Clinical trial NCT03569098
Conditions: Hallux Abducto Valgus
Sponsor: Ipsen
Start date: 2018-06-19; Completion date: 2020-05-22
Enrollment: 186 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate the efficacy and safety of treatment with multiple doses of Dysport in adults suffering from clinically significant pain associated with HAV who have not undergone surgery for their condition.

Detailed description:

Arms: arm 1: Intramuscular injection of Dysport on day 1 of double-blind period, followed by up to 2 open-label injections during open-label cycles, during approximately 36 weeks. arm 2: Intramuscular injection of Dysport on day 1 of double-blind period, followed by up to 2 open-label injections during open-label cycles, during approximately 36 weeks. arm 3: Intramuscular injection of Placebo on day 1 of cycle 1 (double-blind period)
Interventions: intervention 1: Botulinum toxin type A intervention 2: Placebo
Intervention descriptions: intervention 1: Investigators will inject the reconstituted solution into foot muscles. intervention 2: Investigators will inject the reconstituted solution into foot muscles.

Protocol documents:
Prot_000.pdf: 
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IPSEN GROUP 
D-FR-52120-237 
 
CONFIDENTIAL 
PROTOCOL: FINAL: 03 JULY 2019 
PAGE 3/136 
 
Summary of Changes 
The current version of the protocol was released on 7 September 2018 and includes 
Amendment 3. For all protocol amendments, amendment forms were prepared and are provided 
in Appendix 2: Summary of Changes (see Table 1). 
 
Table 1 
List of Protocol Amendments 
Amendment 
Release date 
Amendment form 
1 
22 May 2018 
Appendix 2 
2 
25 May 2018 
Appendix 2 
3 
7 September 2018 
Appendix 2 
4 
15 February 2019 
Appendix 2 
5 
03 July 2019 
Appendix 2 
 
 


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CCI


IPSEN GROUP 
D-FR-52120-237 
 
CONFIDENTIAL 
PROTOCOL: FINAL: 03 JULY 2019 
PAGE 5/136 
 
(i.e. study foot) meeting the study entry criteria. For each subject, the study foot (i.e. the 
foot that will be treated with study treatment during the study) will be evaluated for all 
efficacy analyses, regardless of the presence of HAV in the contralateral foot. For subjects 
presenting with bilateral HAV at Screening, the investigator will determine which foot is 
of greater severity based on his/her clinical judgment following clinical evaluation of the 
degree of pain (including assessment of NPRS score for each foot during Screening), 
degree of disability and clinical evaluation of the degree of angular deviation of the hallux, 
as well as meeting all other study entry criteria. In these subjects, the foot with the greatest 
severity of HAV, based on clinical evaluation by the investigator (and meeting all other 
study entry criteria), will be selected for treatment with DB study treatment in this study.  
Following completion of the DB period (i.e. completion of Cycle 1), subjects who meet 
retreatment criteria will be eligible to participate in the OL period. All retreatment-eligible 
subjects will receive OL treatment with Dysport 300 U at the first retreatment cycle 
(Cycle 2) in the HAV study foot selected during the DB period. At the second retreatment 
cycle (Cycle 3), subjects will be treated with either Dysport 300 U or 500 U in the HAV 
study foot based on investigator judgment and following clinical evaluation at the time of 
retreatment. The decision to increase the dose at the beginning of Cycle 3 will be based on 
1) evaluation of safety and tolerability (review related AEs and consideration of any 
significant changes in the study foot) and 2) severity of pain (considering NPRS score) and 
disability (considering mFFI Disability subscale score) experienced by the subject at the 
time of evaluation. The muscles to be injected and procedures for injection are identical to 
those targeted in the DB period.  
As in the DB period, each treatment cycle in the OL period (Cycles 2 and 3) will be 
separated by at least 12 weeks. After Cycle 1 of the DB period, subjects who do not meet 
the retreatment criteria will be evaluated by the investigator at the next scheduled study 
visit (every 28 days) to determine eligibility to receive retreatment with Dysport in the OL 
period. Subjects who do not meet the retreatment criteria by Week 24 will not be eligible 
for retreatment in the OL period. As such, the maximum duration of participation in the 
study for a given subject will be 36 weeks. 
Subjects will be considered to have completed the study after they complete all of the 
assessments required for the Week 36 visit. The study will be considered complete after 
the last subject has completed their last follow-up visit. 
Number of subjects planned:  
A total of 165 subjects are planned to be enrolled in the study. Subjects enrolled during the 
DB period will roll over into the OL period.  
Diagnosis and criteria for inclusion:  
Inclusion criteria: 
Subjects must meet all inclusion criteria at Screening and Baseline and none of the 
exclusion criteria to be considered for enrolment in the study. 
(1) 
Subjects must provide written informed consent prior to any study related procedure 
(2) 
Male or female, aged 18 years or older 
(3) 
Clinical diagnosis of HAV as determined by the investigator based on evidence of 
lateral deviation of either great toe (left or right), as well as assessment of NPRS 
scores for each foot (in bilateral subjects). 
(4) 
Subjects must present with a score of ≥4 on the NPRS in the study foot at Baseline 
(5) 
Subjects must present with a score of >27 on the mFFI Pain subscale in the study 
foot at Baseline 


IPSEN GROUP 
D-FR-52120-237 
 
CONFIDENTIAL 
PROTOCOL: FINAL: 03 JULY 2019 
PAGE 6/136 
 
(6) 
Subjects must present with a score of >27 on the mFFI Disability subscale in the 
study foot at Baseline 
(7) 
Subjects must present with hallux valgus (HV) angle ≤30° in the study foot great toe 
using radiographic measurements based on guidelines set forth by the AOFAS ad 
hoc Committee on Angular Measurements at Screening only 
(8) 
Subjects must present with an intermetatarsal angle of ≤18°, inclusive in the study 
foot great toe using radiographic measurements based on guidelines set forth by the 
American Orthopedic Foot and Ankle Society ad hoc Committee on Angular 
Measurements at Screening only 
(9) 
Subject’s foot pain associated with HAV condition is refractory to shoe 
modifications, nonsteroidal anti-inflammatory medications, and modification of 
activities 
(10) In the opinion of the investigator the subject's deformity is reducible following 
clinical evaluation including compression of the intermetatarsal angle or rotation of 
the proximal phalanx.  
(11) Female subjects of childbearing potential must have a negative pregnancy test result 
at Screening 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. 
(12) Ability to complete all study requirements in the opinion of the investigator 
(13) Subject can read well enough to understand the informed consent form and other 
subject materials. 
 
