clinical study are protected. 
Investigator 
Physician responsible for the conduct of a clinical study at a study site. 
If a study is conducted by a team of individuals at a study site, the 
investigator is the responsible leader of the team and may be called 
the principal investigator. 
Run-in 
Extension of the screening period to select subjects who have potential 
to respond to Dysport. 
Screen 
Act of determining if an individual meets minimum requirements to 
become part of a pool of potential candidates for participation in a 
clinical study. In this study, screening involves invasive procedures 
(for example, blood draws). For this type of screening, informed 
consent for these screening procedures and/or tests shall be obtained. 
Subject 
Individual who is or becomes a participant in clinical research, either 
as a recipient of the test article or as a control.  
ABBREVIATION 
Wording Definition 
ACE 
Angiotensin converting enzyme 
AE 
Adverse event 
AESI 
Adverse event of special interest 


 
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DEFINITIONS 
Wording Definition  
BTX 
Botulinum neurotoxin 
BTX-A 
Botulinum neurotoxin serotype A 
BTX-A-HAC 
Botulinum neurotoxin type A haemagglutinin complex 
CA 
Competent Authority 
CFR 
Code of Federal Regulations (United States of America) 
CGRP 
Calcitonin gene-related protein 
CRO 
Contract research organisation 
CRU 
Clinical research unit 
DBP 
Diastolic blood pressure 
DOA 
Drug of abuse 
DRG 
Dorsal root ganglion 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ED 
Early discontinuation 
EoS 
End of study 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 
GPS 
Global patient safety 
HR 
Heart rate 
IB 
Investigator’s brochure 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethic Committee 
IMP 
Investigational medicinal product 
IND 
Investigational new drug 
IRB 
Independent Review Board 
MED 
Morphine equivalent dosage 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NRS 
Numerical rating scale 
PP 
Per protocol 
PPT 
Pressure pain threshold 
QoL 
Quality of life 


 
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DEFINITIONS 
Wording Definition  
QST 
Quantitative sensory testing 
SAE 
Serious adverse events 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SmPC 
Summary of product characteristics 
SNAP-25 
Synaptosomal-associated protein 25 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment emergent adverse event 
TFLs 
Tables, figures, and listings 
TMF 
Trial master file 
TRPV1 
Transient receptor potential vanilloid 1 
UK 
United Kingdom 
WHO 
World Health Organisation 


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1 
BACKGROUND INFORMATION 
1.1 
Introduction 
Pain is the most common symptom for which subjects seek medical attention, but pain 
management has unmet needs. Pain is the most frequent reason why subjects visit an emergency 
department and there is a need for additional research on the relative safety and efficacy of 
non-opioid approaches to emergency department analgesia (Todd, 2017). Chronic pain affects 
between one-third and one-half of the population of the United Kingdom (UK), corresponding 
to just under 28 million adults and is likely to increase due to an ageing population (Fayaz et al., 
2016). 
Pain is defined by the International Association for the Study of Pain as: “An unpleasant sensory
and emotional experience associated with actual or potential tissue damage or described in 
terms of such damage” (www.iasp-pain.org). Pain is subjective and this definition links emotion
and past experience to the sensory event thus also highlighting that pain is a complex experience 
that includes multiple dimensions. This is because each individual learns the meaning of the 
word "pain" through experiences related to injury in early life. Stimuli or illnesses that cause 
pain are likely to damage tissue and hence pain is an experience associated with actual or 
potential tissue damage. Pain is almost always unpleasant and therefore an emotional 
experience. Pain is subjective and there are no satisfactory objective measures of pain, hence 
the subject’s self report of pain is the most reliable indicator of pain (American Pain Society,
2006). 
Clostridial neurotoxins from the botulinum neurotoxin (BTX) family are protein complexes, 
derived from the bacterium Clostridium botulinum, which potently inhibit acetylcholine release 
and results in a reversible blockade of the neuromuscular junction. This feature led to the 
clinical development of BTX for neuromuscular disorders. Serotype A BTX (BTX-A) are 
commercially available and clinically used for treatment of disorders characterised by increased 
tonicity or overactivity of specific muscles (Barnes, 2003; Thenganatt et al., 2012), and also for 
treatment of overactivity of secretory glands (Heckman et al., 2001). Along with the 
neuroparalytic effect, it has been reported that BTX-A reduces the pain associated with the 
neuromuscular hyperactivity disorders, such as torticollis (Tsui et al., 1985; Brin et al., 1987; 
Tarsy, 1999). 
BTX-mediated pain relief was initially described in conditions associated with muscle 
contraction and believed to be associated with decreased contraction of affected muscles 
(Arezzo, 2002; Cohen et al., 1989; Mense, 2004). It was proposed that BTX-A, by inhibiting 
the release of acetylcholine in hyper-functional muscular end plates, may indirectly prevent the 
painful ischaemia caused by muscle contractures in spasticity and dystonia (Mense, 2004). 
However, it was reported that the observed pain relief in patients treated for spasmodic 
torticollis was not concurrent with neuromuscular effects since it was present in some patients 
even when dystonic posture of the neck was not improved (Stell et al., 1988). Additionally, 
BTX-A-mediated pain relief does not always occur simultaneously with the observed paralytic 
effect in focal dystonias, and it sometimes even persists after the neuromuscular benefit is no 
longer visible (Aoki, 2003; Freund, 2003). Since the onset of BTX-A action on pain did not 
correspond to the onset of paralytic muscular effects or lasted longer than the paralysis, toxin 
action on sensory or vegetative nerves was suggested (Giladi, 1997; Mense, 2004). 
Independently from pain which might be related to increased muscle contraction, the 
anti-nociceptive effect of BTX-A was also reported in different types of chronic pain not 
associated primarily with muscle hyperactivity, such as migraine (Silberstein et al., 2000; 
Luvisetto et al., 2015) and different types of neuropathic pain (Argoff, 2002; Attal et al., 2016). 
Along with experimental knowledge obtained from preclinical studies, it is now accepted that 
BTX-A effects on pain may be mediated by its direct effects on sensory nerves, and current 


 
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evidence suggests several possible peripheral nervous system and central nervous system 
mechanisms of action, which might account for the analgesic action of peripherally 
administered BTX-A across the whole nociceptive pathway (Pellett et al., 2015): 
• 
BTX-A acts on neurons involved in pain perception and prevents the release of other 
neurotransmitters than acetylcholine, e.g. glutamate, substance P, calcitonin gene-related 
protein (CGRP) and vasopressin as demonstrated in vitro from cultured cells or isolated 
materials (Mc Mahon et al., 1992; Purkiss et al., 2000) and also in vivo in preclinical 
pain models, e.g. in the rat formalin test (Cui, 2004) or the rat capsaicin pain model 
(Bach-Rojecky, 2005; Filipovic et al., 2012; Marino et al., 2014), 
• 
BTX-A may regulate the expression of a variety of receptors and channels implicated in 
peripheral sensitisation, amongst which vanilloid receptors such as the transient receptor 
potential vanilloid 1 (TRPV1) (Apostolidis et al., 2005) whose mobilisation from 
intracellular stores to the plasma membrane involves regulated exocytosis 
(Dolly et al., 2009) and cleavage of the synaptosomal-associated protein 25 (SNAP-25) 
(de Paiva et al., 1993), 
• 
Following endocytosis in the peripheral terminals, some molecules of BTX-A may 
undergo retrograde transport along the axon and reach the dorsal root ganglion (DRG) 
neurons where they would block the vesicular release of neurotransmitters into the 
extracellular milieu of the DRG, which would otherwise activate and excite the 
neighbouring sensory neurons (Dickenson, 1987a; Matak et al., 2012), 
• 
Though speculative, BTX-A may also further undergo intra-vesicular trafficking to the 
central terminals, and block neurotransmission into the brainstem and higher centres for 
pain integration (Coderre et al., 1990; Dickenson, 1987b). 
Dysport® is the trade name for an injectable form of BTX-A, which is isolated and purified 
from the bacterium Clostridium botulinum. Dysport was first registered for the treatment of 
blepharospasm and hemifacial spasm in the UK in 1990. It is licensed in more than 85 countries 
for various indications including: spastic equinus foot deformity due to spasticity in adults 
following a stroke, blepharospasm, adult upper and lower limb spasticity, hemifacial spasm, 
spasmodic torticollis (also known as cervical dystonia), paediatric lower limb spasticity and 
dynamic equinus foot deformity due to cerebral palsy, axillary hyperhidrosis, and glabellar 
lines. 
The present study will investigate the analgesic effects of different doses of Dysport in subjects 
experiencing chronic pain from an abdominal or thoracic scar (chronic post-surgical pain; post-
surgical neuralgia). 
 
1.2 
Name and Description of the Investigational Medicinal Product 
Dysport is formulated as a complex of BTX-A with haemagglutinin (BTX-A-HAC), a large 
therapeutically inert protein used to stabilise the toxin. Dysport is formulated with lactose 
(bulking agent) and human serum albumin, and is supplied as a lyophilised powder. 
A detailed description can be found in the Summary of Product Characteristics (SmPC). 
 
1.3 
Non-Clinical Data 
The analgesic properties of commercially available BTX-A have been investigated in a variety 
of acute and chronic animal pain models. The effectiveness of BTX-A has specifically been 
demonstrated in formalin- (Cui, 2004; Luvisetto et al., 2006) and capsaicin-induced pain 
models (Marino et al., 2014; Ramachandran et al., 2015), as well as in arthritic rats 
(Krug et al., 2009) and dogs (Heikkila et al., 2014). Positive outcome following 


 
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administration of BTX-A has also been evidenced in mononeuropathy (peripheral and 
infraorbital nerve ligation, ventral root transection), polyneuropathy (chemotherapy-induced, 
diabetes) and trigeminal murine pain models (Favre-Guilmard et al., 2009; Bach-Rojecky et al., 
2010; Gazerani et al., 2010;Filipovic et al., 2012; Shimizu et al., 2012;Park et al., 2015). 
 
1.4 
Clinical Data 
Botulinum toxin injection is being increasingly used “off-label” in the clinical management of 
chronic pain, and there have been a number of reviews highlighting the role of treating painful 
conditions with BTX. In their review of BTX in the treatment of chronic pain,
Rivera Dia et al. (2014) discuss several conditions where BTX may have a role, such as 
trigeminal neuralgia, tension headache, chronic migraine, myofascial pain, phantom limb pain 
and joint pain.Park and Park (2017) also reviewed the experimental and clinical evidence of 
the mechanism by which BTX acts on various types of neuropathic pain. They described how 
BTX can be applied as treatment for neuropathic pain conditions such as postherpetic neuralgia, 
post-surgical neuralgia, diabetic neuropathy, occipital neuralgia or spinal cord injury induced 
neuropathic pain. They also provide clear evidence that BTX has an analgesic effect involving 
both peripheral and central elements of the nociceptive pathway for chronic neuropathic and 
nociceptive pain.
Besides use for aesthetic treatments and infocal hyperhidrosis, BTX has also been recently used 
experimentally 
in 
many 
other 
dermatological 
conditions 
with 
good 
results. 
Campanati et al. (2017) analysed the possible BTX “off-label” applications in dermatology and 
specifically collected published data on the application of BTX-A injections in keloids and 
hypertrophic scars. The studies reviewed revealed a great potential for BTX-A with 
improvement of the lesions such as lowering of the erythema, decrease of the itching, pain and 
tenderness sensation, but also decrease in size and flattening of the lesions. Overall, the 
therapeutic satisfaction of the patient and physician was good in the studies reviewed. 
Of relevance for the present study, Schwartz et al. (2004) investigated the effects of 
intradermal injections of BTX-A in relieving chronic post-surgical scar pain. They showed that 
subjects treated with BTX-A exhibited an improved reduction in mean pain scores relative to 
dexamethasone (30% versus 25%) and twice the duration of effect (eight weeks for BTX-A 
versus four weeks for dexamethasone). 
 
1.5 
Rationale for the Study 
The rationale of this study is to test the hypothesis that Dysport is effective in relieving chronic 
scar pain when administered intradermally. This study will also aim at characterising the 
pharmacodynamic profile of any analgesic effect of a predefined dose range (time to onset, 
peak-effect, time to peak-effect and duration of effect). 
 
1.6 
Dosage Selection 
The anhidrotic properties of a range of single intradermal 0.2 mL doses of Dysport (2.5, 10 and 
20 U) were studied in healthy volunteers (Ipsen Study
). These doses were well 
tolerated and showed a dose-related increase in the anhidrotic area using the Minor’s 
starch-iodine test. The maximal mean areas were 1.1, 2.7 and 3.7 cm² (corresponding radius of 
0.6, 0.9 and 1.1 cm) for 2.5, 10 and 20 U respectively. 
Those same dose levels of 2.5, 10 and 20 U and route of administration have been selected for 
the individual injection points in the present study. 
The minimal dose will be 2.5 U injected in four sites (i.e. total dose of 10 U). 
CCI


 
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The maximal diffusion radius (1.1 cm for Dysport 20 U), together with the specification related 
to the maximal length of the pain area (i.e. no more than 10 cm) have been taken into 
consideration for the injection paradigm where individual injection points will be given 
intradermally 2 cm apart and the maximal number of injection points limited to 10 (see 
Figure 1). The maximal allowed total dose in the present study will thus be 200 U in the Dysport 
maximal dose group (20 U), which is consistent with the maximal recommended intradermal 
dose in the product label. 
Figure 1 Injection Paradigm 
 
 
1.7 
Population to be Studied 
This study will enrol male and female subjects with a painful abdominal or thoracic scar. Pain 
should be rated as moderate to severe i.e. numerical rating scale (NRS) score between 4 and 8 
on an 11-point scale (0-10), and stable within one month before screening. The pain should also 
be chronic, i.e. persistent for more than six months after the surgery which led to the painful 
scar. 
To ensure subjects will potentially benefit from intradermal injection of Dysport, they will be 
tested for responsiveness to local anaesthetic (lidocaine) during a pre-randomisation run-in 
period. This is consistent with use of diagnostic local anaesthetic blocks which are used to 
obtain information about of the source of subject’s pain, being target specific and controlled in 
order to exclude false positive results (Bogduk, 2002). This assessment will be performed by 
investigators with experience in managing subjects with painful conditions and pain studies. 
 
1.8 
Known and Potential Risks to Human Subjects 
Dysport is licensed in the UK for the symptomatic treatment of focal spasticity, spasmodic 
torticollis, blepharospasm and hemifacial spasm, injected either intramuscularly or 
subcutaneously targeting the affected muscles or muscle groups, and is also licensed for 
treatment of severe primary hyperhidrosis of the axillae, injected intradermally. 
Side effects of Dysport as experienced with intradermal injection for hyperhidrosis indication 
were local injection site reactions including pain, bruising, pruritis, and oedema. In addition, 
rash and compensatory sweating were also reported. 


 
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The maximum licensed intradermal dose is 200 U per area of injections. This maximum 
recommended intradermal dose will not be exceeded in the present study. Additional 
information regarding risks to human subjects may be found in the SmPC. 
Overall, the safety profile of Dysport is well established after more than 20 years of clinical 
trials and post-marketing experience in various therapeutic and aesthetic indications at various 
doses with maximum dose used for intradermal indication up to 200 U at single area of 
injections. In the current proposed study in subjects with chronic scar pain, we believe the risk 
associated with Dysport use intradermally, to be acceptable, considering the established and 
known safety profile with intradermal use. 


 
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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
• 
To describe the pharmacodynamic analgesic profile (time of onset of meaningful 
analgesic effect, peak-effect, time to peak-effect, duration of effect) of intradermal doses 
of Dysport in subjects with abdominal or thoracic chronic scar pain. 
 
2.2 
Secondary Objectives 
• 
To compare the efficacy of intradermal doses of Dysport to placebo. 
• 
To assess the safety and tolerability of a range of intradermal doses of Dysport. 
 
2.3 
Exploratory Objectives 
• 
To explore improvement of quality of life (QoL) using SF-36 questionnaire. 
• 
To explore concomitant use of rescue medication (analgesia). 


 
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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
The study will consist of two sequential parts, the first being to identify subjects who will 
potentially benefit from intradermal Dysport injection, ‘responders’, who will then progress to 
the second part, which is the double-blind study of the intradermal injection of Dysport or 
placebo:  
• 
Part A: A double-blind, randomised, initial two-period cross-over run-in part, extended 
screening period of placebo or local anaesthetic (lidocaine), 
• 
Part B: A single-dose, double-blind, randomised, parallel part with one of the three 
different doses of Dysport or placebo. 
To ensure subjects will potentially benefit from intradermal injection of Dysport, they will be 
tested for responsiveness to local anaesthetic (lidocaine). 
In Part A, and upon consent and successful screening of medical eligibility, subjects will be 
injected (injection test 1) during a pre-randomisation run-in period in a double blind fashion 
with either saline or local anaesthetic (lidocaine) and assessed for pain perception up to 24 hours 
post-injection. One week later, they will be crossed over, injected with the other agent (injection 
test 2) and assessed for pain perception up to 24 hours post-injection. Pain intensity will be 
scored using a 11-point NRS (from score 0 for “no pain” up to 10 for “worst possible pain”). 
If subjects are assessed as responders, they will enter in Part B, and will be trained and provided 
with an Actiwatch® to enable them to record twice a day their spontaneous NRS scores. 
Before dosing on Day 1, the subjects will perform baseline assessments including a quantitative 
sensory testing (QST) assessing allodynia, hyperalgesia and conditioned pain modulation, 
completion of a QoL questionnaire, and safety assessments (physical examination, vital signs 
measurements, collection of adverse events (AEs) and recording of concomitant medication). 
Subjects will be dosed if considered as consistent in pain perception from the screening visit 
(i.e. variability < 2 for the average spontaneous NRS score pre-injection tests in Part A, 
pre-QST and pre-dosing and as clinically plausible per investigator’s judgement). 
Subjects will then be assessed for pharmacodynamics and safety for a total of 16 weeks 
post-dose. 
Subjects will be discharged from the study after safety assessments (physical examination, vital 
signs) during an end of study (EoS) visit. 
The study design is presented in Figure 2. 
 


 
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Figure 2 Study Design 
 
3.2 
Study Endpoints 
3.2.1 
Primary Endpoints 
The primary endpoints will be: 
• 
Time to onset, i.e. time to decrease from baseline of two points in the spontaneous NRS 
score, 
• 
Peak-effect, i.e. maximal decrease from baseline in the spontaneous NRS score, 
• 
Time to peak-effect, i.e. time to reach the peak-effect, 
• 
Duration of effect, i.e. duration between time to onset and last timepoint for which change 
from baseline in the spontaneous NRS score is ≥ two points. 
 
3.2.2 
Secondary Endpoints 
The following secondary endpoints will be evaluated: 
• 
Change from baseline in the spontaneous NRS score to each scheduled timepoint, 
• 
Change from baseline in the stimulus-evoked NRS score to each scheduled timepoint, 
• 
Safety of three intradermal doses of Dysport. Safety assessments will include monitoring 
of AEs, concomitant medications and changes from baseline in physical examinations 
findings including the examination of the scar at the injection sites and vital signs 
recordings at each scheduled timepoint. 
 
3.2.3 
Exploratory Endpoints 
The following exploratory endpoints will be evaluated:  
• 
Change from baseline in SF-36 scores at each scheduled timepoint, 
• 
Amount of rescue medication taken during the study, 
• 
Time to first intake of rescue medication. 
 
3.3 
Study Duration 
This study will consist of: 
• 
A screening visit: 28 days maximum before IMP dosing, 
• 
A Part A, pre-randomisation run-in period: 
• 
First injection test: 21 days maximum before IMP dosing, 


 
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• 
Second injection test: one week after first injection test, 14 days maximum before 
IMP dosing, 
• 
A Part B, randomised double-blind period: 
• 
A baseline period including a QST and Actiwatch® training, safety assessments 
and a QoL: within 7 days before IMP dosing, 
• 
A one-day IMP dosing, 
• 
A 16-week randomised double-blind period. 
Subjects are expected to participate in this study for a maximum of 20 weeks. 
The study will be considered to have started when the first subject has provided signed informed 
consent and will be considered to have ended after the last subject has completed his EoS visit. 
The overall study is anticipated to last approximately one year. 
 
3.4 
Randomisation and Blinding 
3.4.1 
Method of Randomisation 
At screening, potential subjects will be allocated an 11-digit subject number consisting of: 
• 
The country code (three digits), 
• 
The centre number (three digits), 
• 
The sequential order of entry of the subject in the unit (five digits). 
 
3.4.1.1 
Pre-randomisation Run-in Period (Part A) 
Following confirmation of eligibility after the screening visit, subjects will be assigned to a 
pre-randomisation run-in number and allocated to one of the two treatment sequence groups in 
a chronological order, i.e. first eligible subject after the screening visit will be given the first 
run-in number (as detailed in Table 1). Subjects will be randomised with a ratio 2:2 (blocks of 
eight subjects) to receive: 
• 
Either lidocaine on injection test 1 then placebo (saline) on injection test 2, 
• 
Or placebo (saline) on injection test 1 then lidocaine on injection test 2. 
 
Table 1 
Part A Pre-randomisation Run-in Numbers 
Part A Pre-randomisation Run-in Numbers 
From 
 
 
3.4.1.2 
Randomised Double-blind Period (Part B) 
Subjects will be randomised to receive Dysport 2.5 U, Dysport 2.5 U placebo, Dysport 10 U, 
Dysport 10 U placebo, Dysport 20 U, Dysport 20 U placebo with a ratio 3:1:3:1:3:1 (blocks 
of 12 subjects). 
Following confirmation of eligibility after injection test 2, subjects will be assigned to a 
randomisation number and allocated to one of the treatment groups in a chronological order, 
i.e. first eligible subject will be given the first randomisation number as detailed in Table 2. 
 
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Table 2 
Part B Randomisation Numbers 
Part B Randomisation Numbers 
Part B Replacement Randomisation Numbers 
From 
 
From 
 
 
Mirror lists of randomisation numbers will also be produced to allow the randomisation of 
replacement subjects (e.g. the subjects who withdraw within six first weeks after IMP dosing) 
or to be used for the replacement of kits which could be damaged during the IMP reconstitution. 
For example, number 
 will be used to randomise the replacement for the subject who 
was randomised with number 
. 
The sponsor’s randomisation manager will prepare and keep the master lists of pre-
randomisation run-in numbers and randomisation numbers. A copy of these lists will be sent 
confidentially to: 
• 
Pharmaceutical Development Clinical Supply Chain 
Beaufour Ipsen Industrie SAS 
Rue d’Ethe Virton 
28100 Dreux, France. 
The lists and their copies will be kept confidential in secure locations. Access to the 
randomisation lists will be restricted until authorisation is given to release them for final 
analysis. 
An identification code assigned to each subject will be used in lieu of the subject’s name to 
protect the subject’s identity when reporting AEs and/or other study-related data. 
 
3.4.2 
Blinding 
Only the pharmacist or delegate in charge of drug preparation at the clinical research unit (CRU) 
and the monitor responsible for pharmacy monitoring will be partially unblinded. These 
personnel will be fully trained on the importance of their role in maintaining the blind for the 
subject, the investigator and the remainder of the study team. The unblinded staff at the CRU 
will not carry out any study assessments other than those they are assigned to. 
All other staff at the CRU, the sponsor and the subjects will be blinded to treatment allocations 
during the study. 
 