Exclusion criteria: 
(1) 
Subject has an HV angle of >30° in the study foot 
(2) 
Evidence of cognitive impairment 
(3) 
Inability to walk unassisted 
(4) 
Subject presents with a flat or square metatarsal head in the study foot 
(5) 
Subject presents with metatarsus primus elevatus in the study foot 
(6) 
Subject presents with severe cavus/planus in the study foot 


IPSEN GROUP 
D-FR-52120-237 
 
CONFIDENTIAL 
PROTOCOL: FINAL: 03 JULY 2019 
PAGE 7/136 
 
(7) 
Subject suffers from any other podiatric or orthopaedic condition which, in the 
opinion of the investigator would interfere with the accurate evaluation of pain 
and/or function 
(8) 
Subject presents with medical history or clinical evidence of peripheral vascular 
disease 
(9) 
Subject has a body mass index greater than 40 kg/m2 or less than 18.5 kg/m2 
(10) Any medical history of a diabetic condition 
(11) Subject has glycated haemoglobin level of ≥6.5% at Screening 
(12) Any history of ankle or foot surgery in the study foot 
(13) Subject is using an orthotic device (including over-the-counter toe-spacers) which 
could influence the functioning of the hallux of the study foot in any way, or any 
other device intended for this purpose. Over-the-counter shoe inserts for the study 
foot are permitted if used for at least 30 days prior to screening. 
(14) Subject has medical history or clinical evidence of peripheral neuropathy or 
fibromyalgia 
(15) Subject has metatarsus adductus 
(16) Subject has a history of conditions or disease causing ligamentous laxity (e.g. 
Marfan’s syndrome, Ehlers-Danlos syndrome) 
(17) Subject has a history of allergic reaction or has a known or suspected sensitivity to 
any substance that is contained in the study treatment formulation (including cow’s 
milk protein) 
(18) Any medical condition or disease that might interfere with neuromuscular function, 
e.g. diagnosed myasthenia gravis, Lambert-Eaton syndrome or amyotrophic lateral 
sclerosis. 
(19) Subject demonstrates evidence of inflammatory arthritis (including gout) in the 
study foot or osteoarthritis based in the study foot on either history or clinical 
evaluation 
(20) Subject 
demonstrates 
evidence 
of 
degenerative 
arthritis 
of 
the 
first 
metatarsophalangeal joint based on either history or clinical evaluation 
(21) Subject has an acute or chronic medical condition (other than HAV) that in the 
opinion of the investigator could confound clinical assessments or interfere with the 
ability of the subject to participate in the study. 
(22) Subject has a clinically significant abnormality on screening evaluation including 
physical examination, vital signs, or laboratory tests that the investigator considers 
to be inappropriate to allow participation in the study. 
(23) Subject is currently participating or has participated in a clinical study within the last 
90 days or has participated in more than two clinical studies within the past year. 
This includes studies using marketed compounds or devices.  
(24) Subject is an investigational study site staff member or the relative of an 
investigational study site staff member. 
(25) Treatment with any preparation of botulinum toxin within 4 months prior to 
Screening for any condition, with the exception of glabellar lines or other aesthetic 
face applications of toxin. Subjects who have previously received an injection with 
botulinum toxin in the foot are not eligible to participate in the study.  


IPSEN GROUP 
D-FR-52120-237 
 
CONFIDENTIAL 
PROTOCOL: FINAL: 03 JULY 2019 
PAGE 8/136 
 
(26) Any concomitant therapy usage that, in the investigator’s opinion, would interfere 
with the evaluation of safety or efficacy of the investigational medicinal product, 
and/or confound the study results. 
(27) Subject has planned or ongoing use of opioids; use of antipsychotics or 
antidepressants dose that is not stable for at least 30 days prior to Screening; use of 
anticholinergic treatments that are not stable for at least 6 weeks prior to 
randomisation; or requires continuous treatment with any medication restricted by 
this protocol. 
(28) Evidence of clinically significant chronic drug or alcohol abuse within the last year. 
(29) Use of medications that affect neuromuscular transmission, such as curare-like 
depolarising 
agents, 
lincosamides, 
polymyxins, 
anticholinesterases 
and 
aminoglycoside antibiotics within the last 3 months before Screening. 
(30) Subject is medically unable to discontinue treatment with medications with 
anticoagulant/antiplatelet effects (e.g. warfarin and other coumadin derivatives, 
acetylsalicylic acid and clopidogrel/ticlopidine) for at least 3 days before 
randomisation/injection of study treatment. Subjects are permitted restart 
anticoagulant/antiplatelet medications one day after injection of study treatment (or 
longer at the discretion of the investigator).  
(31) Any condition or situation which, in the investigator’s opinion, puts the subject at 
significant risk, may confound the study results, or may interfere with the subject’s 
participation in the study. 
Test product, dose, mode of administration: 
A blinded kit will be used in this study to maintain the blinding of the study during the DB 
period. Each blinded kit will contain two vials regardless of treatment assignment. The two 
vials in each kit will contain either a Dysport 300 U vial + a placebo vial, a Dysport 500 U 
vial + a placebo vial or two placebo vials, based on treatment assignment. Investigators 
will be blinded to which vial contains Dysport and which vial contains placebo. 
The blinded active study treatment, Dysport, will be provided as a white, lyophilised 
powder in vials containing 300 U or 500 U of BTX-A-haemagglutinin complex 
(abobotulinumtoxinA). Before each administration, the powder in each vial in the blinded 
kit will be reconstituted at the investigational site with 1.0 mL of 0.9% sterile (preservative 
free) sodium chloride for injection. The contents of each vial will be combined for a total 
volume of 2.0 mL (150 U/mL for Dysport 300 U and 250 U/mL for Dysport 500 U). 
Investigators will inject 0.5 mL of the reconstituted solution containing study treatment 
into each of four specified muscles of the foot (2.0 mL total volume) under guidance with 
a peripheral electrical stimulator. Subjects assigned to receive 300 U of Dysport will be 
treated with 75 U of Dysport per muscle (300 U dose divided equally among each of four 
specified muscles of the foot). Subjects assigned to receive 500 U of Dysport will be treated 
with 125 U of Dysport per muscle (500 U dose divided equally among each of four 
specified muscles of the foot). 
To administer the study treatment, a peripheral electrical stimulator (with or without 
complementary techniques for identifying target muscles) will be used to locate the 
muscles in the foot. 
Duration of treatment: DB and OL periods: 36 weeks 
Reference therapy, dose and mode of administration:  


IPSEN GROUP 
D-FR-52120-237 
 
CONFIDENTIAL 
PROTOCOL: FINAL: 03 JULY 2019 
PAGE 9/136 
 
A blinded kit will be used in this study to maintain the blinding of the study during the DB 
period as described above. The placebo study treatment (administered only during the DB 
period) will be provided as a white, lyophilised powder and will be indistinguishable from 
the active product. Placebo will contain only the excipients of Dysport. There will be two 
matching placebo vials: one matching the 500 U Dysport vial and one matching the 300 U 
Dysport vial. A blinded kit will be used in this study to maintain the blinding of the study. 
The procedures for reconstitution of blinded placebo study treatment will be identical to 
that described above for the active study treatment. Before each administration, the powder 
from the vials will be reconstituted at the investigational site with 0.9% sterile (preservative 
free) sodium chloride for injection, to a total volume of 2.0 mL. The total treatment volume 
will be divided equally across the four specified muscles of the foot (i.e. 0.5 mL per 
injection site). 
To administer the study treatment, a peripheral electrical stimulator (with or without 
complementary techniques for identifying target muscles) will be used to locate the 
muscles in the foot. 
Criteria for evaluation (endpoints): 
Efficacy: 
Primary Endpoint: the change from baseline in foot pain as measured by the daily NPRS 
score averaged over the 7 consecutive days prior to the Week 8 DB visit. 
Secondary Endpoints:  
• 
The change from baseline as measured by the daily NPRS score averaged over the 
7 consecutive days prior to Week 4 and Week 12 DB visits and at each scheduled 
visit in the OL period. 
• 
The change from baseline in the daily mFFI Disability subscale score averaged over 
the 7 consecutive days prior to Week 4, Week 8 and Week 12 DB visits and at each 
scheduled visit in the OL period. 
• 
The change from baseline in the daily mFFI Pain subscale score averaged over the 
7 consecutive days prior to Week 4, Week 8 and Week 12 DB visits and at each 
scheduled visit in the OL period. 
• 
The change from baseline in the daily mFFI total score averaged over the 
7 consecutive days prior to Week 4, Week 8 and Week 12 DB visits and at each 
scheduled visit in the OL period. 
• 
The change from baseline in the daily mFFI activity limitation subscale score 
averaged over the 7 consecutive days prior to Week 4, Week 8 and Week 12 DB 
visits, and at each scheduled visit in the OL period. 
• 
The change from baseline in quality of life as measured by the SF-36 at Week 8 and 
Week 12 DB visit and at each scheduled visit in the OL period. 
• 
The change from baseline in HV angle as measured directly by weight-bearing 
anterior-posterior radiographs at Week 4 and Week 12 DB visits and at each 
scheduled visit in the OL period. 
• 
The change from baseline in intermetatarsal angle as measured directly by weight-
bearing anterior-posterior radiographs at Week 4, Week 8 and Week 12 DB visits 
and at each scheduled visit in the OL period. 
• 
Time to retreatment 
• 
Patient Global Impression of Improvement of foot pain score at the Week 4, Week 
8 and Week 12 DB visits and at each scheduled visit in the OL period. 


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IPSEN GROUP 
D-FR-52120-237 
 
CONFIDENTIAL 
PROTOCOL: FINAL: 03 JULY 2019 
PAGE 11/136 
 
TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ...................................................................................... 2 
SYNOPSIS ................................................................................................................................ 4 
TABLE OF CONTENTS ....................................................................................................... 11 
LIST OF ABBREVIATIONS ................................................................................................ 16 
1 
BACKGROUND INFORMATION ............................................................................ 18 
1.1 
Introduction ................................................................................................................... 18 
1.2 
Study Rationale ............................................................................................................. 19 
1.3 
Name and Description of Investigational Medicinal Product ................................... 20 
1.4 
Findings from Nonclinical and Clinical Studies ......................................................... 20 
1.5 
Known and Potential Risks and Benefits to Human Subjects .................................. 21 
1.6 
Selection of Investigational Medicinal Products and Dosages .................................. 21 
1.7 
Compliance Statement .................................................................................................. 21 
1.8 
Population to Be Studied .............................................................................................. 21 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES ..................................... 22 
2.1 
Purpose of the Study ..................................................................................................... 22 
2.2 
Study Objectives ........................................................................................................... 22 
2.2.1 
Primary Objective ........................................................................................ 22 
2.2.2 
Secondary Objectives .................................................................................. 22 
2.2.3 
Exploratory Objective ................................................................................. 22 
3 
STUDY DESIGN ........................................................................................................... 23 
3.1 
General Design and Study Schematic ......................................................................... 23 
3.1.1 
Double-blind Period (Cycle 1): ................................................................... 23 
3.1.2 
Open-label Period (Cycles 2 to 3): .............................................................. 24 
3.1.2.1 
Retreatment Criteria .................................................................................... 25 
3.2 
Primary and Secondary Endpoints and Evaluations ................................................ 25 
3.2.1 
Primary Efficacy Endpoint ......................................................................... 25 
3.2.2 
Secondary Efficacy Endpoints .................................................................... 25 
3.2.3 
Exploratory Efficacy Endpoint ................................................................... 26 
3.2.4 
Safety Endpoints and Evaluations ............................................................. 26 
3.3 
Randomisation and Blinding ....................................................................................... 27 
3.4 
Maintenance of Randomisation and Blinding ............................................................ 27 
3.5 
Study Treatments and Dosage ..................................................................................... 28 
3.6 
Study Duration .............................................................................................................. 28 
3.7 
Stopping Rules and Discontinuation Criteria ............................................................ 29 
3.8 
Source Data Recorded on the Case Report Form ...................................................... 29 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 30 
4.1 
Inclusion Criteria .......................................................................................................... 30 
4.2 
Exclusion Criteria ......................................................................................................... 31 
4.3 
Rationale for Inclusion / Exclusion Criteria ............................................................... 32 
4.4 
Subject Withdrawal Criteria and Procedures ........................................................... 32 