3.4.3 
Code-break 
Two types of code-break envelopes will be set up for the pre-randomisation run-in period 
(Part A) and for the randomised double-blind period (Part B). 
Two sets of individual sealed code-break envelopes of each type will be prepared by the 
sponsor’s randomisation manager to enable emergency code-break procedures for individual 
subjects without compromising the blind of the study. One set will be provided to the CRU and 
one set provided to the sponsor department of global patient safety (GPS). 
In an emergency situation, which requires the identification of the study treatment group, the 
investigator may break the treatment code. If so, the investigator is requested to: 
• 
Inform the monitoring office at the earliest opportunity that the blind has been broken 
for an emergency situation, 
• 
Reseal the code-break envelope, 
• 
Sign, date and provide reason for the code-break on the emergency code-break form, and 
on the sealed envelope. 
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The date and reason for code-breaking should also be recorded in the electronic case report 
form (eCRF). 
Specific case, to check if the subject is a responder at the end of the run-in period, the 
investigator will unblind the subject by (re-)opening the code-break-envelope associated to 
his(her) assigned pre-randomisation run-in number. The investigator will sign, date and specify 
”End of run-in period” as the reason for the code-break on the envelope. 
Monitors should routinely check the integrity of the envelopes that are stored at the study site. 
They must collect envelopes from the study site prior to study close-out and ensure that they 
are all intact. If envelope(s) have been opened at the site or by the sponsor’s representative, the 
monitor must ensure a written explanation is clearly documented (opener’s name, dated 
signature and reason for opening) on the visit status page of the eCRF. 
Confirmation of the integrity of all code-break envelopes at study completion must be 
documented in the trial master file (TMF). All sets of the sealed individual subject envelopes 
must be kept in the TMF in the co-ordinating office at study completion for proof of integrity. 
 
3.5 
Stopping Rules and Discontinuation Criteria 
The complete study can be terminated prematurely at any time if the sponsor judges it necessary 
for any reason. In that case, all scheduled procedures and assessment for subjects who are still 
in the study will be performed. 
Some possible reasons for the closure of a study site may include: 
• 
Failure of the investigator staff to comply with the protocol or with the GCP guidelines, 
• 
New and significant safety concerns, 
• 
Inadequate subject’s recruitment. 
During the conduct of the study, all AEs including serious AEs (SAEs) will be reviewed as they 
are reported from the study site to identify new and significant safety concerns.  
 
3.6 
Source Data Recorded on the Case Report Form 
Data will be collected in the eCRF in compliance with Food and Drug Administration (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. 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), agent and IMP administration, and any AEs and associated concomitant medications. 
Definitions 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). 
No source data will be directly recorded on the eCRF during the present study. 


 
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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
Subjects must fulfil all of the following criteria to be considered eligible for enrolment in the 
study. 
(1a) Male and female subjects aged between 18 and 75 years inclusive at the time of giving 
informed consent. 
(2) 
Subjects suffering from an area of chronic pain post-abdominal or thoracic surgery, 
chronic abdominal or thoracic scar pain. 
(3) 
Longitudinal axis of the pain area of 10 cm long maximum (as mapped upon screening). 
(4) 
Subjects with moderate to severe pain, i.e. spontaneous NRS score of 4-8 which has been 
stable for the previous month before screening. 
(5) 
Stable use of analgesics (or any medication impacting pain perception) during the month 
before screening and expected to be stable for the study duration. 
(6) 
Under stable medication regimen for other medication, i.e. during the month before 
screening. 
(7a) Time from surgery which caused the painful scar more than six months and less than 
ten years at screening. 
(8) 
No other distracting pain either chronic or acute. 
(9) 
Female subjects of childbearing potential must have a negative urine pregnancy test 
result and be willing to use reliable contraceptive measures throughout study 
participation. Reliable forms of contraception include but are not limited to hormonal 
contraceptives (e.g. oral, patch, injection), double-barrier (e.g. male condom plus 
spermicide, or female diaphragm plus spermicide), intrauterine device, male partner has 
had a vasectomy, total abstinence from intercourse with male partners (periodic 
abstinence is not acceptable). Female subjects meeting any of the following criteria are 
not considered to be of childbearing potential: postmenopausal (≥ 47 years of age and 
amenorrhoeic for at least 12 consecutive months), have been sterilised surgically (e.g. 
bilateral tubal ligation), have had a hysterectomy, have had a bilateral oophorectomy. 
(10) The subject’s primary care physician has provided evidence which can be used to 
confirm that within the last 12 months of dosing that there is nothing in their medical 
history that would preclude their enrolment into a clinical study. 
 
4.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will not be considered eligible for enrolment in 
the study. 
(1) 
Previous treatment with BTX (any serotype) during the past six months before screening. 
(2) 
History of hypersensitivity to any of the components of the Dysport formulation (which 
includes human serum albumin and lactose) or allergy to cow's milk protein. 
(3) 
Known hypersensitivity to lidocaine or other anaesthetics of the amide type, known 
hypersensitivity to hydroxybenzoates, complete heart block, hypovolaemia. 
(4) 
Any medical condition that may put the subject at risk with exposure to BTX, including 
diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, 
or any other disease that might interfere with neuromuscular function. 
(5) 
Opioid analgesic use at a Morphine Equivalent Dosage (MED) of >75mg per day. 
(6) 
Neuroma in the scar pain area, diagnosed per ultrasound. 


 
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(7) 
Use of agents that could interfere with neuromuscular transmission, including calcium 
channel 
blockers, 
penicillamine, 
aminoglycosides, 
lincosamides, 
polymixins, 
magnesium sulphate, anticholinesterases, succinylcholine and quinidine. 
(8) 
Need of any prohibited medication. 
(9) 
Any abnormal laboratory value, physical examination, vital signs, or electrocardiogram 
(ECG) that, in the opinion of the investigator, is clinically significant and that would 
compromise the safety of the subject in the study. 
(10) Positive for hepatitis B antigen or hepatitis C virus ribonucleic acid, positive results for 
human 
immunodeficiency 
virus, 
or 
who 
receives 
diagnosis 
for 
acquired 
immunodeficiency syndrome. 
(11) Positive urine screen for drugs of abuse (except for cotinine and unless explained by the 
investigator for therapeutic use of medication) or any history of drug or alcohol abuse, 
misuse, physical or psychological dependence, mood changes, sleep disturbance and 
functional capacity which have an impact on pain perception. 
(12) Significant neurological or psychiatric disorders including mental instability (unrelated 
to the pain) that could interfere with pain assessments; other pre-existing pain syndromes, 
acute or chronic, that might impair the assessment of the scar pain. 
(13) Any medical history of significance and/or inadequately controlled such as 
cardiovascular (e.g. uncontrolled high blood pressure, high risk of cardiovascular events, 
severe heart failure), pulmonary (e.g. uncontrolled asthma or emphysema), 
heamatologic, (e.g. coagulopathy/bleeding disorders), neurological (e.g. swallowing 
problems, blurred or double vision, trouble saying words clearly (dysarthria), hoarseness 
or change or loss of voice (dysphonia)), liver disease (e.g. severe hepatic impairment), 
kidney disease (e.g. impaired renal function in subjects taking diuretics, angiotensin 
converting enzyme (ACE)-inhibitors, or angiotensin II antagonists), endocrine, 
immunologic, dermatologic painful conditions or any other conditions that may 
compromise in the opinion of the investigator the ability of the subject to participate in 
the study. 
(14) If in the investigator’s opinion there are any factors that may confound the analysis of 
the study regarding efficacy and safety (e.g. an NRS > 9). 
(15) Previous randomisation in this study. 
(16) Subjects who participated in a clinical research study involving a new chemical entity or 
an experimental drug within 30 days before screening. 
(17) Subjects who are incapable of complying with the protocol in the judgment of the 
investigator. 
 
4.3 
Rationale for Specific Inclusion / Exclusion Criteria 
Mapping of the painful area is to detect the anatomical relationship to the scar and the previous 
surgery, and to ensure that the longitudinal axis of the pain area length will be consistent with 
the injection paradigm. Pain area should be large enough to have a minimum of 4 injections 
and a maximum of 10 injections. This maximum of 10 injections is set so as not to exceed the 
maximum permitted dose (200 U of Dysport) with the highest dose (20 U). This in turn limits 
the maximum length of the painful area to 10 cm, with five injections, 2 cm apart, either side 
of the longitudinal axis of the pain area, and an estimate of approximately 1 cm spread of dose 
around each injection point. 
 


 
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4.4 
Withdrawal of Subjects 
In accordance with the declaration of Helsinki and International Council for Harmonisation 
(ICH) GCP, each subject is free to withdraw from the study at any time, for any reason (e.g. 
withdrawal of consent, AE). 
The investigator can withdraw a subject from the study at any time for any reason (e.g. protocol 
deviation, non compliance with the protocol conditions, lack of cooperation, in the event of 
concurrent illness, AE, or other reasons concerning the health or well-being of the subject). 
The reason for and date of withdrawal from the study must be recorded in the eCRF. 
If withdrawal is based on subject’s decision every attempt will be made to determine: 
• 
The reason for withdrawal, 
• 
Whether the subject also decides to withdraw his/her consent for the sponsor to collect 
and use the data collected up to the withdrawal point. 
Data collected prior to subject withdrawal may be kept in study records and shared for further 
analyses unless the subject formally specifies his/her decision to withdraw consent for using 
data already collected. 
Should a subject be withdrawn from the study after IMP dosing and before normal study 
completion, all efforts will be made to complete the EoS assessments and report the 
observations up to the time of withdrawal as thoroughly as possible. A complete final evaluation 
at the time of the subject’s withdrawal should be made whenever possible. 
Subjects who withdraw within the first six  weeks after IMP dosing for reasons other than lack 
of efficacy will be replaced. Replacement subjects will receive the same schedule and treatment 
as the subject they have replaced. 


 
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5 
STUDY CONDUCT 
5.1 
Study Schedule of Assessments 
The schedule of procedures and assessments during the study is summarised and presented in 
Section 18.1. Subjects will be monitored throughout the study with review of their pain scores 
at both telephone and physical visits to site. In addition, the subjects can contact the site at any 
time and if required an unscheduled visit can be performed to assess the subject and their 
participation in the study. 
The total volume of blood drawn for each subject and all evaluations throughout this study is 
detailed and presented in Section 18.2. 
 
5.2 
Study Visits and Procedures 
All screened subjects must be identifiable throughout the study. The investigator will maintain 
a list of all subjects screened with subject numbers and names to enable records to be found at 
a later date if required. Records up to the time of premature termination or normal study 
completion should be completed. In the event that a subject is a screen failure (fails after 
screening visit) or is a run-in failure (withdraws in the run-in period), the primary reason will 
be recorded. 
During the screening visit and pre-randomisation run-in period (Part A), tests and assessments 
will be performed to check compliance with inclusion/exclusion criteria and study requirements 
in order to confirm each subjects’ eligibility prior to enrolment in Part B. 
The screening and pre-randomisation run-in procedures/evaluations detailed in Section 18.1 
will be performed during several out-patient visits. 
 
5.2.1 
Screening 
The subjects will attend the CRU for a screening out-patient visit within 28 days prior to IMP 
dosing on Day 1. 
 
5.2.1.1 
Informed Consent 
After a subject has received explanations and responses to his potential questions about the 
study by the investigator (or designee) and has been given reasonable time read and consider 
the patient information sheet, a signed and dated informed consent form will be completed with 
an investigator prior to any study procedures. 
 
5.2.1.2 
Screening Procedures 
After informed consent is obtained, subjects will be allocated a study-specific subject number 
which must comply with formatting specifications provided by the sponsor (see Section 3.4.1) 
and will undergo screening assessments. 
 
5.2.2 
Pre-randomisation Run-in Period (Part A) 
After successful screening of medical eligibility and within 21 days maximum before IMP 
dosing on Day 1, subjects will come back to the CRU for an injection test 1 visit, they will 
receive a pre-randomisation run-in number and be injected in a double blind fashion with either 
local anaesthetic (lidocaine) or placebo (saline). 
They will be assessed for pain perception on site and then be discharged from the CRU from 
1 hour post-injection test 1 and continue to record their NRS score at home as described in 
Section 9.1.2. They will be contacted by telephone by the site to check their safety and collect 


 
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their NRS score post-injection test 1 at the end of the injection test 1 day and on the following 
day. 
Approximately one week later and within 14 days maximum before IMP dosing on Day 1, they 
will come back to the CRU for injection test 2. They will be crossed over and injected with the 
other agent. 
They will be assessed for pain perception on site and then be discharged from the CRU from 
1 hour post-injection test 2 and continue to record their NRS score at home as described in 
Section 9.1.2. They will be contacted by telephone by the site to check their safety and collect 
their NRS score post-injection test 2 at the end of the injection test 2 day and on the following 
day. After completion of subject’s injection test 2, the blind will be broken by an investigator 
to check if the subject is a responder. 
Subjects will be considered as responders and randomised to Part B if: 
• 
The pattern of pain relief is sufficiently greater with lidocaine than saline using the 
formula below: 
[NRS predose - NRS 1 hour post-injection test] placebo – [NRSpredose - NRS 1 hour post-injection test] lidocaine ≥ 2 
• 
The pattern of pain relief is clinically plausible in the investigator’s opinion, e.g. onset 
of pain relief reported by 30 min from time of completing the injections, pain scores after 
the lidocaine injection test rising again by 2-8 hours post-injection, 
• 
The investigator has no concern regarding compliance with study procedures and safety. 
Albeit considered unlikely, should the results be equivocal, or if an unexpected but plausible 
pattern of response emerges, the decision as to whether a subject should proceed in the study, 
will be adjudicated by mutual agreement of the investigator and the sponsor. 
Subjects will be contacted by telephone by an investigator to inform them of the result. If 
subjects are assessed as responders and there are no concerns over subject safety, compliance 
with study assessments, they will enter in Part B. 
The scheduled dates should be with sufficient time between study visits test 1, test 2 and 
baseline. This is to permit the scar area to return to baseline after examination, test dosing or 
QST procedures. 
 
5.2.3 
Randomised Double-blind Period (Part B) 
5.2.3.1 
Baseline visit 
A QST (including light touch, pressure, temperature as stimuli) [stimulus-evoked NRS] and 
completion of QoL questionnaire SF-36 will be performed within 7 days prior to Day 1. 
Subjects will also receive a training on how to use their Actiwatch® (device to be used for 
collection of the spontaneous NRS score). They will start to enter their NRS scores in their 
Actiwatch®, and will be provided with a paper diary as a back-up solution for NRS score 
collection. 
 
5.2.3.2 
Randomised Period 
The subjects will be required to attend the CRU on several occasions during the study: 
• 
On Day 1 in the morning, based on investigator judgement, some of the screening/run-in 
assessments may be redone to confirm that subjects are still compliant with the 
inclusion/exclusion criteria and study restrictions. If the subject is considered as stable 
in pain perception from the screening visit, subjects will undergo pre-dose safety 


 
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assessments and then receive the dose of IMP. After IMP dosing, subjects will undergo 
post-dose assessments as described in Section 18.1. 
They will be instructed to continue entering their NRS score in the Actiwatch® and will 
be provided with a paper rescue medication diary to note their post-dose rescue 
medication intake (i.e. for scar pain) and NRS score immediately before intake at home 
(details on rescue medication are provided in Section 6.2).  
They will be discharged after a minimum of two hours post-dosing. 
• 
Out-patient visits: Subjects will be required to come back to the CRU for out-patient 
visits on Week 6 and Week 12. 
During the randomised double-blind period (Part B), subjects will also be contacted by 
telephone by the CRU every day up to Day 7 (subjects might visit the CRU if required for safety 
purpose) and every two weeks after IMP dosing for collection of AEs, concomitant medications 
and compliance with pain assessments and other study requirements. 
The outpatient visits and calls from Week 2 post-dosing can occur +/- three days around the 
scheduled date. 
 
5.2.4 
Early Discontinuation or End of Study Visit 
Subjects will be discharged from the study after completion of an EoS visit for follow-up 
assessments which will happen 16 weeks after the IMP dosing +/- three days or earlier in case 
of early discontinuation (ED). The principal investigator will inform the family doctor and pain 
clinic (if applicable) with details of participation in the clinical study and any relevant 
information which may help the treating physician in the management of their patient. 
 
5.3 
Lifestyle Restrictions 
5.3.1 
Diet 
As poppy seeds can cause a positive result on the drug of abuse (DOA) test, subjects will be 
advised to avoid eating poppy seeds/food containing poppy seeds for at least 24 hours before 
attending any DOA test. Subjects diet is expected to remain stable for the duration of the study. 
 
5.3.2 
Alcohol 
Subjects should abstain from alcohol for 24 hours prior to each visit to the CRU. Excessive 
alcohol consumption (>21 units per week) should be avoided for the duration of the study. 
 
5.3.3 
Physical Activity 
Subjects should not change their exercise regime from screening until completion of the study. 
 
5.3.4 
Prohibited Concomitant Medications and non Drugs Therapies 
The following medications and therapies should not be started during the study: 
• 
Physiotherapy, 
• 
Transcutaneous electrical nerve stimulation therapy, 
• 
Antidepressants and anxiolytics, 
• 
Anticonvulsant medication used to treat pain, 
• 
Opioids  


 
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• 
Non steroidal anti-inflammatory drugs except for brief periods of treatment (up to two 
days) for other pain or fever, 
• 
Acetylsalicylic acid (aspirin) except for low doses taken for cardioprotection or brief 
periods of treatment (up to two days) e.g. for episodes of fever, 
• 
Corticosteroids (injected to treat the scar pain), 
• 
Local anaesthetics (injected to treat the scar pain, unless for the pre-randomisation run-in 
period), 
• 
Medications listed in the exclusion criteria. 
Rescue medication (as detailed in Section 6.2, i.e. paracetamol up to 4000 mg per day in divided 
doses which can be substituted by co-codamol 30 mg/500 mg for the first week post-IMP 
administration) is allowed except within 12 hours before QST assessments. Subjects must not 
take medication containing paracetamol and rescue medication without having discussed this 
with the investigator. 
Subject will also be cautioned on the use of any other medication (over-the-counter or 
prescription containing paracetamol e.g. Lemsip). 
 
5.4 
Priority Order on Study Procedures 
The following priority order should be followed in case study procedures are scheduled at the 
same timepoint: 
(1) 
NRS, 
(2) 
Vital signs, 
(3) 
Physical examination, 
(4) 
ECG, 
(5) 
Blood sampling, 
(6) 
QST, 
(7) 
Actiwatch® training. 


 
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6 
TREATMENT OF SUBJECTS 
6.1 
Study Drug(s) 
6.1.1 
Dosage Form and Strength 
Preparation of the agents and IMP will be described in the pharmacy manual. 
 
6.1.1.1 
Agents for the Pre-randomisation Run-in Period (Part A) 
The agent is a solution for subcutaneous injections (0.5 mL per injection site) of either lidocaine 
or placebo (saline). A dose of 2.5 mg of lidocaine will be injected per injection site. 
Active doses are prepared extemporaneously at the CRU pharmacy with a marketed lidocaine 
hydrochloride 0.5% v/w solution for injection in 10-mL ampoules. 
Placebo doses are prepared extemporaneously at the CRU pharmacy with a sterile and 
preservative-free sodium chloride solution 0.9% v/w solution for injection (saline) 10-mL 
ampoules. 
The pharmacist preparing the injection syringe will be unblinded as lidocaine and placebo saline 
ampoules are different in appearance. 
After preparation the placebo injection syringe is indistinguishable from the active lidocaine 
and will be appropriately labelled for immediate use. 
The pharmacist will prepare 5 mL of lidocaine or placebo to inject 0.5 mL per injection site 
with a maximum of 10 injections in the scar pain area. 
 
6.1.1.2 
IMP for the Randomised Double-blind Period (Part B) 
The IMP is a solution for single intradermal injection (0.2 mL per injection site) of either 
Dysport or placebo. 
Active doses are prepared extemporaneously at the CRU pharmacy with marketed Dysport 
500 U powder for solution for injection reconstituted and further diluted with saline to reach 
the targeted dose as indicated on the Dysport/placebo vial. 
Placebo doses are prepared extemporaneously at the CRU pharmacy with a placebo powder for 
solution for injection reconstituted and further diluted with saline using the same procedure as 
for the corresponding Dysport dose. They are indistinguishable from the active (Dysport) 
formulation after reconstitution. 
The pharmacist preparing the injection syringe will be blind on the treatment group and 
unblinded on the dose. 
The pharmacist will prepare 2 mL of Dysport/placebo solution to inject 0.2 mL per injection 
site with a maximum of 10 injections in the scar pain area. 
 
6.1.2 
Supplies 
The CRU will be provided with: 
• 
Part A: Pre-randomisation run-in kits containing all material for injection test 1 and 
injection test 2 (lidocaine, lidocaine placebo (saline), injection syringes, injection 
syringes labels, needles). 
• 
Part B: Randomisation kits (with the white label) and replacement kits (with the blue 
label) containing all material for Day 1 injection (Dysport or Dysport placebo, ampoules 
of saline for dilution, injection syringes, injection syringes labels, needles). 


 
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lidocaine, lidocaine placebo (saline), Dysport and Dysport placebo will be supplied with lot 
number, expiry date, certificate of analysis and certificate of compliance or corresponding 
documentation for the release of the agent and IMP. 
 
6.1.3 
Packaging and Labelling 
Pre-randomisation run-in kits, randomisation and replacement kits, lidocaine, lidocaine placebo 
(saline), Dysport and Dysport placebo will be provided in box, vials or ampoules, labelled 
according to applicable regulations requirements and national laws in force. 
 
6.1.4 
Storage 
The investigator, or an approved representative (e.g. pharmacist), will ensure that all agents, 
IMP and any other study-related materials are stored in a secured area, under recommended 
temperature monitored storage conditions, in accordance with applicable regulatory 
requirements. 
Pre-randomisation run-in kits for Part A (lidocaine and lidocaine placebo (saline)) should be 
stored between +15°C and +25°C. 
Randomisation kits for Part B (Dysport, Dysport placebo and saline used for Dysport/placebo 
reconstitution) should be stored between +2°C and +8°C. 
 
6.1.5 
Dispensing, Treatment and Administration Procedure 
All agents and IMP provided to the CRU pharmacist will be allocated and dispensed by 
appropriately trained staff. Agents and IMP injections will occur under medical supervision. 
Subcutaneous injections will be performed under a standard volume of 0.5 mL for lidocaine 
and lidocaine placebo. 
Intradermal injections will be performed under a constant volume of 0.2 mL for Dysport and 
Dysport placebo. 
A maximum of 10 sites will be injected in the scar pain area. 
The scar pain area reported by the subject will be mapped and drawn on the skin with a skin 
marker pen. The longitudinal axis of the painful area will be measured. The boundary of the 
spontaneous pain felt by the subject as well as the sites for injection at 2-cm intervals and 
starting 1 cm from the edge of the longitudinal axis of the pain area will be marked as 
represented in Figure 3. A photograph will be recorded with a ruler for scale and used to 
reproduce the administration scheme on injection test  1, injection test 2 and dosing on Day 1. 


 
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Figure 3 Administration Scheme 
 
 
 
6.1.6 
Accountability 
The investigator (or designee) will ensure adequate records (allocation, disposition, shipment, 
dispensing and returned drugs) are maintained in an agent and IMP accountability log. 
 
6.2 
Rescue Medication 
Paracetamol (acetaminophen), taken orally as required, is the rescue pain medication during the 
randomised double-blind period (Part B) and will be provided by the CRU to the subject. It can 
be taken up to four times a day and should not exceed a daily dose of 4000 mg in divided doses. 
A single dose of rescue medication is defined as 1000 mg (two tablets). 
The single paracetamol dose may be lowered to 500 mg (one tablet) if the investigator/subject 
feels that the dose is higher than what may be required to provide adequate analgesic effect. 
For the first week, in Part B post-dose, the investigator may substitute paracetamol with 
co-codamol (30 mg/500 mg, maximum 4000 mg of paracetamol per day). 
If the subject takes the maximum rescue medication dose of 4000 mg paracetamol per day for 
three consecutive days and still reports uncontrolled scar pain, the investigator should consider 
discontinuing the subject from the study. If uncontrolled pain elsewhere in the body were to 
develop, the management of this should be handled on a case-by-case basis. 
The rescue medication should be swallowed whole with water and must not be broken or 
crushed. 
The subject will be cautioned on the use of any other medication (over-the-counter or 
prescription containing paracetamol e.g. Lemsip). 
Rescue medication should not be taken in conjunction with other analgesic medication unless 
discussed with the investigator. 
If rescue medication is taken, an AE and the corresponding rescue medication should be 
recorded in the eCRF. 


 
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The sponsor medical monitor should be contacted if further guidance is required. For questions 
on concomitant medications prescribed prior to study participation, the sponsor medical 
monitor should be contacted before the subject is included in the study. 
 