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CONFIDENTIAL 
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4.4.1 
Withdrawal from the Study ......................................................................... 32 
4.4.2 
Withdrawal from Study Treatment ............................................................. 33 
5 
STUDY PROCEDURES .............................................................................................. 34 
5.1 
Study Schedule .............................................................................................................. 34 
5.2 
Study Visits .................................................................................................................... 40 
5.2.1 
Screening and Enrolment ........................................................................... 40 
5.2.2 
Additional Follow-up Visits (Double-blind and Open-label Periods) ....... 40 
5.2.3 
End of Study or Early Withdrawal Visit .................................................... 40 
6 
TREATMENT OF SUBJECTS ................................................................................... 41 
6.1 
Investigational Medicinal Product Preparation Storage and Accountability ......... 41 
6.1.1 
Investigational Medicinal Product Storage and Security .......................... 41 
6.1.2 
Investigational Medicinal Product Preparation ........................................ 41 
6.1.3 
Investigational Medicinal Product Accountability .................................... 41 
6.2 
Study Drugs Administered ........................................................................................... 41 
6.2.1 
Dysport ......................................................................................................... 42 
6.2.2 
Placebo ........................................................................................................ 42 
6.2.3 
Injection –Guided Technique ..................................................................... 42 
6.3 
Concomitant Medication/Therapy .............................................................................. 43 
6.4 
Lifestyle Restrictions/Recommendations .................................................................... 43 
6.5 
Procedures for Monitoring Subject Compliance ....................................................... 44 
6.6 
Priority Order on Study Procedures ........................................................................... 44 
7 
ASSESSMENT OF EFFICACY .................................................................................. 44 
7.1 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data ......... 44 
7.1.1 
Numeric Pain Rating Scale ........................................................................ 44 
7.1.2 
Modified Foot Function Index ................................................................... 45 
7.1.3 
Intermetatarsal Angle, Hallux Valgus Angle and Sesamoid Position ...... 45 
7.1.4 
36-Item Short Form Health Survey............................................................ 45 
7.1.5 
Patient Global Impression of Improvement of Foot Pain ......................... 46 
7.1.6 
Patient Global Impression of Severity of Foot Pain .................................. 46 
7.1.7 
Patient Global Impression of Improvement of Disability .......................... 46 
7.1.8 
Patient Global Impression of Severity of Disability ................................... 46 
8 
ASSESSMENT OF SAFETY ....................................................................................... 47 
8.1 
Adverse Events .............................................................................................................. 47 
8.1.1 
Definition of an Adverse Event .................................................................. 47 
8.1.2 
Categorisation of Adverse Events ............................................................... 47 
8.1.2.1 
Intensity Classification ................................................................................. 47 
8.1.2.2 
Causality Classification ............................................................................... 47 
8.1.2.3 
Assessment of Expectedness ......................................................................... 47 
8.1.2.4 
Laboratory Test Abnormalities .................................................................... 47 
8.1.2.5 
Abnormal Physical Examination Findings .................................................. 48 
8.1.2.6 
Other Investigation Abnormal Findings ...................................................... 48 


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8.1.3 
Adverse Events of Special Interest ............................................................. 48 
8.1.4 
Recording and Follow up of Adverse Events ............................................. 48 
8.1.4.1 
Reporting of Adverse Events ........................................................................ 49 
8.1.5 
Reporting of Serious Adverse Events ......................................................... 49 
8.1.6 
Pregnancy .................................................................................................... 50 
8.1.7 
Deaths .......................................................................................................... 51 
8.1.8 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events .......................................................................................................... 51 
8.1.9 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators ....... 51 
8.2 
Clinical Laboratory Tests ............................................................................................ 51 
8.2.1 
Haematology ................................................................................................ 51 
8.2.2 
Blood Biochemistry ..................................................................................... 51 
8.2.3 
Pregnancy Test ............................................................................................ 52 
8.2.4 
Drug of Abuse Testing ................................................................................ 52 
8.2.5 
Immunogenicity .......................................................................................... 52 
8.3 
Physical Examination ................................................................................................... 52 
8.4 
Examination of the Study Foot .................................................................................... 53 
8.4.1 
Dermatologic Examination......................................................................... 53 
8.4.2 
Neurologic Examination............................................................................. 53 
8.4.3 
Musculoskeletal Examination .................................................................... 53 
8.5 
Vital Signs ...................................................................................................................... 54 
9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS .......... 55 
10 
EXPLORATORY BIOMARKERS AND BIOBANKING ....................................... 56 
11 
STATISTICS ................................................................................................................. 57 
11.1 Analyses Populations .................................................................................................... 57 
11.1.1 
Populations Analysed .................................................................................. 57 
11.1.2 
Reasons for Exclusion from the Analyses ................................................. 57 
11.2 Sample Size Determination .......................................................................................... 57 
11.3 Significance Testing and Estimations ......................................................................... 59 
11.4 Statistical/Analytical Methods ..................................................................................... 59 
11.4.1 
Demographic and Other Baseline Characteristics .................................... 59 
11.4.2 
Subject Disposition and Withdrawals ......................................................... 59 
11.4.3 
Efficacy Evaluation ..................................................................................... 59 
11.4.3.1 
Analysis of the Primary Efficacy Endpoint .................................................. 59 
11.4.3.2 
Analysis of Secondary Efficacy Endpoints ................................................... 61 
11.4.3.3 
Analysis of Exploratory Efficacy Endpoints ................................................ 63 
11.4.4 
Adjustment for Centre Effect ...................................................................... 64 
11.4.5 
Safety Evaluation ........................................................................................ 64 
11.5 Subgroup Analyses ....................................................................................................... 64 
11.6 Interim Analyses ........................................................................................................... 64 
11.7 Primary Analyses .......................................................................................................... 65 
12 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ............................... 66 