6.3 
Concomitant Medications 
Any prior or concomitant medication given to a subject 30 days prior to dosing and during the 
study will be reported in the eCRF. Dose and trade name will be recorded. The dose of the 
concomitant medications taken during the randomised double-blind period should be kept 
constant, where possible, until the EoS. 
All medications not prohibited by the protocol and considered necessary for the subject’s 
welfare may be administered and/or continued under the supervision of the investigator. 
Only analgesia medication which has been stable during the previous month prior to entry into 
the study will be allowed. 
 
6.4 
Subject Compliance Monitoring 
The investigator will be responsible for monitoring subject compliance. 


 
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7 
SAFETY ASSESSMENTS 
The following safety parameters will be collected and reviewed during the study at specific 
timepoints as described in the study schedule of assessments in Section 18.1: 
• 
AEs, 
• 
Concomitant medications, 
• 
Medical and surgical history, 
• 
Physical examination (including height, body weight, body temperature, examination of 
the scar at the injection sites), 
• 
Vital signs (including heart rate (HR), and diastolic (DBP) and systolic blood pressures 
(SBP). 
Further routine medical assessments or any additional safety procedures may be performed 
during the study, if warranted and agreed upon between the sponsor and the investigator, or 
when clinically indicated. 
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 set up of a discharge plan if needed. 
Every effort should be made to ensure that all safety evaluations are completed by the same 
individual who made the initial baseline determination. 
The sponsor medical monitor and the GPS physician will monitor safety data throughout the 
course of the study. 
Any new clinically significant finding should be recorded as an AE from the time informed 
consent is given. 
 
7.1 
Adverse Events 
Adverse events will be monitored and reviewed regularly by the sponsor from the time that a 
subject gives informed consent and throughout the study, and will be elicited by direct, 
nonleading questioning or by spontaneous reports. 
 
7.1.1 
Definition of an Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
preexisting-medical condition, 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, 
ECG). 
An AE can include an undesirable medical condition occurring at any time, even if no agent or 
IMP has been administered. 
This definition includes events occurring from the time of the subject giving informed consent 
until the EoS/ED. 
 
7.1.2 
Adverse Events Categorisation, Recording, and Follow-up 
For all AEs, sufficient information should be obtained by the investigator to determine the 
causality of the AE (i.e. agent or IMP administration, study procedure or other illness). The 
investigator is required to assess causality and record that assessment in the eCRF. 
Adverse events will be classified by the investigator as mild, moderate or severe according to 
the following criteria: 


 
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• 
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 well-being, significant impairment of 
function or incapacitation. 
The relationship of an AE to agent or IMP administration will be classified by the investigator 
according to the following: 
• 
Related: Reports including good reasons and sufficient information (e.g. plausible time 
sequence, dose-response relationship, pharmacology) to assume a causal relationship 
with agent or 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 agent or IMP administration. 
 
7.1.2.1 
Assessment of Expectedness 
The expectedness of an AE shall be determined by the sponsor according to the latest approved 
version of the Dysport Investigator’s brochure (IB) and the lidocaine SmPC in the UK 
(Marketing authorisation number 
). 
 
7.1.2.2 
Follow-Up of Adverse Events 
Any AEs already recorded and designated as “continuing” should be reviewed at each 
subsequent assessment. 
If an AE is still present at the end of the study, reasonable follow-up clinical monitoring (and 
up to 30 days after the end of the study) should be managed by the investigator or any 
appropriate physician until the event or its sequelae resolves or stabilises at an acceptable level, 
as judged by the investigator. The frequency of follow-up evaluation is left to the investigator’s 
discretion. 
 
7.1.2.3 
Reporting of Adverse Events 
Any AE considered related to agent or IMP administration that the investigator becomes aware 
of after completion of the EoS/ED visit must be reported to the sponsor and will be recorded in 
the corresponding database. 
 
7.1.3 
Serious Adverse Event Assessment and Reporting to Sponsor 
The investigator must pursue and obtain adequate information to determine the outcome of the 
AE and to assess whether it meets criteria for classification as an SAE requiring immediate 
notification to the GPS department of the sponsor. 
An SAE is any AE that: 
• 
Results in death, 
• 
Is life-threatening, that is any event that places the subject at immediate risk of death 
from the event as it occurs. It does not include an event that, had it occurred in a more 
severe form, might have caused death, 
• 
Results in in-patient hospitalisation or prolongation of existing hospitalisation, excluding 
admission for social or administrative reasons, 
CCI


 
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- 
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 noted in the 
subject’s screening documentation. 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, 
• 
Results in a persistent or significant disability/incapacity, where disability is a substantial 
disruption of a person's ability to conduct normal life functions, 
• 
Results in congenital anomaly/birth defect in the offspring of a subject who received the 
agent or IMP, 
• 
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 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. 
All SAEs regardless of treatment group or suspected relationship to agent or IMP must be 
reported immediately (within 24 hours of the investigator’s knowledge of the event) using the 
fax number specified on the front page of the current document. 
Any appropriate means of notification may be used. If the immediate report is submitted by 
telephone, this must be followed by detailed written reports using the SAE report form. 
The following information is the minimum that must be provided to the sponsor: 
• 
Study number, 
• 
CRU, 
• 
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. 
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. 
 


 
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7.1.4 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the latest approved Dysport IB or the lidocaine SmPC in the UK and that the investigator 
identifies as related to agent or IMP or procedure. 
 
7.1.5 
Pregnancy 
Investigators are instructed to report any pregnancy within 24 hours of first awareness of the 
pregnancy. Information regarding any pregnancy must be collected on the AE page of the eCRF 
and also on the standard pregnancy outcome report form. Ipsen will request further information 
from the investigator concerning the course and the outcome of the pregnancy (including the 
medical condition of the mother, fetus and neonate) using the form. 
Information received on any pregnancy with conception date within the time interval specified 
in the study protocol will be reported in the final clinical study report. 
 
7.1.6 
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 BTX effects. 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 are AEs that suggest a possible remote 
spread of effect of the toxin or hypersensitivity. A list of preferred terms of AESIs will be 
provided in the statistical analysis plan (SAP). All AEs will be monitored by the sponsor to 
determine if they meet the criteria of AESIs. These AESIs will be further analysed to determine 
if there is a plausible possibility that they represent distant spread of toxin or hypersensitivity. 
In order to perform the analysis, variables including alternate aetiology (medical history, 
concomitant medication, or diagnosis which could account for the symptoms), location of 
Dysport administration, and temporal relationship to Dysport administration will be considered 
by the sponsor. 
 
7.1.7 
Deaths 
All AEs resulting in death during the study period must be reported as a SAE. 
The convention for recording death is as follows: 
• 
AE 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”. 
 
7.1.8 
Reporting to Competent Authorities, IECs/IRBs and other Investigators 
The sponsor will ensure that processes are in place for submission of reports of SUSARs 
occurring during the study to the Competent Authorities (CAs), Independent Ethics Committees 


 
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(IECs)/Institutional Review Boards (IRBs) and other investigators concerned by the agent or 
IMP. 
Reporting will be done in accordance with the applicable regulatory requirements. 
The sponsor must report all SUSARs to European Medicines Agency’s EudraVigilance 
database within 15 days. Fatal and life-threatening SUSARs should be reported within 
seven calendar days, with another eight days for completion of the report. 
The sponsor can prepare additional reports for other authorities (e.g. FDA). 
 
7.2 
Specific Safety Assessments 
The investigator is responsible to monitor subjects’ safety at any time during the study. 
For each assessment performed, the investigator must document his review of the result(s) in 
the source document(s). In case of abnormal result or value(s) falling outside of predefined 
normal ranges, the investigator should specify whether the finding is considered as “clinically 
significant” (CS) or “not clinically significant” (NCS). 
Any finding, whether judged CS or NCS may lead to retest at the discretion of the investigator. 
 
7.2.1 
Physical examinations 
Physical examinations including height, body weight, body temperature (only at screening) and 
pain description will be conducted as presented in the schedule of assessments in Section 18.1. 
Physical examination includes inspection of general appearance, skin, neck (including thyroid), 
eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, vascular system, extremities, 
musculo-skeletal system and nervous system. 
The nature of the scar pain will be assessed using standardised descriptors e.g. sharp, dull, 
aching, burning, shooting, stabbing, electric shocks. 
Any changes from baseline in physical examination findings judged to be clinically significant 
by the investigator/ will be recorded 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. 
 
7.2.2 
Vital Signs 
Vital signs, including HR, SBP and DBP will be assessed as presented in the schedule of 
assessments in Section 18.1. 
SBP, DBP and HR assessments will be performed with an automated device so that 
measurements are independent of the observer. These parameters will be recorded after at least 
5 minutes rest in supine position for supine assessment, followed by 1 minute in sitting position 
before standing up where applicable. The standing assessment will be performed after at least 
2 minutes standing (only at screening visit). The investigator will record any clinically 
significant abnormal value as AEs. All AEs will be discussed regularly with the sponsor. 
 
7.2.3 
Electrocardiograms 
Twelve-lead computerised standard ECGs, with paper printout, will be obtained while the 
subject is in resting supine position for at least five minutes and until four regular consecutive 


 
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complexes are available, at the screening visit only as presented in the schedule of assessments 
in Section 18.1. 
The ECG will be interpreted by a qualified physician at the CRU as soon after the time of ECG 
collection as possible, and ideally while the subject is still present, for immediate subject 
management. The qualified physician will document his review and interpretation (including 
evaluation of clinical significance in case of abnormality) on every ECG printout. 
The paper printouts will be kept in the source documents at site. Only the interpretation and 
abnormalities will be reported in the eCRF for integration with other clinical study data. These 
paper ECGs may be subject to further review, if appropriate. The investigator will review each 
safety laboratory test results, document the review, and record any clinically significant 
abnormal value as AEs. All AEs will be discussed regularly with the sponsor. 
 
7.2.4 
Clinical laboratory tests 
Blood and urine samples collection will be performed for standard clinical laboratory tests, 
including biochemistry, haematology, serology and urinalysis panels, as well as specific tests 
such as urine drug screening and urine pregnancy tests for women of childbearing potential, as 
indicated in the schedule of assessments in Section 18.1. 
Full details related to the samples processing, labelling, storage, shipment and destruction 
procedures will be documented in a laboratory stand-alone document. 
The results of laboratory tests performed during the screening phase must be obtained before 
injection test 1. 
The investigator will review each safety laboratory test results, document the review, and record 
any clinically significant abnormal value as AEs. All AEs will be discussed regularly with the 
sponsor. 
 
7.2.4.1 
Blood Analyses 
Parameters to be assessed are listed in Section 18.3. 
 
7.2.4.2 
Urinalysis 
Freshly voided urine samples (at least 10 mL) will be collected to perform a dipstick assessment 
of the parameters listed in Section 18.3. In case of abnormal result on the dipstick, a 
confirmatory analysis or additional assessments might be requested to the local laboratory, at 
the discretion of the investigator. 
Microscopy will be performed, if indicated, but results will not be collected in the eCRF. If in 
the opinion of the investigator there are any clinically significant abnormalities in microscopy, 
they will be recorded as an AE in the eCRF. 
 
7.2.4.3 
Pregnancy Test 
Human chorionic gonadotrophin will be assessed using an urinary dipstick in all female subjects 
as specified in the schedule of assessments in Section 18.1. It may be repeated at any time 
during the study according to investigator’s judgement. 
 
7.2.4.4 
Drug of Abuse 
Urine drug screen testing will be performed as specified in Section 18.1 and at any time at the 
discretion of the investigator. If positive the subject may still continue in the study if there is a 


 
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clinically plausible reason for the result and no concerns by the investigator e.g. a positive 
opioid test due to the subject taking as prescribed an opioid containing compound as analgesic. 
 
7.2.5 
Scar Ultrasound 
An ultrasound of the scar will be performed to exclude subjects exhibiting a neuroma in their 
scar-related painful area. 


 
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8 
PHARMACOKINETIC ASSESSMENTS 
Not applicable. 


 
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9 
PHARMACODYNAMIC ASSESSMENTS 
The following pharmacodynamic parameters will be collected and reviewed during the study 
at specific timepoints as described in the study schedule of assessments in Section 18.1. 
 
9.1 
Numerical Rating Scale 
The NRS is a 11-point scale to assess subject pain perception as described in Figure 4. Subjects 
will be asked for their score. 
Figure 4 Numerical Rating Scale 
 
 
9.1.1 
Spontaneous Average and Worst Pain NRS Score during the Screening Visit 
Subjects will be asked to record their average scar-related pain intensity for the previous 
24 hours. The subjects will be asked the following question: 
“Please rate your pain by selecting the one number that best describes your pain on average 
during the last 24 hours.” 
Subjects will be asked to record their worst scar-related pain intensity for the previous 24 hours. 
The subjects will be asked the following question: 
“Please rate your pain by selecting the one number that best describes your pain at its worst 
during the last 24 hours.” 
 
9.1.2 
Spontaneous Current Pain NRS Score in Part A 
On the day of the injection test, before the injection test (predose), subjects will be asked what 
are their current NRS score, the pain felt by the subject at the time of the assessment. The 
subjects will be asked to answer the following question: 
“Please rate your pain by selecting the one number that best describes how much pain you 
have right now.” 
Subjects will then be injected and will report their pain relief within 30 minutes after the 
injection test if any. Subjects will be asked for their current NRS score at 30 minutes and 
one hour post-injection test, according to the question just described previously. 
Subjects will be provided with a paper diary after injection tests 1 and 2. They will be invited 
to record at home after discharge their current NRS scores hourly up to eight hours and between 
20 and 24 hours post-injection test in this diary. 
 
0 
No 
pain 
PAIN SCORE 0- 10 NUMERICAL RATING 
2 
3 
4 
5 
Moderate 
pain 
6 
7 
8 
9 
10 
Worst 
possible 
pain 


 
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9.1.3 
Spontaneous Average and Worst Pain NRS Score in Part B 
If subjects are responders, they will be provided with an Actiwatch® during an Actiwatch® 
training visit to record their spontaneous NRS score at home. They will start NRS score 
recording from the training visit on Actiwatch® use. 
The Actiwatch® will alarm and alert the subjects twice a day to record their average and 
maximal NRS scores over the preceding 12 hours. The questions will be asked of the subject 
by the Actiwatch®: 
“Please rate your pain by selecting the one number that best describes your pain on average 
during the last 12 hours.” 
“Please rate your pain by selecting the one number that best describes your pain at its worst 
during the last 12 hours. 
The Actiwatch® will allow electronic NRS score collection and storage from the Actiwatch® 
training to EoS. Data will be extracted from the Actiwatch® at each visit. A paper diary will 
also be provided to subjects in the unlikely event of an Actiwatch® malfunction during the 
collection period. One week before post-dosing visit to the CRU, the subjects might be 
requested to complete the paper diary as a quality control check for the data in the Actiwatch® 
and as a back up in case there is a problem with downloading information from the Actiwatch®. 
 
9.2 
Stimulus-evoked NRS Score during Quantitative Sensory Testing 
Subjects will be submitted to stimuli of various nature applied to the painful area. 
Stimulus-evoked NRS score will be collected during the assessments. 
Subjects will be asked what are their current NRS scores predose and post-stimulus. 
At baseline and at the post-dose visits light touch, pressure and temperature will be used as 
stimuli for QST. 
The QST battery of tests is described in full in Sections 18.4 and 18.5. 
 
9.2.1 
Light Touch 
The surface of the painful area will be measured on radial spokes starting from the previously 
mapped painful area applying a von Frey filament. The filament will be applied until it slightly 
bends and be left in place for 4-5 seconds. Subjects will be asked to report when the von Frey 
filament first begins to cause any pain sensation and the distance of that point from the initial 
mapped painful area will be recorded. 
The first painful position will be located on the skin and this process will be done for each radial 
spoke. 
The resulting points will then be transferred onto a tracing paper sheet and connected to define 
the outline of the painful area submitted to light touch. The area of pain will be calculated by 
using 1 cm2 squares on the tracing paper (see Section 9.3). 
 
9.2.2 
Pressure (Pressure Pain Threshold) 
An evoked current NRS score will be recorded for each pressure intensity. The pressure pain 
threshold (PPT) assesses the level of pressure causing pain. In post-surgical neuralgia subjects, 
light, normally non-painful pressure applied at the most painful point causes/may cause intense 
pain. The PPT is assessed by the investigator by using a pressure algometer (contact area 1 cm2), 
documented in the source data, and transferred to the eCRF. The threshold for pressure induced 
pain is measured and then repeated in three series of slowly increasing stimulus intensities (at 
a rate of about 50 kPa/s). The subject must not be able to look at the readings during the 


 
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measurement. For the final PPT, the arithmetic mean of all three consecutive measurements 
will be calculated (Maier et al., 2010; Mainka et al., 2014). 
 
9.2.3 
Temperature 
A thermal stimulation will be provided from a thermode placed on the painful area. 
The temperature of the thermode is controlled by a Medoc TSA II NeuroSensory Analyser 
(Medoc Ramat Yishai, Israel). The TSA-II – NeuroSensory Analyser is a precise, computer-
controlled device capable of generating and documenting response to highly repeatable thermal 
and stimuli, such as warmth, cold, heat-induced pain and cold-induced pain. The thermal 
sensory testing element measures the thresholds for four sensory sub-modalities: 
• 
Warm sensation, for normal subjects, usually at 1- 2ºC above adaptation temperature 
(C fiber mediated sensation), 
• 
Cold sensation, for normal subjects, usually at 1- 2ºC below adaptation temperature 
(A-delta fibers mediated sensation), 
• 
Heat induced pain, threshold around 45ºC (mostly C fiber mediated sensation, with some 
involvement of A-delta fibers). 
Cold induced pain, the most variable and difficult to assess of all previous modalities, at about 
10º C (combination of both C and A-delta fiber mediated sensation).Warm detection and heat 
pain thresholds will be determined. The start of the temperature will be 32°C and gradually 
ramped by 1°C/sec. The heat pain threshold will be obtained when the subject will experience 
a painful feeling. The thermode will automatically shut down at a preset temperature of 53°C 
in order to avoid any tissue damage. 
Cold detection and cold pain thresholds will also be determined, as programmed by the TSA II.  
 
9.3 
Area of Pain 
The scar pain area reported by the subject will be mapped and drawn on the skin with a skin 
marker pen. 
The longitudinal axis of the painful area and the total painful area will be measured. The 
boundary of the spontaneous pain felt by the subject as well as the sites for injection at 2-cm 
intervals and starting 1 cm from the edge of the longitudinal axis of the pain area will be marked 
as represented in Figure 3 in Section 6.1.5. A photograph will be recorded with a ruler for scale 
and used to reproduce the administration scheme on injection test  1, injection test 2 and IMP 
dosing on Day 1. 


 
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10 
EXPLORATORY ASSESSMENTS 
The following exploratory assessments will be performed during the study at specific 
timepoints as described in the study schedule of assessments in Section 18.1. 
 
10.1 
Quality of Life questionnaire Short Form-36 
The SF-36 is a 36-item, subject-reported survey of subject health. The SF-36 consists of eight 
scaled scores (vitality, physical functioning, bodily pain, general health perceptions, physical 
role functioning, emotional role functioning, social role functioning and mental health). The 
higher the score the less disability. 
 
10.2 
Rescue Medication 
Details on the rescue medication are provided in Section 6.2. 
Subjects will be provided with a rescue diary (paper) to record each rescue medication intake, 
dose, each pain increase (AE), start and stop date and time and current NRS score just before 
the rescue medication is taken. 
If rescue medication is taken, an AE and the corresponding rescue medication should be 
recorded in the eCRF. 


 
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11 
STATISTICAL ANALYSES 
11.1 
Analyses Populations 
The following populations will be used for statistical analyses: 
• 
Screened population: All subjects screened (i.e. who signed the informed consent), 
• 
Run-in population: All subjects who received at least one injection in the 
pre-randomisation run-in period (Part A), 
• 
Randomised population: All subjects randomised in the double-blind period (Part B), 
• 
Safety population: All subjects who received at least one dose of the study drug during 
the randomised double-blind period (Part B), 
• 
Per protocol (PP) population: All subjects from the randomised population for whom no 
major protocol deviation occurred. 
 
11.2 
Sample Size Calculation 
No prospective calculations of statistical power is made. 
An appropriate sample size cannot be determined statistically as no previous human data from 
previous clinical trials are available. A sample size of six subjects per dose of Dysport has been 
selected. Approximately 24 subjects will be randomised in the double-blind period. Subjects 
who withdraw within the six first weeks from dosing will be replaced. 
 
11.3 
Statistical Methods 
A SAP describing the planned statistical analysis in detail with tables, figures, and listings 
(TFLs) templates will be developed as a stand-alone document. 
An overview of the main analysis strategy is provided in the following sections. 
TFLs will be presented by treatment group (placebo, Dysport 2.5, 10 and 20 U). Some tables 
will also be described by total dose received in the painful injection area and the total dose 
received in the painful area divided by the painful area. This will be fully detailed in the SAP. 
 
11.3.1 
Safety Evaluation 
11.3.1.1 Pre-randomisation Run-in Period (Part A) 
Only listings will be provided. 
 
11.3.1.2 Randomised Double-blind Period (Part B) 
Descriptive statistics will be calculated on the safety parameters. No formal statistical tests of 
safety parameters are planned. 
All AEs will be coded according to the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA). 
Treatment emergent AEs (TEAE) summaries will include the overall incidence (by system 
organ class and preferred term), events by maximum intensity, events by relationship to study 
drug, events leading to discontinuation of study drug, and SAEs. 
Physical examination findings, vital signs, ECG recordings and clinical laboratory parameters 
will be summarised descriptively at each timepoint. Actual and change from baseline data will 
be calculated and summarised where data are available. The investigator’s interpretation of 
12-lead ECGs will be listed. 


 
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Concomitant medications will be coded by using the latest version of the World Health 
Organisation (WHO) drug dictionary and will be summarised with the number and percentage 
of subjects receiving concomitant medication by drug class and preferred drug name. 
Demographic variables (age, height, weight and body mass index) and medical and surgical 
history will be summarised. 
 
11.3.2 
Pharmacokinetic Evaluation 
Not applicable. 
 
11.3.3 
Pharmacodynamic/ Efficacy Evaluation 
11.3.3.1 Pre-Randomisation Run-in Period 
Only listing on NRS data will be provided.  
 
11.3.3.2 Randomised Double-blind Period 
 
Analysis of the primary endpoints 
Four endpoints have been defined to meet the study primary objective. They are presented in 
Table 3 with their associated estimate and estimand. 
 
Table 3 
Primary Objective - Analysis of Primary Endpoints 
 
Objective 
Assessments 
Endpoints 
Estimate of 
treatment effect 
Estimand 
To describe the 
pharmacodynamic 
analgesic profile 
of 
intradermal 
doses of Dysport 
in subjects with 
abdominal 
or 
thoracic 
chronic 
scar pain. 
 
Worst pain and 
average 
pain 
within the last 
12 
hours 
as 
assessed by the 
spontaneous 
NRS score. 
Time to onset, i.e. time 
to 
decrease 
from 
baseline of two points in 
the spontaneous NRS 
score. 
The number (%) of 
subjects who reach the 
time to onset in each 
treatment group. 
The mean time to onset 
in 
each 
treatment 
group. 
For 
each 
estimate, 
the 
associated 
estimand will be 
based 
on 
"treatment 
policy" 
strategy 
(i.e. regardless of 
the 
intake 
of 
rescue 
medication). 
Peak-effect, 
i. 
e. 
maximal decrease from 
baseline 
in 
the 
spontaneous 
NRS 
score. 
The mean peak in each 
treatment group. 
Time to peak-effect, i.e. 
time to reach the peak-
effect. 
The mean time to reach 
the peak-effect in each 
treatment group. 
Duration of effect, i.e. 
duration between time 
to 
onset 
and 
last 
timepoint with change 
from baseline in the 
spontaneous NRS score 
is ≥2 points. 
The mean duration of 
effect in each treatment 
group (for the subjects 
who reach the time to 
onset).  
Only descriptive statistics will be provided. No statistical test will be performed. 


 
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As described in the above table, the estimand will be based on “treatment policy” strategy, 
which is the estimate of the treatment effect regardless of whether the subject has an intercurrent 
event during the study. 
The following potential intercurrent events will be considered: 
 The short-term use of rescue medication, 
 The change in use of rescue medication. 
Supplementary and sensitivity analysis will be performed to take into account these intercurrent 
events and to handle missing data. These analysis will be detailed in the SAP. 
 
Analysis of the secondary endpoints 
Endpoints have been defined to meet the study secondary objectives. They are presented in 
Table 4 with their associated estimate and estimand. 
 
Table 4 
Secondary Objectives - Analysis of Secondary Endpoints 
 
Objective 
Assessments 
Endpoints 
Estimate of 
treatment effect 
Estimand 
To compare the 
efficacy of 
intradermal 
doses of Dysport 
to placebo. 
 
Spontaneous 
pain as 
assessed by the 
spontaneous 
NRS score. 
Change from baseline 
in the spontaneous 
NRS score to each 
scheduled timepoint. 
Difference between 
each Dysport doses 
and the placebo 
group, in the mean 
change from baseline 
in the spontaneaous 
NRS score to each 
scheduled timepoint. 
For each estimate, 
the associated 
estimand will be 
based on "treatment 
policy" strategy (i.e. 
regardless of the 
intake of rescue 
medication). 
Stimulus-
evoked pain as 
assessed by the 
NRS score 
during QST. 
Change from baseline 
in the stimulus-
evoked NRS score to 
each scheduled 
timepoint. 
Difference between 
each Dysport doses 
and the placebo 
group, in the mean 
change from baseline 
in the stimulus-
evoked NRS score to 
each scheduled 
timepoint. 
For each estimate, 
the associated 
estimand will be 
based on "treatment 
policy" strategy (i.e. 
regardless of the 
intake of rescue 
medication). 
To assess the 
safety and 
tolerability of a 
range of 
intradermal 
doses of Dysport 
Refer to Section 11.3.1. 
 
Only descriptive statistics will be provided. No statistical test will be performed. Supplementary 
and sensitive analysis will be performed to take into account the intercurrent event and to handle 
missing data. These analysis will be detailed in the SAP. 


 
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Exploratory efficacy endpoints 
Endpoints have been defined to meet the study exploratory objectives. They are presented in 
Table 5 with their associated estimate and estimand. 
 
Table 5 
Exploratory Endpoints - Analysis of Exploratory Endpoints 
 
Objective 
Assessments 
Endpoints 
Estimate of 
treatment effect 
Estimand 
To explore 
improvement of 
QoL using SF-36 
questionnaire. 
QoL assessed 
by the SF-36. 
Change from baseline 
in SF-36 scores at each 
scheduled timepoint 
(scores/domain that 
will be used will be 
described in the SAP). 
Difference between 
each Dysport doses 
and the placebo group 
in the SF-36 scores at 
each scheduled 
timepoint. 
For each 
estimate, the 
associated 
estimand will be 
based on 
"treatment 
policy" strategy 
(i.e. regardless of 
the intake of 
rescue 
medication). 
To explore 
concomitant use 
of rescue 
medication 
(analgesia). 
Use of rescue 
medication 
during the 
study. 
- Amount of rescue 
medication taken 
during the study. 
- Time to first intake of 
rescue medication. 
- Difference between 
each Dysport doses 
and the placebo group, 
in amount of rescue 
medication intake 
during the randomised 
double-blind period. 
- Difference between 
each Dysport doses 
and the placebo group, 
in the time to first 
intake of rescue 
medication during the 
randomised double-
blind period. 
 
Only descriptive statistics will be provided. No statistical test will be performed. 
 
11.3.4 
Interim Analyses 
No interim analyses are planned for this study. 


 
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12 
DATA HANDLING AND RECORD KEEPING 
12.1 
Data Collection 
In compliance with GCP, the source data, i.e. medical records/medical notes, etc, should be 
clearly marked and permit easy identification of a subject’s participation in the specified clinical 
study. 
Source data identification and location will be specified in a stand-alone document signed by 
the investigator(s). 
The investigator must record all data relating to protocol procedures, study drug administration, 
laboratory data, safety, pharmacodynamic/efficacy data on the source documents and report 
requested data on electronic eCRFs provided for the study (see Section 12.2).  
To ensure accurate, complete, and reliable data, the sponsor or its representative will provide 
instructional material to the study site(s), as appropriate. Training session will be given during 
a start-up/initiation meeting for instructions on the completion/data entry of any source data 
documents and eCRF. 
The investigators or their designees must verify that all data entries in the eCRF are accurate 
and consistent with source data records . If certain information is not available for a particular 
timepoint and/or subject, specific instructions should be followed, e.g. to document that the 
procedure was either not done or not applicable. 
 
12.2 
Data Reporting 
Electronic data capture will be utilised for collecting subject data. The study site is required to 
have a computer and internet connection available for study site entry of clinical data. All 
entries in the eCRF will be made 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. 
 
12.3 
Data Management 
Details of all data management procedures, from the initial planning to the archiving of final 
datasets/documents following database freeze/lock will be documented in appropriate stand-
alone data management and validation plan(s). 
Data management will be conducted by a contract research organisation (CRO) approved by 
the sponsor. All data management procedures will be completed in accordance with the sponsor 
and contracted CRO standard operating procedures (SOPs). Prior to data becoming available 
for processing at the assigned data management CRO, they will be monitored. Data 
documentation removed from the CRU 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 that suitable queries are raised to resolve any missing or inconsistent data. At the end of the 
study, the investigator will receive the data from the clinical study in an electronic format (PDF 
files), which will be an exact copy of the eCRF, 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 data management CRO. It is the central study monitor’s responsibility to ensure that 
all queries are resolved by the relevant parties. 


 
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The CRO will also ensure, via SAE reconciliation, that SAE data collected in the eCRF are 
consistent with SAE data held in the sponsor’s GPS department (and vice versa). 
The coding of an AE, medical history, surgical procedures and concomitant medication terms 
will be performed by a contracted CRO, managed by the sponsor’s Biometry department, and 
reviewed and approved by the sponsor. Concomitant medications will be coded using 
WHODRUG-B3 and AEs/medical history terms will be coded using MedDRA.  
Only 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, the reason for screen failure and the potential AEs will be reported in the eCRFs and 
collected in the sponsor’s database. 
For run-in failure subjects , at least all data recorded for screen failure subjects will be collected 
in addition to NRS data and previous/concomitant medications. 
 
12.4 
Record Keeping 
The investigator will keep records of all original source data. This might include laboratory 
tests, medical records, and clinical notes. 
During the prestudy and initiation visits, 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 two 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 two 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 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 study 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 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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13 
REGULATORY AND ETHICAL CONSIDERATIONS 
13.1 
Regulatory Considerations 
The study will be conducted in compliance with IECs/IRBs, informed consent regulations, the 
Declaration of Helsinki and ICH Guidelines related to GCP. Any episode of noncompliance 
will be documented. The electronic data capture (EDC) system will comply with the FDA, 
21 CFR Part 11, Electronic Records, Electronic Signatures, and FDA, Guidance for Industry: 
Computerized Systems Used in Clinical Trials. 
In addition, the study will adhere to all applicable international and local regulatory 
requirements. 
All or some of the obligations of the sponsor will be assigned to a CRU or a CRO.  
An identification code assigned to each subject will be used in lieu of the subject’s name to 
protect the subject’s identity when reporting AEs and/or other trial-related data (see Section 
3.4.1). 
 
13.2 
Ethical Review Considerations 
The following documents should be submitted to the relevant ethics committee(s) (EC) 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 EC(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 EC 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 EC approval or favourable opinion. 
During the study, any update to the following documents will be sent to the EC either for 
information, or for review and approval, depending on how substantial the modifications are: 
(1) IB; (2) reports of SAEs; (3) 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. 
 
13.3 
Subject Information Sheet and Consent 
The investigator is responsible for ensuring that the subject understands the potential risks and 
benefits of participating in the study, including answering, orally and/or in writing, to any 
questions the subject may have throughout the study and sharing any new information that may 
be relevant to the subject’s willingness to continue his or her participation in the study in a 
timely manner. 
The subject information sheet and consent document will be used to explain the potential risks 
and benefits of study participation to the subject in simple terms before the subject is entered 


 
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into the study, and to document that the subject is satisfied with his/her understanding of the 
study and desires to participate. 
The investigator is ultimately responsible for ensuring that the EC-approved informed consent 
is appropriately signed and dated by each subject prior to the performance of any study 
procedures. Informed consent obtained under special circumstances may occur only if allowed 
by local laws and regulations. 
 
13.4 
Final Report Signature 
The investigator or designee will be proposed to review and sign the clinical study report for 
this study, indicating agreement with the analyses, results, and conclusion of the report. 
 


 
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14 
INSURANCE AND FINANCE 
14.1 
Insurance 
The sponsor declares that it has taken out a product liability insurance covering all subjects 
screended and enrolled in this study in respect to risks involved in the study.  
 
14.2 
Financial Agreement 
Since this study is to be performed in partnership with a CRO, separate financial agreements 
between the sponsor and the CRO on one side, and the CRO and the CRU on the other side, 
will be signed prior to initiating the study, outlining overall sponsor and investigators 
responsibilities in relation to the study. 


 
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15 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure accurate, complete, and reliable data, the sponsor or its representatives will provide 
instructional material to the study sites, as appropriate. A start-up training session will be done 
prior to screening start to instruct the investigators and study coordinators. This session will 
give instruction on the protocol, the completion of the eCRF, and all study procedures. 
 
15.1 
Protocol Amendments and Protocol Deviations and Exceptions 
15.1.1 
Protocol Amendments 
In the event that an amendment to this protocol is required, it will be classified into one of the 
following three categories: 
• 
Non-substantial amendments are those that are not considered ‘substantial’ 
(e.g. administrative changes) and as such only need to be notified to the IECs or 
regulatory authorities for information purposes. 
• 
Substantial amendments are those considered ‘substantial’ to the conduct of the clinical 
study where they are likely to have a significant impact on: 
- 
the safety or physical or mental integrity of the subjects, 
- 
the scientific value of the study, 
- 
the conduct or management of the study, 
- 
or the quality or safety of the study drug used in the study. 
Substantial amendments must be submitted to and approved by the IECs and relevant 
regulatory authorities, according to local regulations, prior to implementing changes. 
• 
Urgent amendments are those that require urgent safety measures to protect the study 
subjects from immediate hazard and as such may be implemented immediately by the 
sponsor with subsequent IECs and regulatory authority notification, forthwith. 
The principal investigator and the sponsor will sign the protocol amendment. 
 
15.1.2 
Protocol Deviations and Exceptions 
Protocol deviations are defined and classified as either major or minor for a given study. Major 
deviations (or a combination of minor becoming major) may or may not impact on the analysis 
population. All minor and major protocol deviations will be identified and recorded by CRU 
personnel and should be traceable. 
Major Protocol Deviation Definition 
Any changes 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 and which may affect 
the subject’s rights, safety or well-being, or the completeness, accuracy and reliability of the 
study data. 
Minor Protocol Deviation Definition 
Any changes 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 but that do not have 
an important impact on the subject’s rights, safety or well-being, 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 is required before the subject will be allowed to enter the study. 


 
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If investigative CRU personnel learn that a subject who did not meet the protocol eligibility 
criteria was entered in a study (eligibility criteria deviation), they must immediately inform the 
sponsor. Such subjects will be discontinued from the study, except in exceptional 
circumstances, following review and written approval by the sponsor. 
 
15.1.3 
Information to Study Personnel 
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 CRU 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. 
 
15.2 
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 well-being of 
subjects are protected, 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. 
Before the study initiation visit, the sponsor assigned study monitor will write a monitoring 
plan indicating the monitoring procedures and at which occasions during the study monitoring 
visits will be performed. 
Periodic visits will be made to the study site throughout the study at mutually agreeable times. 
Any appropriate communication tools will be set up to ensure the sponsor and/or its 
representative is/are available for consultation, so they can stay in contact with the study site 
personnel. 
Adequate time and space for monitoring visits should be made available by the investigator. 
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. 
Quality of the paper-based or electronic data will be reviewed to detect errors in data collection 
and, if necessary, to verify the quality of the data. 
The eCRF is expected to be completed an ongoing basis to allow regular review by the study 
monitor, both remotely by the internet and during site visits. The study monitor will use 
functions of the EDC system to address any queries raised while reviewing the data entered by 
the study site personnel in a timely manner. 
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, leaving the date of 
birth visible, and annotated with the subject number as identification. 
 


 
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15.3 
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 EC 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. 
 
15.3.1 
Audit and Inspection 
Authorised personnel from external CAs and the sponsor’s authorised quality assurance 
personnel may carry out inspections and audits. 
 
15.3.2 
Data Quality Assurance 
Monitored eCRFs shared between the investigational site and Data Management CRO will be 
reviewed (Data Review) for completeness, consistency, legibility and protocol compliance. 
Reasons should be given in 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 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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16 
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. 


 
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Sci 1997;152:132-5. 
Heckman M, Ceballos-Baumann A, Plewig G. Botulinum toxin A for axillary hyperhidrosis 
(excessive sweating). N Engl J Med 2001;344:488-93. 
Heikkila HM, Hielm-Bjorkman AK, Morelius M, Larsen S, Honkavaara J, Innes JF, 
Laitinen-Vapaavuori OM. Intra-articular botulinum toxin A for the treatment of osteoarthritic 
joint pain in dogs: A randomized, double-blinded, placebo-controlled clinical trial. Vet J 
2014;200:162–9. 
Krug HE, Frizelle S, Mc Garraugh P, Mahowald ML. Pain behavior measures to quantitate joint 
pain and response to neurotoxin treatment in murine models of arthritis. Pain Med 
2009;10:1218-28. 
Luvisetto S, Marinelli S, Lucchetti F, Marchi F, Cobianchi S, Rossetto O, Montecucco C, 
Pavone F. Botulinum neurotoxins and formalin-induced pain: Central vs. Peripheral effects in 
mice. Brain Res 2006;1082:124–31. 
Luvisetto S, Gazerani P, Cianchetti C, Pavone F. Botulinum toxin type A as a therapeutic agent 
against headache and related disorders. Toxins 2015;7:3818-44. 
Maier C, Baron R, Tölle TR, Binder A, Birbaumer N, Birklein F, Gierthmühlen J, Flor H, Geber 
C, Huge V, Krumova EK, Landwehrmeyer GB, Magerl W, Maihöfner C, Richter H, Rolke R, 
Scherens A, Schwarz A, Sommer C, Tronnier V, Uçeyler N, Valet M, Wasner G, Treede RD. 
Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): 
somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain 
2010;150(3):439-50. 
Mainka T, Bischoff FS, Baron R, Krumova EK, Nicolas V, Pennekamp W, Treede RD, Vollert 
J, Westermann A, Maier C. Comparison of muscle and joint pressure-pain thresholds in patients 
with complex regional pain syndrome and upper limb pain of other origin. Pain 
2014;155(3):591-7. 
Marino MJ, Terashima T, Steinauer JJ, Eddinger KA, Yaksh TL, Xu Q. Botulinum toxin B in 
the sensory afferent: transmitter release, spinal activation and pain behavior. Pain 
2014;155:674–84. 


 
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Matak I, Riederer P, Lackovic Z, 2012. Botulinum toxin’s axonal transport from periphery to 
the spinal cord. Neurochem Int 2012;61:236–9. 
Mc Mahon HT, Foran P, Dolly JO, Verhage M, Wiegant VM, Nicholls DG. Tetanus toxin and 
botulinum toxins type A and B inhibit glutamate, gamma-aminobutyric acid, aspartate, and met-
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Park HJ, Marino MJ, Rondon ES, Xu Q, Yaksh TL. The effects of intraplantar and intrathecal 
botulinum toxin type B on tactile allodynia in mono and polyneuropathy in the mouse. Anesth 
Analg 2015;121:229–38. 
Park HJ, Park JH. Botulinum toxin for the treatment of neuropathic pain. Toxins 2017;9:260-75. 
Pellett S, Yaksh TL, Ramachandran R. Current status and future directions of botulinum 
neurotoxins for targeting pain processing. Toxins 2015;7:4519-63. 
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cultured dorsal root ganglion neurons: Involvement of two distinct mechanisms. Biochem 
Pharmacol 2000;59:1403-6. 
Ramachandran R, Lam C, Yaksh TL. Botulinum toxin in migraine: Role of transport in 
trigemino-somatic and trigemino-vascular afferents. Neurobiol Dis 2015;79:111–22. 
Rivera Dia RC, Arcila Lotero MA, Avellaneda Suarez MV, Echeverri Saldarriaga S, Gomez 
Martinez M. Botulinum toxin for the treatmentof chronic pain. Review of the evidence. Rev 
Colomb Anestesiol 2014;42(4):205-13. 
Schwartz M, Freund B. Dexamethasone and botulinum toxin type A in the treatment of chronic 
scar pain: A Cross-over Study. Arch Phys Med Rehabil 2004;65:E38. 
Shimizu T, Shibata M, Toriumi H, Iwashita T, Funakubo M, Sato H, Kuroi T, Ebine T, Koizumi 
K, Suzuki N. Reduction of trpv1 expression in the trigeminal system by botulinum neurotoxin 
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Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive 
treatment. Headache 2000;40:445-50. 
Stell R, Thompson PD, Marsden CD. Botulinum toxin in spasmodic torticollis. J Neurol 
Neurosurg Psychiatry 1988;51:920-3. 
Tarsy D, First ER. Painful cervical dystonia: Clinical features and response to treatment with 
botulinum toxin. Mov Disord 1999;14:1043-5. 
Thenganatt MA, Fahn S. Botulinum toxin for the treatment of movement disorders. Curr Neurol 
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Todd KH. A review of current and emerging approaches to pain management in the emergency 
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spasmodic torticollis. Lancet 1985;2:245–7. 


 
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18 
ATTACHMENTS 
18.1 
Attachment 1 – Study Schedule of Assessments 
 
Study Procedures 
Screening 
D-28 max 
Injection 
test 1 
D-21 
max 
Injection 
test 2 
D-14 
max 
Baseline 
from 
D-7 max 
D1 
pre-
dose 
D1 
post-
dose 
D2-D7 
W2 
[a] 
W4 
[a] 
W6 
[a] 
W8 
[a] 
W10 
[a] 
W12 
[a] 
W14 
[a] 
W16 
EoS/
ED 
[a] 
Part 
Screening 
Part A 
Part B 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic visit 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
X 
 
X 
Subject call 
 
X [b] 
X [b] 
X [c] 
 
 
X [d] 
X [d] 
X [d] 
 
X [d] 
X [d] 
 
X [d] 
 
Eligibility check 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug of abuse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(female subjects 
only) 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Physical examination 
X 
 
 
X 
X 
 
 
 
 
X [f] 
[g] 
 
 
 
 
X 
Vital signs 
X [e] 
X [g] 
X [g] 
X [g] 
X [g] 
X [g] 
 
 
 
X [g] 
 
 
 
 
X [g] 
ECG, Safety lab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scar ultrasound 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Painful area mapping 
X 
X 
X 
X 
X [h] 
 
 
 
 
X 
 
 
X 
 
X 


 
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Study Procedures 
Screening 
D-28 max 
Injection 
test 1 
D-21 
max 
Injection 
test 2 
D-14 
max 
Baseline 
from 
D-7 max 
D1 
pre-
dose 
D1 
post-
dose 
D2-D7 
W2 
[a] 
W4 
[a] 
W6 
[a] 
W8 
[a] 
W10 
[a] 
W12 
[a] 
W14 
[a] 
W16 
EoS/
ED 
[a] 
Pre-randomisation 
Part A 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lidocaine/placebo 
injection (saline) 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
NRS score collection 
and diary providing 
 
X [i] 
X [i] 
 
 
 
 
 
 
 
 
 
 
 
 
Actiwatch® training 
and providing 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomisation in 
Part B 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Dysport/placebo 
injections 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Spontaneous NRS 
X [j] 
X [k] 
X [k] 
X [l] 
X [l] 
X [l] 
X [l] 
X [l] 
X [l] 
X [l] 
X lk] 
X [l] 
X [l] 
X [l] 
X [l] 
Rescue medication 
diary provided 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Reminder about 
analgesia washout 
12-hour period pre-
injections or QST 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
QST (stimulus-
evoked NRS) 
 
 
 
X [m] 
 
 
 
 
 
X [m] 
 
 
X [m] 
 
 
QoL (SF-36) 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Concomitant 
medications and 
adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Visit to be performed ± 3 days around the scheduled date. 
b 
In the evening and on the following morning to check safety and collect spontaneous NRS scores. 


 
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c 
Once the NRS scores from injection tests 1 and 2 are known and blind has been broken, the subject’s responder status is determined. Subjects will be contacted by telephone 
by an investigator to inform of the result, and in the case of responders, they will enter in Part B. 
d 
Subjects will be contacted by telephone by the CRU every day up to Day 7 and every 2 weeks after IMP dosing for collection of AEs, concomitant medications and 
compliance with pain assessments and other study requirements. 
e 
Vital signs in both standing and supine position. 
f 
Includes an examination of the scar at injection sites. 
g 
Vital signs in supine position only. 
h 
Just before the IMP dosing. 
i 
Subjects will be provided with a paper diary after injection tests 1 and 2. They will be invited to record at home after discharge their current NRS scores hourly up to 
8 hours and between 20 and 24 hours post-injection test in this diary. 
j 
Subjects will be asked what were their average and worst NRS scores within 24 hours before the visit. 
k 
Subjects will be asked what is their current NRS score pre-injection test. They will report their pain relief within 30 minutes after the injection test if any. They will be 
asked for their current NRS score at 30 minutes and 1 hour post-injection test. They will be discharged home and collect their current NRS scores hourly up to 8 hours and 
between 20 and 24 hours post-injection test. 
l 
The Actiwatch® will alarm and alert the subjects twice a day to record their worst and average NRS scores over the preceding 12 hours. The Actiwatch® will allow 
electronic NRS score collection and storage from the Actiwatch® training to EoS. Data will be extracted from the Actiwatch® at each visit.A paper diary will also be 
provided to subjects in the unlikely event of an Actiwatch® malfunction during the collection period. One week before post-dosing visit to the CRU, the subjects might 
be requested to complete the paper diary in case of Actiwatch® malfunction or data quality check. 
m 
QST (light touch, pressure, thermal) to be performed before D-3, at week 6 and week 12. Predose NRS score is the current pain. 
 


 
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18.2 
Attachment 2 – Blood Sampling Summary 
This table summarises the maximum number of (veni) punctures and blood volumes for all 
blood sampling (screening safety laboratories) during the study.   
Fewer venipunctures and blood draws may actually occur if needed for safety purposes, but this 
will not require a protocol amendment. 
 
Purpose 
Maximum  
Blood volume 
per sample 
(mL) 
Maximum 
Number of 
Blood 
Samples 
Maximum 
Total 
Volume 
(mL) 
Screening 
Clinical laboratory tests : Haematology, 
biochemistry and serology 
25 
1 
25 
Provision for repeat tests (local lab) 
10 
1 
10 
Total over 
35 
Approximately 35 mL 


 
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18.3 
Attachment 3 – Clinical Laboratory Tests 
 
Haematology 
Clinical Chemistry 
Serology 
Erythrocyte count 
Alanine aminotransferase 
Hepatitis B surface antigen 
Haematocrit 
Albumin 
Hepatitis C virus ribonucleic acid 
Haemoglobin 
Alkaline phosphatase 
Human immunodeficiency virus 
Leukocyte count 
Aspartate 
aminotransferase 
 
Mean cell haemoglobin Bicarbonate 
 
Mean cell haemoglobin 
concentration 
Calcium 
 
Mean cell volume 
Chloride 
 
Absolute counts of: 
Conjugated bilirubin 
 
 Neutrophils 
Creatinine 
 
 Lymphocytes 
Creatine kinase 
 
 Monocytes 
C-reactive protein 
 
 Eosinophils 
Gamma-glutamyl 
transferase 
 
 Basophils 
Glucose (fasting) 
 
 Platelets 
Phosphorus 
 
 
Potassium 
 
 
Sodium 
 
 
Total bilirubin 
 
 
Total cholesterol 
 
 
Total protein 
 
 
Triglycerids 
 
 
Urea 
 


 
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Urinalysis (dipstick) 
Specific Parameters 
Bilirubin 
Urine drug screen, including at least amphetamines, 
methamphetamines, benzodiazepines, cocaine, opiates, 
tetrahydrocannabinol and barbiturates 
Blood 
Urine pregnancy test (women of childbearing potential) 
Glucose 
Urine pregnancy test (women of childbearing potential) 
Ketones 
Microscopic examination of 
sediment (if indicated) 
Nitrite 
pH 
Protein 
Urobilinogen 


 
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18.4 
Attachment 4 – Quantitative Sensory Testing 
 
Quantitative Sensory Testing Procedure Guideline (QST) 
 
St Pancras Clinical Research 
Prepared by: 
 
Checked by: 
 
Approved by: 
 
 
1. Document owner 
St Pancras Clinical Research (SPCR) 
 
2. Affected parties 
All trained staff performing QST at SPCR. 
 
3. Purpose 
The purpose of this SOP is to provide detailed instructions for performing QST in a structured 
manner by a trained staff in order to get consistent and reproducible results. 
 