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D-FR-52120-237 
 
CONFIDENTIAL 
PROTOCOL: FINAL: 03 JULY 2019 
PAGE 14/136 
 
13 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 67 
13.1 Protocol Amendments and Protocol Deviations ........................................................ 67 
13.1.1 
Protocol Amendments ................................................................................. 67 
13.1.2 
Protocol Deviations and Exceptions........................................................... 67 
13.2 Information to Study Personnel .................................................................................. 67 
13.3 Study Monitoring .......................................................................................................... 68 
13.4 Investigator’s Regulatory Obligations ........................................................................ 68 
13.5 Audit and Inspection .................................................................................................... 68 
13.6 Data Quality Assurance ................................................................................................ 68 
14 
ETHICS ......................................................................................................................... 69 
14.1 Compliance with Good Clinical Practice and Ethical Considerations .................... 69 
14.2 Informed Consent for Participation in the Study ...................................................... 69 
14.3 Health Authorities and Independent Ethics Committees/Institutional Review 
Boards ............................................................................................................................ 69 
14.4 Confidentiality Regarding Study Subjects ................................................................. 70 
15 
DATA HANDLING AND RECORD KEEPING ....................................................... 71 
15.1 Data Recording of Study Data ..................................................................................... 71 
15.2 Data Management ......................................................................................................... 71 
15.3 Record Archiving and Retention ................................................................................. 72 
16 
FINANCING AND INSURANCE ............................................................................... 73 
16.1 Contractual and Financial Details ............................................................................... 73 
16.2 Insurance, Indemnity and Compensation .................................................................. 73 
17 
REPORTING AND PUBLICATIONS OF RESULTS ............................................. 74 
17.1 Publication Policy ......................................................................................................... 74 
17.2 Clinical Study Report ................................................................................................... 74 
18 
REFERENCES .............................................................................................................. 75 
19 
LIST OF APPENDICES .............................................................................................. 77 
 


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CCI


IPSEN GROUP 
D-FR-52120-237 
 
CONFIDENTIAL 
PROTOCOL: FINAL: 03 JULY 2019 
PAGE 16/136 
 
LIST OF ABBREVIATIONS 
 
ABBREVIATION 
Wording Definition  
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
AOFAS 
American Orthopedic Foot and Ankle Scale 
BTX 
Botulinum Toxin 
BTX-A 
Botulinum Toxin Type A 
BTX-A-HAC 
Botulinum Toxin Type A Hemagglutinin Complex 
CA 
Competent Authorities 
CMC 
Chemistry Manufacturing Control 
CFR 
Code of Federal Regulations (United States of America) 
CRO 
Contract research organisation 
CSR 
Clinical Study Report 
DB 
Double-blind 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration 
FFI 
Foot Function Index 
GCP 
Good Clinical Practice 
HAV 
Hallux Abducto Valgus 
HV 
Hallux Valgus (angle) 
ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional review board 
IRT 
Interactive response technology 
ITT 
Intention-to-treat 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
mFFI 
Modified Foot Function Index 
NPRS 
Numeric Pain Rating Scale 
OL 
Open-label 


IPSEN GROUP 
D-FR-52120-237 
 
CONFIDENTIAL 
PROTOCOL: FINAL: 03 JULY 2019 
PAGE 17/136 
 
ABBREVIATION 
Wording Definition  
PP 
Per protocol 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS® 
Statistical Analysis System® 
SD 
Standard deviation 
SF-36 
36-item Short Form 
SOP 
Standard Operating Procedure 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
Treatment emergent adverse event 
US(A) 
United States (of America) 
WHO 
World Health Organisation 


IPSEN GROUP 
D-FR-52120-237 
 
CONFIDENTIAL 
PROTOCOL: FINAL: 03 JULY 2019 
PAGE 18/136 
 
1 
BACKGROUND INFORMATION 
1.1 
Introduction 
Hallux abducto valgus (HAV or bunion) is a highly prevalent and chronic foot deformity 
characterized by lateral deviation of the great toe (hallux) causing debilitating foot pain, 
morphological changes in the appearance of the foot, functional impairments in gait and 
balance, as well as significantly impaired quality of life. Although HAV affects approximately 
23% of adults worldwide [1], very few effective treatments exist to treat this condition. The 
morphological changes observed in HAV patients present clinically as lateral deviations of 
hallux which can be measured directly using the hallux valgus (HV) angle and intermetatarsal 
angle (Figure 1). 
Figure 1 Hallux Abductus Angle 
 
Adapted from: Coughlin and Jones [2] 
 
Clinical evaluation of HAV includes establishment of the functional status of the patient 
including pain and the degree of disability [3] in addition to the morphological changes 
observed in the foot. While HAV is typically managed initially by orthotic applications such as 
splints, inserts or braces used to correct foot biomechanics, the efficacy of these interventions 
is widely considered to be largely ineffective with substantial evidence suggesting that these 
devices are no more effective than no treatment at all [4]. The standard of care for HAV patients 
is limited to surgical intervention in which the deformed bone and/or soft tissue is removed to 
ameliorate the deformity. However, recovery time and required physical therapy following 
surgery are significant and the procedure is associated with post-surgical pain of significant 
duration [5]. Moreover, a proportion of patients fail to derive long-term benefit with surgical 
interventions and experience recurrence of HAV [6]. 
Development of HAV is associated with extrinsic factors (high heeled or constricting shoes, 
excessive weight bearing) as well as intrinsic factors, including genetics, age, and a number of 
morphological and muscular podiatric abnormalities (e.g. pes planus) [6]. There is strong 
evidence to suggest that the structural abnormalities and subsequent mechanical dysfunction 
that result in the development of HAV are related to progressive changes in the muscles of the 
affected foot. For example, muscle imbalance of the abductor and adductor hallucis muscles 
have been shown to be apparent in HAV patients, with the abductor hallucis muscle showing 
decreased activity compared with the adductor hallucis muscle in these patients [7]. This 
imbalance allows the adductor hallucis muscle to gain mechanical advantage thereby pulling 
the hallux laterally forcing the first metatarsal head to drift medially off of the sesamoid 
apparatus, causing the proximal phalanx to move into a valgus position as it is tethered at its 