4. Scope 
For all staff who are suitably trained to perform QST at SPCR.  
 
5. Definitions 
Sensory Threshold (ST): ST is the weakest stimulus that a subject can detect. 
Pain Perception Threshold (PPrT): PPrT is the lowest intensity of a painful stimulus at which 
the subject perceives pain. 
Static Mechanical Allodynia (SMA): SMA is the response to light sustained normally 
innocuous pressure against the skin. 
Dynamic Mechanical Allodynia (DMA): DMA is the response to a normally innocuous light 
moving mechanical stimulus on the skin. 
  
  
Temporal summation (TS): TS is a condition, which demonstrates an increased perception of 
pain to repetitive painful stimuli. 
Pressure Pain Threshold (PPT): PPT is the minimum force applied (pressure) which induces 
pain. 
Conditioned Pain Modulation (CPM), also known as Diffuse Noxious Inhibitory Control 
(DNIC): CPM refers to an endogenous pain modulatory pathway. This is described as "pain 
inhibits pain". CPM occurs when a response to a second, often spatially distant, noxious stimuli 
inhibits the response from a painful stimulus. 
Cold Detection Threshold (CDT): CDT is the temperature which is perceived as a ‘change’ 
when the temperature is decreased from 32 degrees. 
PPD
PPD
PPD


 
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Warm Detection Threshold (WDT): WDT is the temperature which is perceived as a ‘change’ 
when the temperature is increased from 32 °C. 
Cold Pain Threshold (CPT): CPT is the temperature which is perceived as ‘painful’ when the 
temperature is decreased from 32 °C. 
Heat Pain Threshold (HPT): HPT is the temperature which is perceived as ‘painful’ when the 
temperature is increased from 32 °C. 
 
6. Preparation 
6.1. Environment:  
All tests are performed in comfortable, quite room at room temperature (around 20 °C). Ensure 
there is a comfortable adjustable couch for the subject to sit or lie down. As some of the tests 
ideally should be run uninterrupted, it is best to avoid unnecessary distractions or interruptions. 
6.2. Equipments: The following equipments are required to perform the QST. 
von Frey filaments 
Camel hair brush (1cm brush width) 
Hand-held pressure algometer (Algometer type II, Somedic Production AB, Sweden, diameter 
contact tip 10mm; cover 2mm thick rubber; standardised and constant speed of pressure 
increase of 0.3kg/s) 
TSA-II Quantitative NeuroSensory Analyzer; Medoc, Ramat Yishai, Israel 
Timer/ stop watch 
Sharps container 
Alcohol wipes 
Marker pen 
6.3. Operator and training 
The tests should be performed by a single trained operator for each patient.  
7. Performing the tests: 
Always perform the test in the same order below. Mark/ map the area of painful site for testing 
and identify the suitable non-painful/ contralateral site for testing. Always do test over the non-
painful site and then do the painful site for comparison (unless mentioned otherwise below). 
Do all tests with the patients eyes closed. Explain to the patient before each test to ensure a 
consistent response and if required demonstrate the procedure on the patient. 
Sensory Threshold (ST): Seventeen, progressively rigid, monofilament, von Frey fibers 
(filaments represent stimuli from 0.039 – 4386mN) will be used for this test. Test the area with 
von Frey’s filament, starting from the lowest/ thinnest monofilament. Each filament should be 
applied to the skin at a 90° angle with sufficient force to bend or bow the filament. The filament 
is held in place for 1.5 seconds and then removed. The exact threshold is found by repetitive 
testing ascending fibre sizes. The patient is instructed to respond ‘‘Yes’’ when a stimulus was 
felt. Each filament is applied up to 3 times in increasing filament thickness and the patient 
should say ‘Yes’ at least twice for the threshold filament.  
Pain Perception Threshold (PPrT): This test is performed similar to ST but the response is the 
monofilament producing discomfort/ pain.  
Static Mechanical Allodynia (SMA): This test is performed by applying the plastic base of a 
von Frey filament for 10 seconds with sufficient pressure, indenting the skin-testing area. This 
is recorded in a 11-point Numerical Rating Scale (NRS). 


 
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Dynamic (Brush evoked) Mechanical Allodynia (DMA): DMA is evoked by gently stroking 
the test area with a foam brush. This is recorded in a 11-point Numerical Rating Scale (NRS). 
Temporal summation: This test is done only on the painful site. A baseline NRS score will be 
obtained from the patient with the vFF as part of the PPrT measurement. This fibre will be used 
for the test. The patient is given a repetitive stimulation consisting of 30 repetitions of a pressure 
stimulus applied for 1 second duration for 30 seconds. The magnitude of the stimulus is set at 
the level of the subjects’ pressure pain threshold. Patients rate the pain intensity on a NRS at 
the end of the 30 seconds and this is repeated for up to 10 sets or until you or the patient decide 
to stop due to the level of discomfort. 
Pressure Pain Threshold (PPT): A hand-held pressure algometer (Algometer type II, Somedic 
Production AB, Sweden, diameter contact tip 10mm; cover 2mm thick rubber; standardised and 
constant speed of pressure increase of 0.3kg/s) is used to measure the PPT’s in KPa (Kilo 
Pascal). The probe is placed perpendicular to the skin and standard incremental pressure is 
applied until the subject perceived the pressure as pain when the procedure is immediately 
terminated. At each site, a set of 3 measurements are taken at 4 different nearby points and an 
average PPT value is calculated from the 12 measurements. If the patient feels too 
uncomfortable then please restrict to fewest number of consistent readings (3 to 4).  
Ischemic arm test to measure DNIC: DNIC is measured by inducing a heterotopic noxious 
conditioning stimulation. This is evoked by an inflated blood pressure cuff and thereby creating 
an ischaemic compression of the arm. Blood pressure cuff positioned on the arm was inflated 
above systolic pressure (200 mmHg) for 10 minutes, or until a Numerical Rating Scale of 6 was 
achieved. The point on the painful site with the lowest PPT value (average of 3 measurements) 
is chosen to measure the CPM response. A set of 3 PPT measurements are then taken at this 
point following which the cuff is deflated. The average of the 3 PPT measurements are taken. 
Temperature Thresholds: This test measures the CDT, WDT, CPT and HPT and paradoxical 
heat sensation. Four sensory sub-modalities are measured using a computer-controlled 
thermode with surface area of 9 cm2 which is connected to a patient-activated push-button 
(TSA-II Quantitative NeuroSensory Analyzer; Medoc, Ramat Yishai, Israel). The system 
contains a pre-loaded software which dictates the temperature changes. The baseline 
temperature is automatically set at 32 °C. The temperature then decreases at a constant rate of 
1 °C /s until the subject perceived the thermode as cold and immediately pressed a push-button. 
Four consecutive measurements are taken with the thermode returning to baseline temperature 
each time. Similarly, HDT, is measured but with the temperature increased from 32°C. 
Subsequently, CPT and HPT are determined in a similar manner, and in that order but by taking 
an average of 3 consecutive measurements. To avoid thermal injury the thermode with 
automatically cut off at 0°C at the lower end and at 50°C at the higher end. 
 
8. Termination of QST 
Terminate the tests once you have done all the tests as per this SOP or at patients request or if 
you feel it is inappropriate to continue the test for any reason (such as level of patient 
discomfort, patient refuses consent, patient psychologically inappropriate, unable to get 
consistent response or equipment malfunction). 
 
 
9. Equipment care 
It is the operators responsibility to ensure that sufficient care is given while handling the 
equipment. Disposable sharps should be put in the sharps bin. Please ensure that the non-


 
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disposable equipment, which has a patient contact is cleaned with alcohol swabs and standard 
hospital infection control policies are adopted. 
There is a copy of the equipment available which can be consulted for any clarification. 
The algometer needs regular calibration and the thermal equipment needs refilling with distilled 
water and servicing. 


 
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18.5 
Attachment 5 – Criteria to be evaluated for each subject 
 
According to Treede 
 
Pain with a distinct neuroanatomically plausible distribution a 
A history suggestive of a relevant lesion or disease affecting the peripheral or central 
somatosensory system b 
Demonstration of the distinct neuroanatomically plausible distribution by at least 1 
confirmatory test c 
Demonstration of the relevant lesion or disease by at least 1 confirmatory test d 
 
Grading for certainty for the presence of neuropathic pain 
 
Definite neuropathic pain 
All (1 to 4) 
Probable neuropathic pain 1 and 2, plus either 3 or 4 
Possible neuropathic pain 
1 and 2 without confirmatory evidence from 3 or 4 
 
A region corresponding to a peripheral innervation territory or to the topographic representation 
of a body part in the central nervous system. 
The suspected lesion or disease is reported to be associated with pain, including a temporal 
relationship typical for the condition. 
As part of the neurologic examination, these tests confirm the presence of negative or positive 
neurologic signs concordant with the distribution of pain. Clinical sensory examination may be 
supplemented by laboratory and objective tests to uncover subclinical abnormalities. 
As part of the neurologic examination, these tests confirm the diagnosis of the suspected lesion 
or disease. These confirmatory tests depend on which lesion or disease is causing neuropathic 
pain. 


 
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18.6 
Attachment 6 – Protocol Amendment #2 Summary 
 
All additions have been identified by the use of underline and all deletions by strikethroughs. 
 
 
 


 
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3.1  
Overall Study Design and Plan 
 
Before dosing on Day 1, the subjects will perform baseline assessments including a full 
quantitative sensory testing (QST) assessing allodynia, hyperalgesia and conditioned pain 
modulation, completion of a QoL questionnaire, and safety assessments (physical examination, 
vital signs measurements, collection of adverse events (AEs) and recording of concomitant 
medication). 
 
4.1 
Inclusion Criteria 
Subjects must fulfil all of the following criteria to be considered eligible for enrolment in the 
study. 
(1) 
(1a)     Male and female subjects aged between 18 and 65 75 years inclusive at the time 
of giving informed consent. 
(2) 
Subjects suffering from an area of chronic pain post-abdominal or thoracic surgery, 
chronic abdominal or thoracic scar pain. 
(3) 
Longitudinal axis of the pain area of 10 cm long maximum (as mapped upon screening). 
(4) 
Subjects with moderate to severe pain, i.e. spontaneous NRS score of 4-8 which has been 
stable for the previous month before screening. 
(5) 
Stable use of analgesics (or any medication impacting pain perception) during the month 
before screening and expected to be stable for the study duration. 
(6) 
Under stable medication regimen for other medication, i.e. during the month before 
screening. 
(7) 
(7a)   Time from surgery which caused the painful scar more than six months and less 
than five ten years at screening. 
(8) 
No other distracting pain either chronic or acute. 
(9) 
Female subjects of childbearing potential must have a negative urine pregnancy test 
result and be willing to use reliable contraceptive measures throughout study 
participation. Reliable forms of contraception include but are not limited to hormonal 
contraceptives (e.g. oral, patch, injection), double-barrier (e.g. male condom plus 
spermicide, or female diaphragm plus spermicide), intrauterine device, male partner has 
had a vasectomy, total abstinence from intercourse with male partners (periodic 
abstinence is not acceptable). Female subjects meeting any of the following criteria are 
not considered to be of childbearing potential: postmenopausal (≥ 47 years of age and 
amenorrhoeic for at least 12 consecutive months), have been sterilised surgically (e.g. 
bilateral tubal ligation), have had a hysterectomy, have had a bilateral oophorectomy. 
(10) The subject’s primary care physician has provided evidence which can be used to 
confirm that within the last 12 months of dosing that there is nothing in their medical 
history that would preclude their enrolment into a clinical study. 
 
 
 
 
 


 
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5.2.2  
Pre-randomisation Run-in Period (Part A) 
 After successful screening of medical eligibility and within 21 days maximum before IMP 
dosing on Day 1, subjects will come back to the CRU for an injection test 1 visit, they will 
receive a pre-randomisation run-in number and be injected in a double blind fashion with either 
local anaesthetic (lidocaine) or placebo (saline). 
They will be assessed for pain perception on site and then be discharged from the CRU from 
1 hour post-injection test 1 and continue to record their NRS score at home as described in 
Section 9.1.2. They will be contacted by telephone by the site to check their safety and collect 
their NRS score post-injection test 1 at the end of the injection test 1 day and on the following 
day. 
Approximately one week later and within 14 days maximum before IMP dosing on Day 1, they 
will come back to the CRU for injection test 2. They will be crossed over and injected with the 
other agent. 
They will be assessed for pain perception on site and then be discharged from the CRU from 
1 hour post-injection test 2 and continue to record their NRS score at home as described in 
Section 9.1.2. They will be contacted by telephone by the site to check their safety and collect 
their NRS score post-injection test 2 at the end of the injection test 2 day and on the following 
day. After completion of subject’s injection test 2, the blind will be broken by an investigator 
to check if the subject is a responder. 
Subjects will be considered as responders and randomised to Part B if: 
• 
The pattern of pain relief is sufficiently greater with lidocaine than saline using the 
formula below: 
[NRS predose - NRS 1 hour post-injection test] placebo – [NRSpredose - NRS 1 hour post-injection test] lidocaine ≥ 2 
• 
The pattern of pain relief is clinically plausible in the investigator’s opinion, e.g. onset 
of pain relief reported by 30 min from time of completing the injections, pain scores after 
the lidocaine injection test rising again by 2-8 hours post-injection, 
• 
The investigator has no concern regarding compliance with study procedures and safety. 
Albeit considered unlikely, should the results be equivocal, or if an unexpected but plausible 
pattern of response emerges, the decision as to whether a subject should proceed in the study, 
will be adjudicated by mutual agreement of the investigator and the sponsor. 
Subjects will be contacted by telephone by an investigator to inform them of the result. If 
subjects are assessed as responders and there are no concerns over subject safety, compliance 
with 
study 
assessments, 
they 
will 
enter 
in 
Part B. 
The scheduled dates of the subjec’t visit should be with sufficient time between study visits test 
1, test 2 and baseline. This is to permit the scar area to return to baseline after examination, test 
dosing or QST procedures. 
 
18.6.1.1 Baseline visit 
A full QST (including light touch, pressure, temperature as stimuli) [stimulus-evoked NRS] and 
completion of QoL questionnaire SF-36 will be performed within 7 days prior to Day 1. 
Subjects will also receive a training on how to use their Actiwatch® (device to be used for 
collection of the spontaneous NRS score). They will start to enter their NRS scores in their 
Actiwatch®, and will be provided with a paper diary as a back-up solution for NRS score 
collection. 
 


 
CONFIDENTIAL 
 
Study number D-FR-52120-244 - Protocol version 3.0 - Date: 04 December 2018 
Page 82 of 89 
 
9.2 
Stimulus-evoked NRS Score during Quantitative Sensory Testing 
Subjects will be submitted to stimuli of various nature applied to the painful area. 
Stimulus-evoked NRS score will be collected during the assessments. 
Subjects will be asked what are their current NRS scores predose and post-stimulus. 
At baseline all the tests will be performed. At and at the post-dose visits light touch, only light 
touch pressure and temperature will be used as stimuli for light QST. 
The QST battery of tests is described in full in Sections 18.4 and 18.5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
Study number D-FR-52120-244 - Protocol version 3.0 - Date: 04 December 2018 
Page 83 of 89 
 
18.1 
Attachment 1 – Study Schedule of Assessments 
 
Study Procedures 
Screening 
D-28 max 
Injection 
test 1 
D-21 
max 
Injection 
test 2 
D-14 
max 
Baseline 
from 
D-7 max 
D1 
pre-
dose 
D1 
post-
dose 
D2-D7 
W2 
[a] 
W4 
[a] 
W6 
[a] 
W8 
[a] 
W10 
[a] 
W12 
[a] 
W14 
[a] 
W16 
EoS/
ED 
[a] 
Part 
Screening 
Part A 
Part B 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic visit 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
X 
 
X 
Subject call 
 
X [ab] 
X [ab] 
X [bc] 
 
 
X [cd] 
X 
[cd] 
X 
[cd] 
 
X 
[cd] 
X 
[cd] 
 
X 
[cd] 
 
Eligibility check 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug of abuse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(female subjects 
only) 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Physical examination 
X 
 
 
X 
X 
 
 
 
 
X [ef] 
[fg] 
 
 
 
 
X 
Vital signs 
X [de] 
X [fg] 
X [fg] 
X [fg] 
X [fg] 
X [fg] 
 
 
 
X 
[fg] 
 
 
 
 
X 
[fg] 
ECG, Safety lab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scar ultrasound 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Painful area mapping 
X 
X 
X 
X 
X [gh] 
 
 
 
 
X 
 
 
X 
 
X 
Pre-randomisation 
Part A 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
Study number D-FR-52120-244 - Protocol version 3.0 - Date: 04 December 2018 
Page 84 of 89 
 
 
Study Procedures 
Screening 
D-28 max 
Injection 
test 1 
D-21 
max 
Injection 
test 2 
D-14 
max 
Baseline 
from 
D-7 max 
D1 
pre-
dose 
D1 
post-
dose 
D2-D7 
W2 
[a] 
W4 
[a] 
W6 
[a] 
W8 
[a] 
W10 
[a] 
W12 
[a] 
W14 
[a] 
W16 
EoS/
ED 
[a] 
Lidocaine/placebo 
injection (saline) 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
NRS score collection 
and diary providing 
 
X [hi] 
X [hi] 
 
 
 
 
 
 
 
 
 
 
 
 
Actiwatch® training 
and providing 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomisation in 
Part B 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Dysport/placebo 
injections 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Spontaneous NRS 
X [ij] 
X [jk] 
X [jk] 
X [kl] 
X [kl] 
X [kl] 
X [kl] 
X [kl] 
X [kl] 
X [kl] 
X [kl] 
X [kl] 
X [kl] 
X [kl] 
X [kl] 
Rescue medication 
diary provided 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Reminder about 
analgesia washout 
12-hour period pre-
injections or QST 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
QST (stimulus-
evoked NRS) 
 
 
 
X [lm] 
 
 
 
 
 
X [m] 
 
 
X [m] 
 
 
QoL (SF-36) 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Concomitant 
medications and 
adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Visit to be performed ± 3 days around the scheduled date. 
ab 
In the evening and on the following morning to check safety and collect spontaneous NRS scores. 
bc 
Once the NRS scores from injection tests 1 and 2 are known and blind has been broken, the subject’s responder status is determined. Subjects will be contacted by telephone 
by an investigator to inform of the result, and in the case of responders, they will enter in Part B. 


 
CONFIDENTIAL 
 
Study number D-FR-52120-244 - Protocol version 3.0 - Date: 04 December 2018 
Page 85 of 89 
 
cd 
Subjects will be contacted by telephone by the CRU every day up to Day 7 and every 2 weeks after IMP dosing for collection of AEs, concomitant medications and 
compliance with pain assessments and other study requirements. 
de 
Vital signs in both standing and supine position. 
ef 
Includes an examination of the scar at injection sites. 
fg 
Vital signs in supine position only. 
gh 
Just before the IMP dosing. 
hi 
Subjects will be provided with a paper diary after injection tests 1 and 2. They will be invited to record at home after discharge their current NRS scores hourly up to 
8 hours and between 20 and 24 hours post-injection test in this diary. 
ij 
Subjects will be asked what were their average and worst NRS scores within 24 hours before the visit. 
jk 
Subjects will be asked what is their current NRS score pre-injection test. They will report their pain relief within 30 minutes after the injection test if any. They will be 
asked for their current NRS score at 30 minutes and 1 hour post-injection test. They will be discharged home and collect their current NRS scores hourly up to 8 hours and 
between 20 and 24 hours post-injection test. 
kl 
The Actiwatch® will alarm and alert the subjects twice a day to record their worst and average NRS scores over the preceding 12 hours. The Actiwatch® will allow 
electronic NRS score collection and storage from the Actiwatch® training to EoS. Data will be extracted from the Actiwatch® at each visit.A paper diary will also be 
provided to subjects in the unlikely event of an Actiwatch® malfunction during the collection period. One week before post-dosing visit to the CRU, the subjects might be 
requested to complete the paper diary in case of Actiwatch® malfunction or data quality check. 
lm 
Full QST (light touch, pressure, thermal) battery to be performed before D-3, week 6 and week 12. Predose NRS score is the current pain. 
m 
QST (light touch, pressure, thermal). 
 


 
CONFIDENTIAL 
 
Study number D-FR-52120-244 - Protocol version 3.0 - Date: 04 December 2018 
Page 86 of 89 
 
18.4 
Attachment 4 – Quantitative Sensory Testing 
Quantitative Sensory Testing Procedure Guideline (QST) 
 
St Pancras Clinical Research 
Prepared by: 
 
Checked by: 
 
Approved by: 
 
 
1. Document owner 
St Pancras Clinical Research (SPCR) 
 
2. Affected parties 
All trained staff performing QST at SPCR. 
 
3. Purpose 
The purpose of this SOP is to provide detailed instructions for performing QST in a structured 
manner by a trained staff in order to get consistent and reproducible results. 
 
4. Scope 
For all staff who are suitably trained to perform QST at SPCR.  
 
5. Definitions 
Sensory Threshold (ST): ST is the weakest stimulus that a subject can detect. 
Pain perception threshold Perception Threshold (PPrT): PPrT is the lowest intensity of a painful 
stimulus at which the subject perceives pain. 
Static mechanical allodynia Mechanical Allodynia (SMA): SMA is the response to light 
sustained normally innocuous pressure against the skin. 
Dynamic Mechanical Allodynia (DMA): DMA is the response to a normally innocuous light 
moving mechanical stimulus on the skin. 
Punctate hyperalgesia (PH): PH is a response to a painful stimuli such a pin prick. 
Vibration disappearance threshold (VDD): This is the threshold at which the vibration is not 
longer detected while testing with 64 Hz graduated Rydel and Seiffer tuning fork.  
Temporal summation (TS): TS is a condition, which demonstrates an increased perception of 
pain to repetitive painful stimuli. 
Pressure pain threshold Pain Threshold (PPT): PPT is the minimum force applied (pressure) 
which induces pain. 
Conditioned Pain Modulation (CPM), also known as Diffuse Noxious Inhibitory Control 
(DNIC): CPM refers to an endogenous pain modulatory pathway. This is described as "pain 
inhibits pain". CPM occurs when a response to a second, often spatially distant, noxious stimuli 
inhibits the response from a painful stimulus. 
Cold Detection Threshold (CDT): CDT is the temperature which is perceived as a ‘change’ 
when the temperature is decreased from 32 degrees. 
PPD
PPD
PPD


 
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Study number D-FR-52120-244 - Protocol version 3.0 - Date: 04 December 2018 
Page 87 of 89 
 
Warm Detection Threshold (WDT): WDT is the temperature which is perceived as a ‘change’ 
when the temperature is increased from 32 degree °C. 
Cold Pain Threshold (CPT): CPT is the temperature which is perceived as ‘painful’ when the 
temperature is decreased from 32 degree °C. 
Heat Pain Threshold (HPT): HPT is the temperature which is perceived as ‘painful’ when the 
temperature is increased from 32 degree °C. 
 
6. Preparation 
6.1. Environment:  
All tests are performed in comfortable, quite room at room temperature (around 20 °C). Ensure 
there is a comfortable adjustable couch for the subject to sit or lie down. As some of the tests 
ideally should be run uninterrupted, it is best to avoid unnecessary distractions or interruptions. 
6.2. Equipments: The following equipments are required to perform the QST. 
von Frey filaments 
Camel hair brush (1cm brush width) 
Neurotips™ 
64 Hz graduated Rydel and Seiffer tuning fork 
Hand-held pressure algometer (Algometer type II, Somedic Production AB, Sweden, diameter 
contact tip 10mm; cover 2mm thick rubber; standardised and constant speed of pressure 
increase of 0.3kg/s) 
TSA-II Quantitative NeuroSensory Analyzer; Medoc, Ramat Yishai, Israel 
Timer/ stop watch 
Sharps container 
Alcohol wipes 
Marker pen 
6.3. Operator and training 
At The tests should be performed by a single trained operator for each patient.  
7. Performing the tests: 
Always perform the test in the same order below. Mark/ map the area of painful site for testing 
and identify the suitable non-painful/ contralateral site for testing. Always do test over the non-
painful site and then do the painful site for comparison (unless mentioned otherwise below). 
Do all tests with the patients eyes closed. Explain to the patient before each test to ensure a 
consistent response and if required demonstrate the procedure on the patient. 
Sensory Threshold (ST): Seventeen, progressively rigid, monofilament, von Frey fibers 
(filaments represent stimuli from 0.039 – 4386mN) will be used for this test. Test the area with 
von Frey’s filament, starting from the lowest/ thinnest monofilament. Each filament should be 
applied to the skin at a 90° angle with sufficient force to bend or bow the filament. The filament 
is held in place for 1.5 seconds and then removed. The exact threshold is found by repetitive 
testing ascending fibre sizes. The patient is instructed to respond ‘‘Yes’’ when a stimulus was 
felt. Each filament is applied up to 3 times in increasing filament thickness and the patient 
should say ‘Yes’ at least twice for the threshold filament.  
Pain perception threshold Perception Threshold (PPrT): This test is performed similar to ST but 
the response is the monofilament producing discomfort/ pain.  


 
CONFIDENTIAL 
 
Study number D-FR-52120-244 - Protocol version 3.0 - Date: 04 December 2018 
Page 88 of 89 
 
Static mechanical allodynia Mechanical Allodynia (SMA): This test is performed by applying 
the plastic base of a von Frey filament for 10 seconds with sufficient pressure, indenting the 
skin-testing area. This is recorded in a 11-point Numerical Rating Scale (NRS). 
Dynamic (Brush evoked) Mechanical Allodynia (DMA): DMA is evoked by gently stroking 
the test area with a foam brush. This is recorded in a 11-point Numerical Rating Scale (NRS). 
Punctate hyperalgesia (PH): This is tested using the blunt end of Neurotips™. Apply the 
stimulus twice for about half a second, with a 5-second interval between stimuli for each site. 
This is recorded in a 11-point Numerical Rating Scale (NRS).  
Vibration Disappearance Threshold (VDD): This is tested using a Rydel–Seiffer tuning fork 
(64 Hz, 8/8 scale) by placing it over a bony prominence closest to the test site. 
Temporal summation: This test is done only on the painful site. A baseline NRS score will be 
obtained from the patient with the vFF as part of the PPrT measurement. This fibre will be used 
for the test. The patient is given a repetitive stimulation consisting of 30 repetitions of a pressure 
stimulus applied for 1 second duration for 30 seconds. The magnitude of the stimulus is set at 
the level of the subjects’ pressure pain threshold. Patients rate the pain intensity on a NRS at 
the end of the 30 seconds and this is repeated for up to 10 sets or until you or the patient decide 
to stop due to the level of discomfort. 
Pressure Pain Threshold (PPT): A hand-held pressure algometer (Algometer type II, Somedic 
Production AB, Sweden, diameter contact tip 10mm; cover 2mm thick rubber; standardised and 
constant speed of pressure increase of 0.3kg/s) is used to measure the PPT’s in KPa (Kilo 
Pascal). The probe is placed perpendicular to the skin and standard incremental pressure is 
applied until the subject perceived the pressure as pain when the procedure is immediately 
terminated. At each site, a set of 3 measurements are taken at 4 different nearby points and an 
average PPT value is calculated from the 12 measurements. If the patient feels too 
uncomfortable then please restrict to fewest number of consistent readings (3 to 4).  
Ischemic arm test to measure DNIC: DNIC is measured by inducing a heterotopic noxious 
conditioning stimulation. This is evoked by an inflated blood pressure cuff and thereby creating 
an ischaemic compression of the arm. Blood pressure cuff positioned on the arm was inflated 
above systolic pressure (200 mmHg) for 10 minutes, or until a Numerical Rating Scale of 6 was 
achieved. The point on the painful site with the lowest PPT value (average of 3 measurements) 
is chosen to measure the CPM response. A set of 3 PPT measurements are then taken at this 
point following which the cuff is deflated. The average of the 3 PPT measurements are taken. 
Temperature threshold Thresholds: This test measures the CDT, HDT WDT, CDP CPT and 
HDP HPT and paradoxical heat sensation. Four sensory sub-modalities are measured using a 
computer-controlled thermode with surface area of 9 cm2 which is connected to a patient-
activated push-button (TSA-II Quantitative NeuroSensory Analyzer; Medoc, Ramat Yishai, 
Israel). The system contains a pre-loaded software which dictates the temperature changes. The 
baseline temperature is automatically set at 32 °C. The temperature then decreases at a constant 
rate of 1 °C /s until the subject perceived the thermode as cold and immediately pressed a push-
button. Four consecutive measurements are taken with the thermode returning to baseline 
temperature each time. Similarly, HDT, is measured but with the temperature increased from 
32°C. Subsequently, CPT and HPT are determined in a similar manner, and in that order but by 
taking an average of 3 consecutive measurements. To avoid thermal injury the thermode with 
automatically cut off at 0°C at the lower end and at 50°C at the higher end. 
 
8. Termination of QST 
Terminate the tests once you have done all the tests as per this SOP or at patients request or if 
you feel it is inappropriate to continue the test for any reason (such as level of patient 


 
CONFIDENTIAL 
 
Study number D-FR-52120-244 - Protocol version 3.0 - Date: 04 December 2018 
Page 89 of 89 
 
discomfort, patient refuses consent, patient psychologically inappropriate, unable to get 
consistent response or equipment malfunction). 
 
 
9. Equipment care 
It is the operators responsibility to ensure that sufficient care is given while handling the 
equipment. Disposable sharps should be put in the sharps bin. Please ensure that the non-
disposable equipment, which has a patient contact is cleaned with alcohol swabs and standard 
hospital infection control policies are adopted. 
There is a copy of the equipment available which can be consulted for any clarification. 
The algometer needs regular calibration and the thermal equipment needs refilling with distilled 
water and servicing. 
 

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FORM EFFECTIVE DATE: 30 DECEMBER 2014 
 
PAGE 1 OF 39 
 
 
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CONFIDENTIAL  
 
STATISTICAL ANALYSIS PLAN 
 
[PROTOCOL TITLE: A DOUBLE-BLIND, RANDOMISED, PLACEBO CONTROLLED, 
PROOF-OF-CONCEPT STUDY IN SUBJECTS WITH ABDOMINAL OR THORACIC 
CHRONIC SCAR PAIN TO ASSESS THE ANALGESIC PROPERTIES OF 
INTRADERMAL DOSES OF DYSPORT®] 
[D-FR-52120-244] 
 
This statistical analysis plan is based on: 
PROTOCOL VERSION AND DATE: 3.0 – 04 DECEMBER 2018 
 
SAP Version 
Date 
Final Version 1.0 
28 November 2019 
 
 
 
 
 
 
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CONFIDENTIAL  
 
APPROVAL PAGE 
STUDY NUMBER: 
D-FR-52120-244 
EUDRACT NUMBER 
2018-001703-37 
PROTOCOL TITLE: 
A DOUBLE-BLIND, RANDOMISED, PLACEBO 
CONTROLLED, PROOF-OF-CONCEPT STUDY IN 
SUBJECTS WITH ABDOMINAL OR THORACIC 
CHRONIC SCAR PAIN TO ASSESS THE 
ANALGESIC PROPERTIES OF INTRADERMAL 
DOSES OF DYSPORT®] 
SAP VERSION: 
Final Version 1.0 
SAP DATE: 
28 November 2019 
 
The undersigned agree that all required reviews of this document are complete, and approve this 
Statistical Analysis Plan: 
 
Name 
Company 
Function 
Date 
Signature 
 IPSEN 
 
 
EA 
EA 
 
 
BIOTRIAL 
 
 
EA 
EA 
 
IPSEN 
 
 
EA 
EA 
 
IPSEN 
 
 
EA 
EA 
EA: Electronic Approval 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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CONFIDENTIAL  
 
HISTORY OF CHANGES 
Version Number  Date Description/Rational for change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL  
 
TABLE OF CONTENTS 
1 
INTRODUCTION .......................................................................................................... 9 
2 
PROTOCOL OVERVIEW ............................................................................................ 9 
2.1 
Study Objectives and Hypotheses ................................................................................. 9 
2.2 
Overall Study Design and Investigational Plan ........................................................... 9 
2.3 
Sample Size Determination and Power ....................................................................... 10 
2.4 
Randomisation and Blinding (if applicable) ............................................................... 10 
2.4.1 
Pre-randomisation Run-in Period (Part A) ............................................... 10 
2.4.2 
Randomised Double-Blind Period (Part B) ............................................... 10 
2.5 
Schedule of Assessments ............................................................................................... 10 
2.6 
Change from Statistical Section of the Protocol ........................................................ 10 
3 
PLANNED ANALYSES ............................................................................................... 11 
3.1 
Safety Monitoring ......................................................................................................... 11 
3.2 
Interim Analysis / Primary Analysis ........................................................................... 11 
3.3 
Final Analysis ................................................................................................................ 11 
4 
ANALYSIS POPULATIONS ...................................................................................... 11 
4.1 
Screened population ..................................................................................................... 11 
4.2 
Run-in population ......................................................................................................... 11 
4.3 
Randomised population ................................................................................................ 11 
4.4 
Safety population .......................................................................................................... 11 
4.5 
Per Protocol (PP) Population ....................................................................................... 11 
5 
STATISTICAL METHODS/ANALYSES .................................................................. 11 
5.1 
General Considerations ................................................................................................ 12 
5.1.1 
Outputs Presentation ................................................................................... 12 
5.1.1.1 
Tables Header .............................................................................................. 12 
5.1.1.2 
Presentation of Treatment Group ................................................................ 12 
5.1.1.3 
Presentation of Visits / Timepoints .............................................................. 12 
5.1.2 
Descriptive Statistics ................................................................................... 13 
5.1.3 
Baseline value ............................................................................................. 13 
5.1.4 
Reference Start Date and Study Day .......................................................... 13 
5.2 
Randomisation, Disposition and Population .............................................................. 14 
5.3 
Protocol Deviations ....................................................................................................... 14 
5.4 
Demography and Other baseline characteristics ....................................................... 15 
5.5 
Medical history, non-drug therapies, medications and surgical procedures .......... 15 
5.6 
Compliance .................................................................................................................... 16 
5.7 
Pharmacodynamic/Efficacy Part B ............................................................................. 16 
5.7.1 
General Considerations .............................................................................. 16 
5.7.1.1 
Significance Testing and Estimations .......................................................... 16 
5.7.1.2 
Statistical/analytical issues .......................................................................... 16 
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5.7.2 
Pre-randomisation run-in period ............................................................... 17 
5.7.3 
Randomised double-blind period: Analysis of Primary Efficacy 
Endpoint ...................................................................................................... 17 
5.7.3.1 
Endpoint, Treatment Effect and Estimand Definition .................................. 17 
5.7.3.2 
Primary Analysis .......................................................................................... 18 
5.7.3.3 
Sensitivity Analysis ....................................................................................... 18 
5.7.3.4 
Supplementary Analysis ............................................................................... 18 
5.7.3.5 
Subgroup Analysis ....................................................................................... 18 
5.7.4 
Randomised double-blind period: Analysis of Key Secondary Efficacy 
Endpoints ..................................................................................................... 18 
5.7.4.1 
Endpoint, Treatment Effect and Estimand Definition .................................. 18 
5.7.4.2 
Main Secondary Analysis ............................................................................. 21 
5.7.4.3 
Sensitivity Analysis ....................................................................................... 24 
5.7.4.4 
Subgroup Analysis ....................................................................................... 24 
5.7.5 
Randomised double-blind period: Analysis of Other Secondary Efficacy 
Endpoints ..................................................................................................... 24 
5.7.5.1 
Endpoint, Treatment Effect and Estimand Definition .................................. 24 
5.7.5.2 
Analysis ........................................................................................................ 25 
5.8 
Safety .............................................................................................................................. 26 
5.8.1 
General Consideration ................................................................................ 26 
5.8.2 
Extent of exposure ...................................................................................... 26 
5.8.3 
Adverse Events ............................................................................................ 27 
5.8.4 
Laboratory Data .......................................................................................... 29 
5.8.5 
Vital Signs ................................................................................................... 29 
5.8.6 
Electrocardiogram (ECG)........................................................................... 29 
5.8.7 
Physical Examination ................................................................................. 30 
5.8.8 
Pregnancy tests ............................................................................................ 30 
5.9 
Pharmacokinetics (if applicable) ................................................................................. 30 
5.10 Anti-drug Antibodies (if applicable) ........................................................................... 30 
6 
DATA HANDLING ...................................................................................................... 30 
6.1 
Visit window .................................................................................................................. 30 
6.2 
Unscheduled Visits, Retest, Withdrawal Visit, ........................................................... 30 
7 
DERIVED DATA .......................................................................................................... 31 
8 
REFERENCES .............................................................................................................. 33 
9 
APPENDICES ............................................................................................................... 35 
A1. SAS code ........................................................................................................................ 35 
A2. Normal ranges ............................................................................................................... 35 
A3. Partial/Missing Date Convention ................................................................................ 36 
Algorithm for Prior/ Concomitant ................................................................................. 36 
Algorithm for TEAE ...................................................................................................... 36 
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A4. Programming Convention for Outputs ....................................................................... 37 
A5. Listings conventions ...................................................................................................... 38 
A6. EudraCT categories for age ......................................................................................... 39 
 
LIST OF TABLES 
Table 1 
Data imputation algorithm for AE start date (AESTDT) ............................... 37 
 
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CONFIDENTIAL  
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABBREVIATION 
Wording Definition 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ATC 
Anatomic Therapeutic Class 
AUE 
Area Under the Effect 
C 
Concomitant 
CHMP 
Committee for Medicinal Products for Human Use  
CHG 
Change from Baseline 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
E 
Electronic 
EA 
Electronic Approval 
ECG 
Electrocardiogram 
ED 
Early Discontinuation 
EMA 
European Medicines Agency 
EoS 
End of Study 
FDA 
Food and Drug Administration 
ICH 
International Conference on Harmonisation  
IMP 
Investigational Medicinal Product 
LOQ 
Limit Of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numerical Rating Scale 
P 
Prior 
PC 
Prior and Concomitant 
PCSA 
Potentially Clinically Significant Abnormalities 
PN 
Preferred Name 
PP 
Per Protocol 
PPT 
Pressure Pain Threshold 
PT 
Preferred Term 
QoL 
Quality of Life 
QST 
Quantitative Sensory Testing 
SAE 
Serious Adverse Event 
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CONFIDENTIAL  
 
ABBREVIATION 
Wording Definition 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System® 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SI 
Standard International 
SMQ 
Standardised MedDRA Query 
SOC 
System Organic Class 
SOP 
Standard Operating Procedure 
SPID 
Sum Pain Intensity Differences 
TEAE 
Treatment Emergent Adverse Event 
TFLs 
Tables, Figures and Listings 
U 
Unit 
WHO-DD 
World Health Organization – Drug dictionary 
WOCF 
Worst Observation Carried Forward 
 
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1 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to outline the planned 
analyses to be completed to support the completion of the Clinical Study Report 
(CSR) for protocol D-FR-52120-244. It describes the rules and conventions to be 
used in the analysis and presentation of data, the data to be summarized and 
analyzed, including specificities of the statistical analyses to be performed.  
Exploratory analyses not necessarily identified in this SAP may be performed to 
support the clinical development program. Any post-hoc, or unplanned, analyses not 
identified in this SAP performed will be clearly identified in the respective CSR. 
The SAP is to be finalized prior to database lock. A separate shell will be provided 
for tables, figures and listings.  
Any deviations from the SAP after database lock will be documented in the CSR 
(section 9.8 “Changes in the conduct of the study or planned analyses” as per ICH 
E3).  
2 
PROTOCOL OVERVIEW 
2.1 
Study Objectives and Hypotheses 
The primary objective is: 
• 
To describe the pharmacodynamic analgesic profile (time of onset of 
meaningful analgesic effect, peak-effect, time to peak-effect, duration of effect) 
of intradermal doses of Dysport in subjects with abdominal or thoracic chronic 
scar pain. 
 
The secondary objectives are: 
• 
To compare the efficacy of intradermal doses of Dysport to placebo. 
• 
To assess the safety and tolerability of a range of intradermal doses of Dysport. 
 
The exploratory objectives are: 
• 
To explore improvement of quality of life (QoL) using SF-36 questionnaire. 
• 
To explore concomitant use of rescue medication (analgesia). 
 
2.2 
Overall Study Design and Investigational Plan 
The study will consist of two sequential parts, the first being to identify subjects 
who will potentially benefit from intradermal Dysport injection, ‘responders’, who 
will then progress to the second part, which is the double-blind study of the 
intradermal injection of Dysport or placebo: 
• 
Part A: A double-blind, randomised, initial two-period cross-over run-in part, 
extended screening period of placebo or local anaesthetic (lidocaine), 
• 
Part B: A single-dose, double-blind, randomised, parallel part with one of the 
three different doses of Dysport or placebo. 
To ensure subjects will potentially benefit from intradermal injection of Dysport, 
they will be tested for responsiveness to local anaesthetic (lidocaine). 
 
Study design is presented in details in section 3.1 of the protocol. 
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2.3 
Sample Size Determination and Power 
No prospective calculations of statistical power are made. 
This is an exploratory trial which will use a standard early phase dosing scheme for 
single escalating dose and will also generate data for future regulatory trials. 
An appropriate sample size cannot be determined statistically as no previous human 
data from previous clinical trials are available. A sample size of six subjects per 
dose of Dysport has been selected. Approximately 24 subjects (3 actives and 1 
placebo per group so 4x6 subjects) will be randomised in the double-blind period. 
Subjects who withdraw within the six first weeks from dosing will be replaced. 
2.4 
Randomisation and Blinding (if applicable) 
2.4.1 
Pre-randomisation Run-in Period (Part A) 
Following confirmation of eligibility after the screening visit, subjects will be 
assigned to a pre-randomisation run-in number and allocated to one of the two 
treatment sequence groups in a chronological order, i.e. first eligible subject after 
the screening visit will be given the first run-in number. Subjects will be randomised 
with a ratio 2:2 (blocks of eight subjects) to receive: 
• 
Either lidocaine on injection test 1 then placebo (saline) on injection test 2, 
• 
Or placebo (saline) on injection test 1 then lidocaine on injection test 2. 
 
2.4.2 
Randomised Double-Blind Period (Part B) 
 
Subjects will be randomised to receive Dysport 2.5 U, Dysport 2.5 U placebo, 
Dysport 10 U, Dysport 10 U placebo, Dysport 20 U, Dysport 20 U placebo with a 
ratio 3:1:3:1:3:1 (blocks of 12 subjects). 
Following confirmation of eligibility after injection test 2, subjects will be assigned 
to a randomisation number and allocated to one of the treatment groups in a 
chronological order, i.e. first eligible subject will be given the first randomisation 
number. 
 
Mirror lists of randomisation numbers will also be produced to allow the 
randomisation of replacement subjects (e.g. the subjects who withdraw within six 
first weeks after Investigational Medicinal Product (IMP) dosing) or to be used for 
the replacement of kits which could be damaged during the IMP reconstitution. For 
example, number 
 will be used to randomise the replacement for the subject 
who was randomised with number 
. 
2.5 
Schedule of Assessments 
Schedule of assessments is presented in section 18.1 from the protocol. 
2.6 
Change from Statistical Section of the Protocol 
The following endpoints were not planned in the statistical section of the Protocol 
but were added in section 5.7.4.1 (Efficacy parameters) and 5.7.5.1 (Rescue 
medication): SPID and AUE. The reason for this change is to have additional 
information for the description of the pain response. Date of agreement of change is 
03MAY2019. 
The sensitivity analyses originally planned in the protocol in section 11.3.3.2 to take 
into account the intake of rescue medication and to handle missing data will not be 
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performed due to the low number of rescue medication taken and the difficulty to 
associate the NRS score assessment to the rescue medication. This will be 
confirmed during the blind data review meeting, before the database lock. Date of 
agreement of change is 04JUN2019. 
3 
PLANNED ANALYSES 
3.1 
Safety Monitoring  
No independent Data Monitoring Committee will be used in this study. 
3.2 
Interim Analysis / Primary Analysis 
No interim analysis will be performed. 
3.3 
Final Analysis 
Planned analyses will be done when all subjects completed study and after database 
lock. 
4 
ANALYSIS POPULATIONS  
4.1 
Screened population 
All subjects screened (i.e. who signed the informed consent). 
4.2 
Run-in population 
All subjects who received at least one injection in the pre-randomisation run-in 
period (Part A). 
For analyses and displays, subjects will be classified according to randomised 
treatment allocated in part A. 
4.3 
Randomised population 
All subjects randomised in the double-blind period (Part B). 
For analyses and displays, subjects will be classified according to randomised 
treatment allocated in part B. 
4.4 
Safety population 
All subjects who received at least one dose of the study drug during the randomised 
double-blind period (Part B). 
For analyses on the safety population, subjects will be classified according to 
treatment received. If there is any doubt whether a subject was treated or not, he/she 
will be assumed treated for the purposes of analysis. 
4.5 
Per Protocol (PP) Population 
All subjects from the randomised population for whom no major protocol deviation 
occurred. 
5 
STATISTICAL METHODS/ANALYSES 
The statistical analyses will be performed in accordance with ICH E9 guideline and 
guidelines presented in section 8. 
The statistical analyses will be performed by the Biostatistics unit of BIOTRIAL 
BIOMETRICS in agreement with the sponsor. 
 
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5.1 
General Considerations 
All statistical analyses will be performed using the SAS® software version 9.4 or 
higher. 
 
For Part A, only listings will be provided. For Part B, tables, figures and listings will 
be provided. 
 
5.1.1 
Outputs Presentation 
5.1.1.1 
Tables Header 
Depending on the type of data, the summary tables will be presented as follows: 
- For disposition, demographic data and baseline data description: by treatment 
group and overall, 
- For efficacy and safety data: by treatment group and all Dysport. 
5.1.1.2 
Presentation of Treatment Group 
For Part A, listings will be displayed using the following treatment group labels, in 
the order presented: 
 
Long label 
Short label 
Lidocaine 2.5mg/injection siteLidocaine
Placebo 
Pbo 
 
For Part B, Tables, Figures and Listings (TFLs) will be displayed using the 
following treatment group labels, in the order presented: 
 
Long label 
Short label 
Placebo 
Pbo 
Dysport 2.5U/Injection site Dysport 2.5U* 
Dysport 10U/Injection site Dysport 10U* 
Dysport 20U/Injection site Dysport 20U* 
* Per injection site 
 
When specified, tables will also be described by total dose received in the painful 
injection area and the total dose received in the painful area divided by the painful 
area. 
 