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D-FR-52120-237 
 
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base to the sesamoids, the deep transverse ligament (via the plantar plate), and the adductor 
hallucis tendon [6; 8]. The extensor and flexor hallucis longus tendons appear to bowstring 
laterally [9], increasing the valgus displacement and occasionally acting as dorsiflexors of the 
proximal phalanx. As the metatarsal head sits on the medial sesamoid as a result of lateral 
displacement of the hallux, erosion of the cartilage and the crista have been observed.  
Functionally, these structural changes cause the bursa overlying the medial eminence to thicken 
because of the pressure effect of footwear on a prominent medial eminence, leading to 
significant and chronic pain and severe mobility limitations.  
Given the considerable involvement of these specific musculoskeletal abnormalities of the foot 
in the development and progression of HAV, it is reasonable to consider the utility of targeted 
local injections of botulinumtoxinA for the treatment of HAV, given the demonstrated ability 
of these toxins to reduce localized hypertonia in injected muscles. Intramuscular 
botulinumtoxinA injections reduce muscle hypertonicity by blocking the release of presynaptic 
acetylcholine at the neuromuscular junction. BotulinumtoxinA injections have been proven 
useful in treating muscle imbalance, muscle spasms and in providing significant pain reduction 
in patients with foot disorders such as plantar fasciitis [8; 10; 11]. Moreover, there is direct 
evidence to suggest that injection of botulinumtoxinA into specific muscles of the foot results 
in clinically meaningful changes in hallux valgus angle, foot pain and functional mobility [8; 
10]. In a double blind, randomised, placebo-controlled study of botulinumtoxinA, Wu, et al. 
injected botulinumtoxinA divided across the oblique and transverse heads of the adductor 
hallucis, the flexor hallucis brevis, and the extensor hallucis longus muscles in patients with a 
diagnosis of HAV. The primary outcome measures in this study were subscales on pain and 
disability in the Taiwan Chinese version of the Foot Function Index (FFI). The results of this 
study showed robust improvements in pain (p<0.001) and disability (p<0.05) in the group 
treated with botulinumtoxinA compared with those treated with normal saline (placebo).  An 
immediate reduction in pain intensity was noted in the botulinumtoxinA group, reaching a 
plateau in the second month and persisting for up to six months post injection. [10]. Reduction 
in foot pain following treatment with botulinumtoxinA as demonstrated in these studies is of 
particular relevance in HAV. Several studies have demonstrated that foot pain is the primary 
outcome measure used to define efficacy in HAV (i.e. following surgical correction) [11] and 
the use of the Numeric Pain Rating Scale (NPRS) for foot pain is a reliable and widely used 
instrument for this purpose [13; 14; 15]. 
Hallux abducto valgus remains a highly prevalent and debilitating foot abnormality for which 
the standard of care, surgical correction, is associated with a significant recovery time, 
considerable patient burden and elevated risk. Long-term outcomes for this treatment also 
suggest recurrence is common. Given the underlying involvement of selected foot muscles in 
the development of HAV, targeted injections Dysport in the foot has the potential to be a safe 
and effective intervention for the treatment of HAV. The clinical efficacy observed in HAV 
patients following treatment with botulinumtoxinA in prior studies, strongly suggests that this 
treatment would be an important addition to the current treatment armamentarium. 
1.2 
Study Rationale 
Intramuscular botulinumtoxinA injections reduce muscle hypertonicity by blocking the release 
of presynaptic acetylcholine at the neuromuscular junction. BotulinumtoxinA injections have 
been proved useful in treating muscle imbalance, muscle spasms and in providing significant 
pain reduction in patients with foot disorders such as plantar fasciitis. There is also evidence 
showing that botulinumtoxinA injection was effective for the treatment of pain and disability 
associated with HAV. 
Several studies have compared HAV subjects with their normal counterparts and found 
pathologic and electromyographic evidence of HAV-related muscle degeneration [6; 16; 17]. 