5.1.1.3 
Presentation of Visits / Timepoints 
Summaries by visit will be presented using visit number as collected in the 
electronic Case Report Form (eCRF). 
Visits in the TFLs will be presented as follows and in that order: 
 
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Part 
Long Visit Name  
Short Name 
 
Screening 
Scr 
Part A 
Injection test 1 (Day -21 max) 
Inj1 
 
Injection test 2 (Day -14 max) 
Inj2 
Part B 
Baseline (Day -7 Day -1) 
Bsl 
 
Day 1 Pre-dose 
D1 Pre-dose 
 
Day 1 Post-dose 
D1 Post-dose 
 
Day 2 Day 7 
D2 D7 
 
Week 2 
W2 
 
Week 4 
W4 
 
Week 6 
W6 
 
Week 8 
W8 
 
Week 10 
W10 
 
Week 12 
W12 
 
Week 14 
W14 
 
End of Study 
EOS 
 
5.1.2 
Descriptive Statistics 
All raw and derived variables will be listed and described using summary statistics. 
For categorical variables, summary statistics will be displayed using descriptive 
statistics by frequency count and percentages by category. The missing category 
will be presented if there is one missing category for at least one treatment group. 
Except otherwise specified, subjects with missing data will not be included in the 
calculation of percentages. For quantitative variables, summary statistics will be 
displayed using descriptive statistics by number of observations, mean, standard 
deviation (SD), first quartile, median, third quartile, minimum and maximum. 
Missing data will be displayed. 
 
5.1.3 
Baseline value 
Unless otherwise specified, baseline is defined as the last non-missing measurement 
taken within 7 days prior to IMP administration (including unscheduled 
assessments). 
 
For the spontaneous NRS score, baseline will be defined as the mean of all pre-dose 
data (from day -7 and including pre-dose on Day 1). 
 
5.1.4 
Reference Start Date and Study Day 
Reference start date is defined as the day of IMP administration in Part B. 
The day of IMP administration will be Day 1. Study day will be calculated as: 
- The difference between the event date and the reference date plus one day, if the 
event is on or after the reference date. 
- The difference between the event date and the reference date, if the date of event is 
prior to the reference date.  
Study day will appear in any Part B listings where an assessment date or event date 
appears. 
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In case of partial or missing event date, study day will appear missing while any 
associated durations will be presented based on the imputations described in 
appendix A3. 
 
5.2 
Randomisation, Disposition and Population 
A listing presenting randomisation details will be provided for Part A and Part B 
separately. 
 
Following disposition summaries and listings will be provided: 
- 
Summary table with the number and percentage of subjects screened, screen 
failed, reason for screen failures, randomised, completers, withdrawn and reason 
for withdrawal, by treatment group and overall, 
- 
Summary table on duration of subject participation in the study, for Part B. The 
definition of the duration of subject participation is from the date of consent to 
the last study visit, 
- 
Summary table with the number and percentage of non-responders’ subjects at 
the end of Part A, 
- 
Listing of subject disposition, 
- 
Listing of dates of visit including duration of subject participation, 
- 
Listing of screen failure subjects with the criteria not met, 
- 
Listing of withdrawal subjects, 
 
Following analysis population summaries and listings will be provided: 
- 
Listing of all inclusion criteria, 
- 
Listing of subjects violated inclusion criteria, 
- 
Listing of all exclusion criteria,  
- 
Listing of subjects fulfilled exclusion criteria, 
- 
Summary of the number and percentage of subjects in each analysis population 
by treatment group and overall, based on all randomised subjects with reasons 
for exclusion from each analysis population, 
- 
Summary of the number and percentage of subjects in the run-in population with 
reasons for exclusion from this population, 
- 
Listing including flag for each analysis population and reason for exclusion 
from each population. 
 
5.3 
Protocol Deviations 
An exhaustive list of major protocol deviations that may occur during the study and 
any action to be taken regarding exclusion of subjects will be defined in Protocol 
Deviation Plan. Major protocol deviations will be determined before unblinding of 
the study, finalized during the blind data review and documented in a separate 
document. 
Number and percentage of subjects with protocol deviations by deviation category 
(see DV section of Standard SDTM+ user guide) will be summarized on all 
randomised subjects. Listings of major protocol deviations will also be provided on 
the randomised population for Part B and on the run-in population for Part A. 
 
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5.4 
Demography and Other baseline characteristics 
All demographic and baseline characteristics summaries will be provided for the 
randomised population. No statistical comparison between treatment groups will be 
performed. 
 
Following summaries will be provided on: 
- 
Demographic variables (refer to appendix A6 for EudraCT age categories), 
- 
Other baseline characteristics (e.g. drug abuse tests, postmenopausal status, 
serology), 
- 
Disease characteristics at day 1 pre-dose (e. g. longitudinal axis, total painful 
area and baseline values for spontaneous current pain NRS score), 
 
Details of the surgery which caused the painful scar will be listed (Surgical 
procedure, indication and date of surgery). 
 
Listings will also be provided for all the summaries listed above. 
An additional listing with demographic variables for subjects non included in part B 
will also be provided. 
 
5.5 
Medical history, non-drug therapies, medications and surgical procedures 
 
Medical and surgical history, non-drug therapies and surgical procedures will be 
coded using the latest version of MedDRA in effect within IPSEN at the time of 
database lock. Medications will be coded using the latest version of WHO-Drug 
dictionary in effect within IPSEN at the time of database lock. 
 
Medication, non-drug therapies and surgical procedures start and stop dates will be 
compared to the date of the IMP administration (Part B) to allow classification as 
either Prior only, Prior and Concomitant, or Concomitant only: 
 
Prior (P) 
Start and stop dates prior to the date of IMP administration. 
Prior and 
Concomitant (PC) 
Start date before the date of IMP administration and stop date on or 
after the date of IMP administration. 
Concomitant (C) 
Start date on or after the date of 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”. 
 
See detailed rules in appendix A3 for classification of prior and concomitant 
medication/non-drug therapies, surgical procedures in case of partial/missing date. 
 
The therapeutic class will correspond to the second level of ATC code, that is, 
corresponding to the first 3 figures. 
 
Following summaries, presenting count and percentages of subjects will be 
provided: 
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- 
Medical and surgical history by primary system organ class (SOC) and preferred 
term (PT), 
- 
Prior medications (P) by ATC class and PN (ATC level 2), 
- 
Concomitant medications (PC, C) by ATC class and PN (ATC level 2), 
- 
Concomitant medications (PC, C) related to medical history by ATC class and 
PN (ATC level 2), 
- 
Prior non-drug therapies (P) by primary SOC and PT, 
- 
Concomitant non-drug therapies (PC, C) by primary SOC and PT, 
- 
Concomitant surgical procedures (C) by primary SOC and PT, 
 
A 
specific 
listing 
of 
medications 
from 
the 
class 
ANALGESICS, 
ANTIINFLAMMATORY 
AND 
ANTIRHEUMATIC 
PRODUCTS, 
ANTIPRURITICS, INCL. ANTIHISTAMINES, ANESTHETICS, ETC. and 
PSYCHOANALEPTICS (ATC level 2) and a specific listing of the concomitant 
medication related to medical history will be provided. 
 
Listings will be provided for all the summaries listed above for Part B. These 
listings should include a flag indicating the category (P, PC, C) as described in the 
table above. 
 
5.6 
Compliance 
Treatment compliance will be summarized on the run-in population for Part A and 
on the safety population for Part B using a listing of administrations and planned 
and performed injected volumes (overall and by injection site). 
 
5.7 
Pharmacodynamic/Efficacy Part B 
5.7.1 
General Considerations 
5.7.1.1 
Significance Testing and Estimations 
The statistical analysis of efficacy and safety is only descriptive therefore no formal 
statistical significance testing will be performed. 
 
5.7.1.2 
Statistical/analytical issues 
Adjustments for Covariates  
Not applicable 
 
Handling of Dropouts or Missing Data  
The strategy for missing data handling is specified in each relevant section. 
 
Interim Analyses and Data Monitoring 
Please refer to section 3. 
 
Multicentre Studies 
Not applicable 
 
Multiple Comparisons/Multiplicity  
No formal statistical significance testing will be performed. 
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Use of an "Efficacy Subset" of Subjects  
Not applicable 
 
Active-Control Studies Intended to Show Equivalence (if applicable) 
Not applicable 
 
Examination of Subgroups 
Subgroups analyses will be detailed in the concerned sections. 
 
5.7.2 
Pre-randomisation run-in period 
A listing presenting NRS data will be provided. The listing will present, by subject, 
the planned visit and timepoint, the treatment administered, the assessment dates 
and the NRS scores. 
5.7.3 
Randomised double-blind period: Analysis of Primary Efficacy Endpoint 
5.7.3.1 
Endpoint, Treatment Effect and Estimand Definition 
To assess the primary objective, the treatment policy estimand is defined by the 
following key attributes: 
- 
Population: Subjects in the randomized population 
- 
Assessment: Worst pain and average pain within the last 12 hours as assessed by 
the spontaneous NRS score 
- 
Variables (Endpoints): Described in table below 
- 
Population-level summary (estimate of the treatment effect): Described in table 
below 
 
Variables (Endpoints) 
Population-level summary (estimate of the treatment 
effect) 
Time to onset i.e. time to decrease from baseline of two 
points in the spontaneous NRS score. 
Derivation: First scheduled time point for which the 
change from baseline is ≤ - 2 points. 
The number (%) of subjects who reach the time to onset 
in each treatment group. 
The mean time to onset in each treatment group 
Peak effect i.e. maximal decrease from baseline in the 
spontaneous NRS score. 
Derivation:  Minimum change from baseline amongst 
the scheduled timepoints 
The mean peak in each treatment group 
Time to peak-effect i.e. time to reach the peak-effect 
Derivation: First timepoint for which the peak effect is 
reached 
The mean time to reach the peak-effect in each 
treatment group 
Duration of effect (in days) i.e. duration between time to 
onset and last timepoint with decrease from baseline in 
the spontaneous NRS score is ≥ two points 
Derivation: Duration is calculated as: last timepoints for 
which change from baseline ≤ -2 – time to onset (in 
days) 
The mean duration of effect in each treatment group (for 
the subjects who reach the time to onset) 
 
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Each endpoint will be evaluated using the worst pain within the last 12 hours and 
using the averaged pain within the last 12 hours. 
5.7.3.2 
Primary Analysis 
For each estimate, analysis will be based on the treatment policy estimand: No 
adjustment will be made in case of intake of rescue medication. No handling of 
missing data will be performed in the primary analysis. 
 
Listings will be provided including all subjects with missing values for the 4 
primary endpoints based on the NRS score. For subjects with missing values, the 
listings will provide all observed data related to the primary endpoints i.e. all 
measurements recorded prior to the missing value, any measurements recorded after 
the missing value, important baseline characteristics, the reason for study 
discontinuation and the timing of study discontinuation. 
 
Summary table for time to onset, peak-effect, time to peak effect and duration of 
effect will be computed for each assessment, by treatment group and Placebo versus 
all Dysport groups. 
 
The number and percentage of subjects who reach the time to onset will be 
presented for each assessment, by treatment group. 
 
For each assessment, scatter plots and box whisker plots will be generated for the 
comparison of the peak effects between the treatment groups and all Dysport 
groups. 
 
5.7.3.3 
Sensitivity Analysis 
The same analyses as described in section 5.7.3.2 will be performed on the PP 
population using the uncorrected parameters if important differences, i.e. at least 2 
patients in the same treatment group, between the randomised population and the PP 
population are observed: the need for this analysis will be discussed during the blind 
data review meeting. 
5.7.3.4 
Supplementary Analysis 
Not applicable. 
 
5.7.3.5 
Subgroup Analysis 
No subgroup analyses will be performed. 
 
5.7.4 
Randomised double-blind period: Analysis of Key Secondary Efficacy Endpoints 
5.7.4.1 
Endpoint, Treatment Effect and Estimand Definition 
To assess the secondary objectives, the treatment policy estimand is defined by the 
following key attributes: 
- 
Population: Subjects in the randomised population 
- 
Assessments: Described in table below 
- 
Variables (Endpoints): Described in table below 
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- 
Population-level summary (estimate of the treatment effect): Described in table 
below 
 
Assessment 
Variables (Endpoints) 
Spontaneous pain as assessed by the 
spontaneous NRS score 
Change from baseline in the spontaneous NRS score to each 
schedule timepoint 
Stimulus evoked pain as assessed by the NRS 
score during QST 
Change from baseline in the stimulus evoked NRS score to 
each scheduled timepoint 
 
Spontaneous NRS Score 
For each visit, spontaneous NRS (average and worst pain) score is assessed twice 
per day. The 2 assessments will be described separately as well as the daily average 
(mean of the NRS score assessed in the morning and in the evening) for the average 
NRS and the daily worst value for the worst NRS scores (worst NRS score assessed 
by day). 
 
Baseline will be derived as defined in section 5.1.3. 
 
To support the analyses of NRS score, the following endpoints will be considered: 
- 
Time weighted Sum Pain Intensity Differences (SPID) from time 0 to each 
visit: 
SPID0-Wx = ∑
ܥܪܩ௜
௜ୀ௡
௜ୀ଴
ሺݐ௜ାଵെݐ௜ሻ where t0 is the baseline time, ti is the 
scheduled assessment time and CHGi is the change from baseline in pain 
intensity at each post-dose scheduled timepoint. 
- 
Sum Pain Intensity Differences Area Calculation (Area Under the Effect 
(AUE)): 
AUE0-Wx = ∑
ሺܥܪܩ௜
௜ୀ௡ሺ
௜ୀ଴
൅ ܥܪܩ௜ାଵሻ/2ሻ∗ሺݐ௜ାଵെݐ௜ሻ where t0 is the 
baseline, ti is the scheduled assessment time and CHGi is the change from 
baseline in pain intensity at each post-dose scheduled timepoint. 
SPID and AUE will be evaluated at each visit (Week 6, Week 12 and end of study) 
using the worst pain within the last 12 hours and using the average pain within the 
last 12 hours, based on the spontaneous NRS score. 
 
Painful Area Mapping 
Painful area mapping includes longitudinal axis (cm) and total painful area (cm²). It 
is assessed at screening, injection test 1 and 2, baseline, day 1 pre-dose, week 6, 
week 12 and end of study. Change from baseline will be derived for each parameter. 
 
QST 
 
The stimulus evoked NRS score is assessed during QST at baseline (day -7 day -1), 
week 6 and week 12, and include the following parameters: 
- 
Baseline assessment on contralateral/non-painful area on painful area: 
NRS assessment is performed on each area (baseline assessments). 
 
Change from baseline will also be derived at each timepoint for baseline 
assessment, for the painful area only. 
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- 
Temporal summation on painful area only: NRS score is recorded pre-
stimulus and 10 attempts are performed after stimulus. 
Change from baseline will also be derived at each time point as follows: 
NRS score from the last set of attempts – NRS pre-stimulation. 
 
- 
Tactile detection thresholds on contralateral/non-painful area and on 
painful area: results (in g) will be assessed to determine sensory and pain 
perception threshold on each area. 
Thresholds are assessed on a logarithmic scale. It will be converted to a 
linear scale for the analysis (see section 7). 
Change from baseline will also be derived at each time point, for the 
painful area only. 
 
- 
Mechanical pain sensitivity and dynamic mechanical allodynia on 
contralateral/non-painful area and on painful area: on each area, NRS-
score will be assessed during static mechanical allodynia and dynamic 
mechanical allodynia. 
Change from baseline will be derived at each time point, for the painful 
area only. 
 
- 
Pressure pain thresholds (PPT) (in kg/cm²) on contralateral/non-
painful area and on painful site: 3 readings of PPT, as well as their 
average, will be assessed in 4 positions, on each area. The global average 
of all the PPT values from all the positions will be derived for the painful 
and non-painful area. 
Change from baseline on the global average PPT will also be derived for 
the painful area only. 
 
- 
Conditioned pain modulation (CPM) on painful area will be performed 
and the following parameters will be determined: 
a. 2 NRS scores: baseline and resulting NRS (cuff in situ). 
b. Duration of cuff occlusion (in min:sec) 
c. Clenching (Yes/No) 
d. Pressure applied (in mmHg) 
e. 3 PPT readings (in kg/cm²) and their average. 
CPM is assessed at the point on the painful area with the lowest PPT 
value from the previous test. A flag should be added if CPM is not 
evaluated at the lowest PPT position. Change from baseline on the 
average PPT for the painful area will also be derived. 
 
- 
Thermal detection and pain thresholds on contralateral/non-painful 
area and on painful area including cold sensation (in °C; 4 replicates and 
the average), warm sensation (in °C; 4 replicates and the average), cold 
pain (in °C; 3 replicates and the average) and heat pain (in °C; 3 
replicates and the average). 
For each subject, the number of incorrect perception of temperature by 
test will be derived for the painful and non-painful area. 
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Temperatures below or equal to 0°C and temperatures above or equal to 
50°C are not reliable for the analyses and therefore will be excluded from 
the statistical analyses. 
5.7.4.2 
Main Secondary Analysis 
For each estimate, analysis will be based on the treatment policy estimand: No 
adjustment will be made in case of intake of rescue medication. 
 
Painful Area Mapping 
 
Summary table for raw data and changes from baseline of the longitudinal axis and 
the total painful area will be provided by treatment group and measurement time 
and Placebo versus all Dysport groups by measurement time. 
 
Spontaneous NRS scores 
 
Each analysis on the spontaneous NRS score will be produced separately for the 
Average Numeric Pain Rating and the Worst Numeric Pain Rating. 
 
Summary table for raw data and changes from baseline in the spontaneous NRS 
score will be produced by treatment group, and measurement times, only for the 
daily average for the average NRS scores and for the daily worst for the worst NRS 
scores). 
 
The graph of arithmetic mean ± SD over time will be provided for the change from 
baseline in the spontaneous NRS score (daily average for the average NRS and the 
daily worst for the worst NRS) with all treatment groups on the same graph. Size 
groups at each time point will also be presented on the graph. 
 
The graph of arithmetic mean ± SD over time will be provided for the change from 
baseline for the morning score and evening score on the same graph, separately for 
each treatment group. 
 
Individual raw data and change from baseline spontaneous NRS score versus time 
profiles will be presented graphically for each subject with the worst numeric pain 
rating within the last 12 hours and the average numeric pain rating within the last 12 
hours on the same graph. 
 
Listings of individual data of the spontaneous NRS scores will be provided 
including all subjects with missing data. Values measured on a day where a rescue 
medication was taken will be flagged. 
 
Summary table for SPID and AUE parameters will be computed for each 
assessment, by treatment group and visit. 
For each assessment, scatter plots and box whisker plots will be generated for the 
comparison of SPID and AUE between the treatment groups. 
 
Listing of individuals values of SPID and AUE will be provided. 
 
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QST analyses 
 
Baseline assessments 
Summary tables for raw data and changes from baseline in the NRS score will be 
produced by treatment group and measurement times. 
 
Scatter plots of individual values at each time point will be presented with the 
arithmetic means by time point, linked by treatment group. All treatment groups will 
be presented on the same graph. 
Individual values-time profiles (spaghetti plots) will also be presented for each 
treatment group on linear scale. 
For the baseline assessments, individual histograms of the raw values of the NRS 
score will be provided to compare non-painful area with the painful area, for each 
measurement times. Values at painful and non-painful areas will be presented on the 
same graph. 
 
Tactile detection thresholds 
 
For each test (sensory threshold and pain perception threshold), summary tables for 
raw data and changes from baseline will be produced by treatment group and 
measurement times. 
For the painful area, scatter plots of Von Frey sensory threshold and pain perception 
threshold will be provided with arithmetic means linked between the visits for each 
group. All treatment groups will be presented on the same graph. 
 
Individual values-time profiles (spaghetti plots) for each test will also be presented 
for each treatment group on linear scale. 
 
For each test, individual histogram will be provided: for each subject, the Von Frey 
reference will be represented at each time point for the painful area and the non-
painful area on the same graph. For each value, the associated force value will be 
presented on the graph. 
 
Mechanical pain sensitivity and dynamic mechanical allodynia 
 
For each test (static mechanical allodynia and dynamic mechanical allodynia), 
summary tables for raw data and changes from baseline in the stimulus-evoked NRS 
scores will be produced by treatment group and measurement times. 
 
For each test, for the painful area, scatter plots of stimulus-evoked NRS scores will 
be provided with arithmetic means linked between the visits for each group. All 
treatment groups will be presented on the same graph. 
 
Individual NRS score-time profiles (spaghetti plots) for each test will also be 
presented for each treatment group on linear scale. 
 
For each test (static mechanical allodynia and dynamic mechanical allodynia), 
individual histogram will be provided: for each subject, the raw NRS data will be 
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represented at each time point for the painful area and the non-painful area on the 
same graph. 
 
Temporal summation at painful area 
 
Summary tables for the pre-stimulus NRS score and the 10 attempts post-
stimulation will be provided for raw data by treatment group and measurement 
times. Summary tables will also be provided for change from baseline by treatment 
group and measurements. 
The number of repetitions will also be described by treatment group and 
measurement times. 
 
The graph of arithmetic means according to the stimulation set numbers will also be 
provided for each treatment group with all visits on the same graph. Treatment 
groups will be presented on separated graph. 
 
Individual graphs of the NRS-score profile (pre-stimulus and post-stimulus) will 
also be provided, with all visits on the same graph: raw NRS score will be displayed 
(y-axis) according to the stimulation set number (x-axis). The Von Frey filaments 
used (von Frey Reference) will be indicated on each individual graph. 
 
Pressure pain thresholds (PPT) 
 
Summary tables of raw data and changes from baseline (only for the painful area) 
for the global average PPT will be produced by treatment group and measurement 
times. 
For the painful area, scatter plots of the global average PPT will be provided with 
arithmetic means linked between the visits for each group. All treatment groups will 
be presented on the same graph. 
 
Individual values-time profiles (spaghetti plots) for the global average PPT will also 
be presented for each treatment group on linear scale. 
 
Individual histogram of the average pressure at each timepoint will be provided. 
Values for painful and non-painful area will be represented on the same graph. 
 
Conditioned pain modulation 
 
Average raw data and change from baseline will be described by treatment group 
and measurement times. Average PPT measured during previous test, at the same 
position as the CPM will also be described in this table. 
 
Box-whisker plots will be generated for the comparison of CPM and PPT between 
treatment groups. 
 
Individual histogram of the average PPT measured during CPM on the painful area 
and the average PPT measured during the previous test, at the same position on the 
painful area at each timepoint will be provided. Footnote will be added if CPM is 
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not evaluated at the lowest PPT position. Position chosen will be reported for each 
time point. 
 
Thermal detection and pain thresholds 
 
For each test (cold sensation, warm sensation, cold pain and warm pain), average 
raw data will be described by treatment group and measurement times. 
For each test, summary tables of the correctness of the answers will also be 
provided by treatment group and measurement times. 
For each test, for the painful area, scatter plots of the average sensation temperature 
will be provided with arithmetic means linked between the visits for each group. All 
treatment groups will be presented on the same graph. 
 
Summary table with the number of subjects with not done assessments will be 
provided with the reason for not done, by treatment group and measurement times. 
Subjects with excluded values (values ≤0 and values ≥50) will be included in this 
table with the reason ‘Values excluded from analyses as threshold exceeded’. 
 
Individual average sensation temperature-time profiles (spaghetti plots) for each test 
will also be presented for each treatment group on linear scale. 
 
For each test, individual histogram of the average temperature for the change 
sensation will be provided at each time point. Values at painful and non-painful area 
will be presented on the same graph. 
 
A listing of the number of incorrect perception of temperature will be provided. 
 
All categories for QST 
 
Listings of individual assessments performed during QST will be provided by 
category of QST. 
 