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CONFIDENTIAL 
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These findings imply that it is possible to manage HAV-related pain and deformities through 
management of the muscle groups that act on the first metatarsophalangeal joint. Muscle 
imbalance of the abductor and adductor hallucis muscles has been demonstrated in HAV 
patients. When the adductor hallucis is dysfunctional, the action of the abductor hallucis is 
exaggerated and pulls the phalanx into pronation. The muscles that coordinate the movement 
of the first metatarsophalangeal joint consist of the oblique and transverse head of the adductor 
hallucis, extensor hallucis brevis, and flexor hallucis brevis. In patients with HAV, early onset 
of stance phase activities was found in these four muscles. Hoffmeyer et al. examined the 
relationship between muscle pathology and HAV and found not only enlarged mitochondria 
with paracrystalline inclusions but also myogenic and neurogenic alterations in patients with 
HAV [18]. An ultrasonic evaluation of the abductor hallucis muscle in patients with HAV also 
suggested that morphological changes may occur early in the development of the deformity. 
These findings suggest that a treatment strategy focused on intervention in HAV-related muscle 
groups may provide pain and disability relief, and may even suppress the progression of HAV. 
Therefore, the efficacy and tolerability of Dysport injections for the treatment of HAV in adult 
subjects will be evaluated in the present study. 
1.3 
 Name and Description of Investigational Medicinal Product 
The investigational medicinal product being evaluated is Clostridium botulinum toxin type A 
haemagglutinin complex (BTX-A-HAC), (United States generic name, abobotulinumtoxinA) 
hereafter referred to as Dysport. Dysport is a protein complex derived from Clostridium BTX-A 
consisting of the neurotoxin and other proteins. Dysport is supplied as a white lyophilised 
powder, for reconstitution. 
The selection of Dysport doses to be evaluated in the present study (300 U and 500 U) are based 
on the demonstrated safety and efficacy of these doses in reducing hypertonia in muscles of 
similar size and volume to those planned for evaluation in this study (see Section 3.1) in the 
context of adult upper and lower limb spasticity with no unacceptable safety findings observed.  
A more detailed description of the product is given in Section 3.4. 
1.4 
Findings from Nonclinical and Clinical Studies 
In nonclinical studies, in vivo experiments demonstrate the efficacy of low doses of botulinum 
toxin (BTX) in various cholinergic pathways. Pharmacokinetic and distribution studies 
performed with BTX-A have demonstrated that the majority of the toxin remained localised at 
the injection site, supporting the local effect of the toxin as the principal location of action. 
The results of the single- or repeat dose toxicity studies in animal models demonstrated that 
BTX-A administered in striated muscle possesses no potential for producing toxicity unrelated 
to its pharmacological activity or specific target organ. The effects on injected muscles 
(decrease in muscle and myofibre size) were related to the pharmacological activity of BTX-A, 
and were consistent with the results of the pharmacodynamic Rat Muscle Force Test. 
Intramuscular administration of Dysport in healthy juvenile rats did not alter male or female rat 
fertility with toxicological profiles in juvenile animals observed to be similar to adults. 
No clinical studies have been conducted with Dysport for the treatment of adults with HAV. 
However, Dysport has been in clinical use since 1990 and is now licensed in more than 
80 countries worldwide for various therapeutic indications including: blepharospasm, 
hemifacial spasm, upper and lower limb spasticity in adults, cervical dystonia (spasmodic 
torticollis), paediatric leg spasticity associated with cerebral palsy, and axillary hyperhidrosis. 
Studies conducted in these indications have shown Dysport to provide greater improvement in 
symptoms of these conditions compared with placebo, as well as demonstrating an acceptable 
safety profile. 
Further details may be found in the investigator’s brochure (IB). 


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1.5 
Known and Potential Risks and Benefits to Human Subjects 
Dysport has proved to be an effective treatment for a number of therapeutic indications, and to 
have an acceptable benefit-risk ratio. The posology and safety of Dysport has been established 
in numerous clinical studies and over 20 years of postmarketing experience. The majority of 
treatment-emergent adverse events (TEAEs) reported for Dysport are mild to moderate in 
intensity and of limited duration. This safety profile is thought to be related to the pharmacology 
of the toxin, which may potentially result in excess paralysis of the injected and adjacent 
muscles in some patients. Dysport is generally well-tolerated, although temporary paralysis of 
non-targeted muscle groups may occur. AEs resulting from a possible remote spread of the 
toxin from its site of injection have been very rarely reported (including excessive muscle 
weakness, dysphagia, and aspiration pneumonia). Local spread of the toxin from the injection 
site has also been reported and therefore the safety profile is dependent on the site of injection.  
The profile of adverse reactions reported during postmarketing use reflects the pharmacology 
of the product and AEs seen during clinical studies. There have been occasional reports of 
hypersensitivity.  In order to minimize the risk of serious reactions representing remote 
distribution of the effect of toxin, the guidance provided in the IB and/or in this protocol must 
be strictly followed. Additional information regarding risks and benefits to human subjects may 
be found in the IB. 
1.6 
Selection of Investigational Medicinal Products and Dosages 
The safety and efficacy of Dysport is already well established in various indications including 
adult upper and lower limb spasticity, and cervical dystonia. The doses to be evaluated in this 
study (i.e. Dysport 300 U and 500 U) were selected based on the demonstrated safety and 
efficacy of these doses in reducing hypertonia in muscles of similar size and volume in the 
context of adult upper and lower limb spasticity including, but not limited to, the flexor 
digitorum longus, flexor hallucis longus, flexor digitorum profundus, flexor digitorum 
superficialis, flexor carpi radialis, flexor hallucis brevis and flexor carpi ulnaris muscles. In 
previous studies, each of these muscles were injected with 100 U to 200 U of Dysport in Studies 
Y-55-52120-140, Y-55-52120-142, Y-52-52120-145 and Y-52-52120-148, with no 
unacceptable safety findings observed.  
A more detailed description of administration procedures is given in Section 6.1.  
1.7 
Compliance Statement 
The study will be conducted in compliance with independent ethics committees/institutional 
review boards (IECs/IRBs), informed consent regulations, the Declaration of Helsinki and 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. 
Any episode of noncompliance will be documented. 
In addition, the study will adhere to all local regulatory requirements.  
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject emergency study contact cards, 
subject recruitment procedures (e.g. advertisements), any written information to be provided to 
subjects and a statement from the IEC/IRB that they comply with GCP requirements. The 
IEC/IRB approval must identify the protocol version as well as the documents reviewed. 
1.8 
Population to Be Studied 
The study will enrol adult male and female subjects aged 18 years or older suffering from 
clinically significant HAV who have not undergone surgery for their condition. 