5.7.4.3 
Sensitivity Analysis 
No sensitivity analysis will be performed. 
 
5.7.4.4 
Subgroup Analysis 
No subgroup analyses will be performed. 
 
5.7.5 
Randomised double-blind period: Analysis of Other Secondary Efficacy 
Endpoints 
5.7.5.1 
Endpoint, Treatment Effect and Estimand Definition 
To assess the exploratory objectives, the treatment policy estimand is defined by the 
following key attributes: 
- 
Population: Subjects in the randomized population 
- 
Assessments: Described in table below 
- 
Variables (Endpoints): Described in table below 
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- 
Intercurrent event: None 
- 
Population-level summary (estimate of the treatment effect): Described in table 
below 
 
Assessment 
Variables (Endpoints) 
Population-level summary (estimate of the 
treatment effect) 
QoL assessed by the 
SF-36 questionnaire 
Change from baseline in SF-36 scores at 
each scheduled timepoint 
Difference between each Dysport doses and 
the placebo group in the SF-36 scores at each 
scheduled timepoint 
Use of rescue 
medication during the 
study 
Amount of rescue medication taken during 
the study 
Difference between each Dysport doses and 
the placebo group, in amount of rescue 
medication intake during Part B 
Use of rescue 
medication during the 
study 
Time to first intake of rescue medication in 
days 
Derivation: Difference in days between date 
of the first intake of rescue medication and 
date of IMP administration. 
Difference between each Dysport doses and 
the placebo group, in the time to first intake 
of rescue medication during Part B 
 
Quality of life 
 
QoL is assessed at day -1, week 6 and week 12 by the SF-36 questionnaire. The SF-
36 consists of 36 questions divided in 9 scaled scores: General health, Reported 
health transition, Physical functioning, Role physical, Role emotional, Social 
functioning, Bodily pain, Vitality, Mental health. For more details about the 
derivation of the scores, see section 7. Two versions of the questionnaire were used 
in the study, mapping was performed to homogenize the answers, see section 7 for 
details about mapping rules. 
 
In addition, a global score per patient will be derived as the sum of the individual 
scores at each question. It will range from 0 to 3600. 
 
Rescue Medication 
 
Rescue medications will be coded using the latest version of WHO-DD in effect 
within IPSEN at the time of database lock. 
 
The total amount of rescue medication will be derived. 
 
5.7.5.2 
Analysis 
 
Quality of Life 
A listing of individual responses to the SF-36 questionnaire will be prepared. 
 
For each question of the SF-36 questionnaire, a summary table presenting the raw 
scores and change from baseline will be generated by dimension, treatment group 
and measurement time. 
Arithmetic means of the global scores will be presented on a histogram by treatment 
group, with all visits and dimensions on the same graph. Arithmetic means of the 
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global scores will also be presented on a histogram by dimension, with all visits and 
treatment group on the same graph. 
Individual histograms presenting mean scores by dimension and visit will be 
produced, with all dimensions on the same graph. 
 
Rescue Medications 
A listing of rescue medications will be provided, including the total amount of 
rescue medication and the time from D1 to first intake of rescue medication. 
 
Summary of count and percentages of subjects having at least one rescue medication 
will be provided by ATC class and preferred Name, by treatment group. 
Summaries of the total amount of rescue medication by preferred Name and the 
time to first intake (in days) will be provided by treatment group and Placebo group 
versus all Dysport groups. The number of subjects using a rescue medication and 
the number of rescue medication taken will also be described by treatment group. 
 
5.8 
Safety 
5.8.1 
General Consideration 
All safety summaries and analyses will be based upon the Safety population. All 
safety data will be included in subject data listings (see listing detail conventions in 
Appendix A5). There will be no statistical comparison between the treatment groups 
for safety data.  
If conversion factors are used, they should be presented either in the relevant section 
or a link to section 7 should be added. 
5.8.2 
Extent of exposure  
In Part B, duration of exposure will be defined in weeks as: 
([date of last visit attended – first IMP injection date] +1)/7. 
 
The total dose received will be derived as followed: 
- 
Total Dose (in U) = Number of injection site*Number of units of Dysport 
received, 
- 
Total dose (in U/cm²) = Total dose / (Total painful area at day 1 pre-dose). 
 
The following extent of exposure summaries will be presented for Part B, by 
treatment group and all Dysport:  
- 
Summary of the number of injections sites, 
- 
Summary of the volume injected (total and per site), 
- 
Summary of the total dose received by treatment group, 
- 
Summary of the total dose in U/cm² received by treatment group. 
The following extent of exposure listings will be presented for Part A and Part B: 
- 
Listing of exposure data (Part B only), 
- 
Listing of subjects receiving test drugs from different batches. 
 
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5.8.3 
Adverse Events 
 
All adverse events (AEs) recorded in the eCRF will be coded using the latest 
version of MedDRA dictionary in effect within IPSEN at the time of the database 
lock. 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 IMP 
administration in Part B and up to End of Study (EoS) visit or Early 
Discontinuation (ED).  
- 
Events whose severity worsens on or after the date and time of IMP 
administration in Part B and up to EoS visit or ED visit,  
- 
Refer to appendix A3 for handling of partial date. In the case where it is not 
possible to define an AE as treatment emergent or not, the AE will be classified 
by the worst case; i.e. treatment emergent. 
 
The following summary will be provided by total dose and treatment group (i.e. by 
injection site dose) and all Dysport for Part B: 
- 
An overview table summarizing the number and percentage of subjects with at 
least one of the following AEs: any AE; any TEAE; any severe TEAE; 
treatment-related TEAE; TEAE leading to discontinuation from the study, 
Serious TEAE, treatment-related Serious TEAE, Serious TEAE leading to death, 
treatment-related Serious TEAE leading to death, Serious TEAE leading to 
discontinuation from the study, any Adverse Events of Special Interest (AESI). 
The ranges to use for the dose will be precisely defined during the data review 
meeting. 
 
The following summaries will be provided for Part B by treatment group and all 
Dysport groups: 
- 
A summary of the number and percentage of subjects reporting a TEAE by 
treatment group, SOC and PT, 
- 
A summary of the number and percentage of subjects reporting a TEAE by 
treatment group and PT, 
- 
A summary of the number and percentage of subjects reporting a TEAE by 
treatment group, causality, SOC and PT, 
- 
A summary of non-serious TEAE by treatment group, SOC and PT. 
 
AEs summaries will be ordered in term of decreasing frequency for SOC and PT 
within SOC in the treatment group (Part B) and then similarly by decreasing 
frequency in the treatment group, and then alphabetically for SOC and PT within 
SOC. 
 
AEs will be counted as follows: 
- 
Subjects with more than one AE within a particular SOC are counted only once 
for that SOC.  Similarly, subjects with more than one AE coding to a particular 
PT are counted only once for that PT; 
- 
Subjects reporting a TEAE more than once within that SOC/ PT, the TEAE with 
the worst-case severity will be used in the corresponding severity summaries; 
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- 
Subjects reporting a TEAE more than once within that SOC/ PT, the TEAE with 
the worst-case relationship to study medication will be used in the 
corresponding relationship summaries; 
- 
If the severity is missing for a TEAE, it will be considered as missing in the 
summary tables; 
- 
If the causality is missing for a TEAE, it will be considered missing in the 
summary tables; 
- 
The non-serious TEAEs table should include a specific row “any non-serious 
TEAE above x%”. 
 
In addition, for each part, a listing with all AEs data will be listed by treatment 
group including non-TEAEs, Treatment-emergence status will be flagged in the 
listing, and AESI will also be flagged.  
 
Deaths, Serious Adverse Events, and Other Significant Adverse Events 
  
Adverse events of special interest (AESIs) for IMP Dysport are TEAEs that suggest 
a possible remote spread of effect of the toxin or events suggestive of 
hypersensitivity like reactions. TEAEs due to possible remote spread of the effects 
of IMP Dysport will be identified using the list of MedDRA 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. A list of MedDRA preferred terms, used to 
identify any potential AESI, is provided in a separate document AESIs MedDRA 
version 21.1.xlsx dated 02 April 2019. 
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 ‘hypersensitivity reactions’ due to study treatment 
administration. Cases will be excluded if they are confounded by presence of 
alternative clinical etiologies (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 summaries, only the final list of AESIs confirmed by the sponsor as “a 
possible remote spread event” or “hypersensitivity reactions” will be taken into 
account. 
The following table will be presented: 
- 
AESIs with the number and percentage of subjects and the number of 
occurrences presented by primary SOC and PT, presented by type of AESI. 
 
The following listings will be provided: 
- 
A listing of all deaths that occurred during the study, 
- 
A listing of all serious adverse events, 
- 
A listing of all adverse events leading to discontinuation of study, 
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- 
A listing of subjects having AESIs. 
 
5.8.4 
Laboratory Data 
All laboratory data will be presented in the units of International System of Units (SI).  
 
The following laboratory parameters will be taken at screening: 
- 
Chemistry: Albumin, Alkaline Phosphatase (ALP), Alanine Aminotransferase 
(ALT), Aspartate Aminotransferase (AST), Bicarbonate, Direct Bilirubin, 
Bilirubin, Calcium, Cholesterol, Creatine Kinase, Chloride, Creatinine, C 
Reactive Protein, Gamma Glutamyl Transferase (GGT), Glucose, Potassium, 
Phosphate, Protein, Sodium, Triglycerides, Urea 
- 
Haematology: Basophils, Eosinophils, Hematocrit, Hemoglobin, Lymphocytes, 
Ery. Mean Corpuscular Hemoglobin, Ery. Mean Corpuscular HGB 
Concentration, Ery. Mean Corpuscular Volume, Monocytes, Neutrophils, 
Platelets, Erythrocytes, Leukocytes 
- 
Urinalysis (Qualitative): Bilirubin, Glucose, Ketones, Nitrite, Occult Blood, 
pH, Protein, Urobilinogen 
 
In addition, the following listings are to be provided for Part A and Part B: 
- 
Listings of all laboratory data (haematology, clinical chemistry and urinalysis). 
Out-of-reference-range values will be flagged as high (H) or low (L), or 
clinically significant (CS). Any unscheduled laboratory assessments will be 
flagged [U] in the listings. 
- 
Laboratory reference ranges (by gender and age where relevant). 
 
5.8.5 
Vital Signs 
 
The following Vital signs parameters will be taken in supine position at screening, 
injection test 1 and 2, baseline, day 1 pre-dose, day 1 post-dose, week 6 and end of 
study and in standing position at screening only: 
- 
Systolic blood pressure (mmHg), 
- 
Diastolic blood pressure (mmHg), 
- 
Heart rate (beats/min). 
 
The following summaries are to be provided for Part B: 
- 
A summary of the actual and change from baseline (only for supine position) in 
each vital sign parameter (systolic blood pressure, diastolic blood pressure and 
heart rate) by treatment group and timepoint, 
 
The following listings are to be provided (Part A and Part B): 
- 
A listing of vital signs data by treatment group, with PCSA values highlighted. 
PCSA criteria are defined in appendix A2. Any unscheduled vital signs will be 
flagged [U] in the listing. 
5.8.6 
Electrocardiogram (ECG) 
 
Results from the local ECG, assessed at screening, will be used. 
 
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An overall Investigator assessment of ECG will be provided as “normal”, 
“abnormal, not clinically significant” and “abnormal, clinically significant”. Only 
investigator assessment and findings (if any) will be recorded in the database. 
 
A summary of the investigator’s interpretation will be provided for Part B. 
For Part A and Part B, the investigator’s interpretation will be listed with abnormal 
findings, if any. 
 
5.8.7 
Physical Examination 
 
Physical examinations include a general inspection, assessed at screening, baseline, 
day 1 pre-dose, week 6 and end of study and a scar physical examination, assessed 
at week 6. 
 
Scar physical examination will be coded using the latest version of MedDRA in 
effect within IPSEN at the time of database lock 
 
The following listings will be provided on Part B: 
- 
A listing of physical examination data, 
- 
A listing of scar physical examination data, 
- 
A listing presenting subjects with at least one physical examination abnormality. 
 
5.8.8 
Pregnancy tests 
 
Urine pregnancy tests will be performed at screening, at day 1 pre-dose and at end-
of-study visit. 
 
A listing with the date of examination, the status of the examination (performed/not 
performed) and the result (positive/negative) will be provided by treatment group, 
subject and examination date. 
 
5.9 
Pharmacokinetics (if applicable) 
Not applicable. 
5.10 
Anti-drug Antibodies (if applicable) 
Not applicable. 
6 
DATA HANDLING 
 
6.1 
Visit window 
Visits can occur +/- three days around the scheduled date. 
6.2 
Unscheduled Visits, Retest, Withdrawal Visit,  
All listings will include retests and unscheduled visits, while for the description by 
visit in the tables, only the scheduled visits according to the protocol will be 
described.  
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Unscheduled visit and retest measurements will be used to provide a measurement 
for a baseline data or endpoint value (e.g. worst value), if appropriate according to 
their definition. These measurements will also be used to determine abnormal 
laboratory, vital signs values or ECG. 
If a value requires a retest (for laboratory values, vital signs and ECG) the closest 
non-missing reliable value to the scheduled visit will be used in the summary tables. 
An assessment will be considered reliable if it is performed without any technical 
problem and if the result is within the range of likely values. 
Subjects who have withdrawn early from the study have their last assessment 
entered as visit 90 in the eCRF. By convention, for these subjects, the visit number 
will be reassigned to the next empty visit number (i.e. if a subject has Visit 1, 2, 3 
and 90 entered in the database, the visit number 90 will be reassigned to visit 
number 4). 
 
7 
DERIVED DATA 
 
QST data – Tactile detection thresholds 
 
During the tactile detection test, the force (in g) recorded is in a logarithmic scale. 
To analyse the data, the values will be converted on a linear scale following the 
table below. 
 
Filament 
A 
B 
C 
D 
E 
F 
G H I 
J K L M N O P Q 
R 
S 
T 
Force (g) 
0.008 0.02 0.04 0.07 0.16 0.4 0.6 1 1.4 2 4 6 8 10 15 26 60 100 180 300 
Conversion 
1 
2 
3 
4 
5 
6 
7 
8 9 
10 11 12 13 14 15 16 17 18 
19 
20 
 
SF-36 Questionnaire – Score derivation 
 
The SF-36 consists of 36 questions divided in 8 dimensions: General health, 
Physical functioning, Role physical, Role emotional, Social functioning, Bodily 
pain, Vitality, Mental health and one additional question on Reported health 
transition. 
 
In each dimension, each question will be coded from 0 to 100, using the table 
below. 
 
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Question number 
Original response 
Analysis 
Value 
1, 2, 6, 8, 11b, 11d 
First modality: Excellent / Much better now than one year ago / Not at 
All / Definitely true 
100 
Second modality: Very good / Somewhat better now than one year ago / 
Slightly / A little bit / Mostly true 
75 
Third modality: Good / About the same / Moderately / Don’t know 
50 
Fourth modality: Fair / Somewhat worse than one year ago / Quite a bit / 
Mostly false 
25 
Fifth modality: Poor / Much worse now than one year ago / Extremely / 
Definitely false 
0 
3a, 3b, 3c, 3d, 3e, 3f, 3g, 
3h, 3i, 3j 
First modality: Yes, Limited a Lot 
0 
Second Modality: Yes, Limited a little 
50 
Third modality: No, Not Limited at All 
100 
4a, 4b, 4c, 4d, 5a, 5b, 5c First modality: Yes 
0 
Second modality: No 
100 
7, 9a, 9d, 9e, 9h 
First modality: None / All of the time 
100 
Second modality: Very mild / Most of the time 
80 
Third modality: Mild / A good bit of the time 
60 
Fourth modality: Moderate / Some of the time 
40 
Fifth modality: Severe / A little of the time 
20 
Sixth modality: Very severe / None of the time 
0 
9b, 9c, 9f, 9g, 9i 
First modality: All of the time 
0 
Second modality: Most of the time 
20 
Third modality: A good bit of the time 
40 
Fourth modality: Some of the time 
60 
Fifth modality: A little of the time 
80 
Sixth modality: None of the time 
100 
10, 11a, 11c 
First modality: All of the time / Definitely true 
0 
Second modality: Most of the time / Mostly true 
25 
Third modality: Some of the time / Don’t know 
50 
Fourth modality: A little of the time / Mostly false 
75 
Fifth modality: None of the time / Definitely false 
100 
 
Within each dimension, scores will be derived as the mean of the responses, thus 
scores will range from 0 to 100, with higher score defining a more favourable 
health. Missing data will not be taken into account and will not be replaced. Table 
below presents the number of questions by dimension. 
 
Area 
Dimension 
Numbers of questions 
Functional status Physical functioning 
10 
Social functioning 
2 
Role physical 
4 
Role Emotional 
3 
Wellbeing 
Mental health 
5 
Vitality 
4 
Bodily pain 
2 
Overall evaluation 
of health 
General Health 
5 
Reported health transition 1 
TOTAL 
36 
 
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SF-36 Questionnaire – Mapping rules between Version 2.0 and 1.0 
 
Question 
Version 2 
Version 1 
Mapping rules 
During the past 4 weeks, 
have you had any of the 
following problems with 
your work or other regular 
daily activities as a result of 
your physical health? 
Modalities used are the 
following:  
- All of the time 
- Most of the time 
- Some of the time 
- A little of the time 
- None of the time 
Modalities used are the 
following:  
- Yes 
- No 
Modalities from version 1 
will be mapped as follow: 
- All of the time => Yes 
- Most of the time => Yes 
- Some of the time => Yes 
- A little of the time => Yes 
- None of the time => No 
During the past 4 weeks, 
have you had any of the 
following problems with 
your work or other regular 
daily activities as a result of 
any emotional problems 
(such as feeling 
depressed or anxious)? 
Modalities used are the 
following:  
- All of the time 
- Most of the time 
- Some of the time 
- A little of the time 
- None of the time 
Modalities used are the 
following:  
- Yes 
- No 
Modalities from version 1 
will be mapped as follow: 
- All of the time => Yes 
- Most of the time => Yes 
- Some of the time => Yes 
- A little of the time => Yes 
- None of the time => No 
These questions are about 
how you feel and how 
things have been with you 
during the past 4 weeks. 
For each question, please 
give the one answer that 
comes closest to the way 
you have been feeling. 
Modalities used are the 
following:  
- All of the time 
- Most of the time 
- Some of the time 
- A little of the time 
- None of the time 
Modalities used are the 
following:  
- All of the time 
- Most of the time 
- A good bit of the time 
- Some of the time 
- A little of the time 
- None of the Time 
No change will be done 
 
8 
REFERENCES 
Reference to ICH regulatory guidelines: 
- 
ICH E3: Structure and Content of Clinical Study Reports 
- 
ICH E6: Good Clinical Practice 
- 
ICH E9: Statistical Principles for Clinical Trials 
- 
ICH E9 (R1) Addendum: Estimands and Sensitivity Analysis in Clinical Trials 
 
Reference to European Medicines Agency (EMA) or point to consider guidelines: 
- 
Adjustment for baseline covariates in clinical trials 
- 
Choice of a non-inferiority margin 
- 
Clinical trials in small populations 
- 
Data monitoring committees 
- 
Investigation of subgroups in confirmatory clinical trials 
- 
Missing data in confirmatory clinical trials 
- 
Application with Meta Analyses, One pivotal study 
- 
Multiplicity issues in clinical trials 
- 
Switching between superiority and non-inferiority 
- 
Guideline on the clinical development of medicinal products intended for the 
treatment of pain 
 
Reference to FDA guidelines: 
- 
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
 
Standard SDTM+ user guide 
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References for guidance on analysing pain response: 
- 
Standard Methods for Analysis and Reporting of VAS or NRS Derived Pain 
Relief Response Scores 
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9 
APPENDICES 
 
A1. SAS code 
Not applicable 
 
A2. Normal ranges 
 
Normal ranges for Vital Signs parameters (Males/Females from 18 to 65 years old): 
Parameter 
Normal ranges 
Systolic Blood Pressure 
≤ 95 mmHg 
≥ 150 mmHg 
Diastolic Blood Pressure 
≤ 60 mmHg 
≥ 90 
Heart Rate 
≤ 51 
≥ 100 
Body Temperature 
≤ 35.5 
≥ 37.5 
Normal ranges refer to ranges agreed with the clinical site. 
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A3. Partial/Missing Date Convention 
 
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 / partial, it is assumed to have occurred 
during the study treatment phase (i.e. a TEAE for AEs) except if the partial onset date 
or the stop date indicates differently. 
- 
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 first IMP 
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). 
 
Algorithm for Prior/ Concomitant  
 
Medication, non-drug 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 only, Prior and 
Concomitant, or Concomitant only.  
In case of partial start and/or stop medication/ non-drug therapies/surgical procedures dates, 
imputation will be done to determine the classification: 
- 
If a partial start date, the first day of the month will be imputed for missing day and 
January for missing month, 
- 
If a partial stop date, the last day of the month will be imputed for missing days and 
December will be imputed for missing month. 
In case incomplete start or stop date does not allow the classification, will be classified as 
concomitant. 
 
Algorithm for TEAE 
For deriving the TEAE flag the following process of temporary date imputation is 
done (for AE start date only assuming no AE end date are missing). The date 
imputation algorithm for incomplete adverse event start dates is described in 
Table 1. Classification of adverse event according to its treatment-emergent status is 
then done using the imputed date. 
 
In the following table, all dates are presented using an YYYY-MM-DD format. As 
an example, suppose First IMP administration = 2002-08-11 and several AEs have 
incomplete start dates. 
 
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Table 1 
Data imputation algorithm for AE start date (AESTDT) 
Description of 
incomplete date 
Imputed numeric 
date 
Example 
 
 
Character date 
Imputed date 
Day is missing 
YYYY-MM < YYYY-
MM of [First IMP 
admin.] 
YYYY-MM-01 
2002-07-XX 
2002-07-01 
YYYY-MM = YYYY-
MM of [First IMP 
admin.] 
Min ([First IMP 
admin.], AE end date) 
2002-08-XX 
Min (2002-08-11, AE 
end date) 
YYYY-MM > YYYY-
MM of [First IMP 
admin.] 
YYYY-MM-01 
2002-09-XX 
2002-09-01 
Day and month are missing 
YYYY < YYYY OF 
[First IMP admin.] 
YYYY-01-01 
2001-XX-XX 
2001-01-01 
YYYY = YYYY OF 
[First IMP admin.] 
Min ([First IMP 
admin.], AE end date) 
2002-XX-XX 
Min (2002-08-11, AE 
end date) 
YYYY > YYYY OF 
[First IMP admin.] 
YYYY-01-01 
2003-XX-XX 
2003-01-01 
Day, month, and year are missing 
XXXX-XX-XX 
Min ([First IMP 
admin.], AE end date) 
Min (2002-08-11, AE 
end date) 
YYYY = non-missing year, MM = non-missing month, DD = non-missing day, XX 
= missing field. 
 
In the pre-randomisation run-in period, the same algorithm as above will be 
followed using the first IMP administration of each period as reference date for the 
imputation. 
 
If AE end date is partial, imputation could be done assuming the latest possible date 
(i.e. last day of month if day unknown, or 31st of December if day and month are 
unknown). 
A4. Programming Convention for Outputs 
 
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. 
 
The mean, median, lower quartile, upper quartile, SD and standard errors of the mean (SE), 
95% confidence interval values will be reported to one decimal place greater than the raw 
data recorded in the database.   
The minimum and maximum values will be reported with the same number of decimal places 
as the raw data recorded in the database. 
In general, the maximum number of decimal places reported should be four for any summary 
statistic. 
 
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Percentages will be presented to one decimal place. Percentages will not be presented for zero 
counts. Percentage will be calculated using n as denominator. The denominator will be 
specified in a footnote for clarification if necessary. If sample sizes are small, the data 
displays will show the percentages, but in the CSR only frequencies should be described. 
 
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. For 
each safety parameter for which it is possible to have values below or above Limit Of 
Quantification (LOQ), the rule to be used in the statistical tables is to replace values below or 
above a limit of quantification by LOQ. 
 
Dates will be presented in the format [ddmmmyyyy] and times in the format [hh:mm]. 
 
A5. Listings conventions 
 
Any listings will contain at least the following data: subject identifier, age and gender. When 
dates are presented, the associated study days should be included. They should be sorted by 
treatment group then subject identifier. For multicentre studies, listings should be broken 
down by centre and treatment group. 
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A6. EudraCT categories for age 
 
For EudraCT results summaries, in addition to quantitative descriptive statistics of age, 
demographic tables should include presentation of age using the following EudraCT 
categories (as applicable): 
 
In utero 
Preterm newborn - gestational age < 37 weeks 
Newborns (0-27 days) 
Infants and toddlers (28 days-23 months) 
Children (2-11 years) 
Adolescents (12-17 years) 
Adults (18-64 years) 
            From 65 to 84 years 
            85 years and over 
 
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