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hallucis muscle; 2) the transverse head of the adductor hallucis muscle; 3) flexor hallucis brevis 
muscle; and 4) the extensor hallucis brevis muscle. The evaluation of efficacy (DB) and 
effectiveness (OL) will be based solely on the foot selected for treatment at Screening (i.e. study 
foot) meeting the study entry criteria. For each subject, the study foot (i.e. the foot that will be 
treated with study treatment during the study) will be evaluated for all efficacy analyses 
regardless of the presence of HAV in the contralateral foot. For subjects presenting with 
bilateral HAV at Screening, the investigator will determine which foot is of greater severity 
based on the clinical judgment of the investigator following clinical evaluation of the degree of 
pain (including assessment of the NPRS scores for each foot during Screening), degree of 
disability and angular deviation of the hallux, and meeting all other study entry criteria. In these 
subjects, the foot with the greatest severity of HAV will be selected for treatment with DB study 
treatment in this study.  
During the DB period, study visits will proceed at the following intervals following study 
treatment administration and assessments on Day 1: 
• Week 1 (Day 8) (clinic visit) 
• Week 4 (Day 29 (clinic visit) 
• Week 8 (Day 57) (clinic visit) 
• Week 12 (Day 85) (clinic visit*) 
• Additional visits every 4 weeks 
(*Note: Subjects will be evaluated for retreatment with Dysport 300 U in an OL fashion). 
3.1.2 
Open-label Period (Cycles 2 to 3): 
Following completion of all protocol-specified procedures for the DB period (i.e. completion 
of Cycle 1), subjects who meet retreatment criteria (see Section 3.1.2.1) will be treated during 
the OL period with Dysport (300 U) in the HAV study foot determined in the DB period. The 
muscles to be injected and procedures for injection are identical to those targeted in the DB 
period.  
During the OL period, subjects may be treated with up to two additional cycles of Dysport with 
intervals of at least 12 weeks between each treatment cycle (see Figure 3). All retreatment-
eligible subjects will receive OL treatment with Dysport 300 U at the first retreatment cycle 
(Cycle 2) in the HAV study foot determined in the DB period. At the second retreatment cycle 
(Cycle 3), subjects will be treated in the HAV study foot with either Dysport 300 U or 500 U 
based on investigator judgment following clinical evaluation of the subject at the time of 
retreatment. The decision to increase the dose at the beginning of Cycle 3 will be based on 1) 
evaluation of safety and tolerability (review related AEs and consideration of any significant 
changes in the study foot) and 2) severity of pain (considering NPRS score) and disability 
(considering mFFI Disability subscale score) experienced by the subject at the time of 
evaluation. 
During the OL period, each treatment cycle (Cycles 2 and 3) will include the following study 
visits after the retreatment injection with Dysport at the beginning of each treatment cycle: 
• Week 1 (Day 8) (clinic visit) 
• Week 4 (Day 29) (clinic visit) 
• Week 8 (Day 57 (clinic visit) 
• Week 12 (Day 85) (clinic visit) 
• Additional visits every 4 weeks 
 


IPSEN GROUP 
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PAGE 25/136 
 
Figure 3 Open-label Period Retreatment Scheme 
 
 
3.1.2.1 
Retreatment Criteria 
Prior to receiving retreatment with Dysport in each of the two retreatment cycles in the OL 
period (Cycles 2 and 3), subjects will be required to meet all the following retreatment criteria: 
• 
Subject is willing to receive a new treatment cycle with Dysport 
• 
Treatment with Dysport is in the best interest of the subject based on the investigator's 
clinical judgment. 
• 
Subject's foot pain is clinically significant as evidenced by an NPRS score ≥3 within 24-
48 hours immediately prior to the retreatment visit. 
• 
Subject has not experienced any unacceptable risk judged by the investigator to require 
postponement of the treatment cycle to the next visit 
• 
At least 12 weeks have passed since the subject's last treatment with Dysport (or blinded 
study treatment) 
Subjects who do not meet the retreatment criteria will be evaluated by the investigator at the 
next scheduled study visit (every 4 weeks) to determine eligibility to receive retreatment with 
Dysport (300 U to 500 U) in the OL period. Subjects who do not meet the retreatment criteria 
by Week 24 will not be eligible for retreatment in the OL period, as treatment is not available 
beyond Week 24 in the study. 
3.2 
Primary and Secondary Endpoints and Evaluations 
3.2.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline in the daily NPRS score averaged 
over the 7 consecutive days prior to the Week 8 DB visit. 
The baseline is defined as the daily NPRS score averaged over the 7 consecutive days prior to 
the baseline visit (Day 1). 
3.2.2 
Secondary Efficacy Endpoints 
The secondary efficacy evaluations and endpoints are presented in Table 2. 


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CCI


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CONFIDENTIAL 
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o 
physical examinations (including physical examination of the foot) 
o 
presence of binding and neutralising antibodies (seroconversion)  
o 
haematology and chemistry (absolute value and change from baseline). 
3.3 
Randomisation and Blinding 
All IMP will be similar in size, colour, smell, taste and appearance allowing the blinded 
conditions of the study to be maintained. Subjects and investigators will remain blinded to 
treatment assignment during the study. 
The sponsor’s randomisation manager who is a statistician independent from the study will 
prepare: 
• 
A list of randomisation numbers (List A). It will be produced in blocks, on a balanced 
ratio (1 placebo: 1 Dysport 300 U: 1 Dysport 500 U) and will be stratified by unilateral 
and bilateral HAV. 
• 
A list of treatment numbers/treatment which will be dispatched to the sites (list B). It will 
be produced in blocks, on a balanced ratio (1 placebo: 1 Dysport 300 U: 1 Dysport 500 
U). 
The randomisation, as well as the treatment number(s) assignation at drug dispensation, will be 
managed by an Interactive Response Technology (IRT). After eligibility is confirmed, at 
baseline, subjects will be assigned to a randomisation number and to the associated treatment 
arm, in sequential order within each centre and within each level of strata.  
Subjects meeting the randomisation criteria will be assigned to a randomisation number, and 
will be allocated to the associated treatment arm, by IRT. A treatment number will be also 
allocated by IRT each time drug is dispensed during the DB and OL cycles. The IRT will also 
manage all the logistical aspects of treatments (e.g.: drug supplies, replacement of lost, 
damaged, quarantined, expiring and expired kits). 
This service provides investigators, site co-ordinators and project team members with a 24-hour 
per day, 7-day per week service (additional details may be found in the IRT reference manual 
provided to each site). In case of medical or technical randomisation or dispensation queries, a 
24-hour helpline is available – see supporting information in the investigator site file. 
Recruitment will stop once 165 evaluable subjects have been randomised.  
Randomised subjects who terminate their study participation for any reason before 
administration of the first dose of randomised study drug will retain their randomisation and 
treatment numbers (i.e. these numbers will not be reused). The next subject will be given 
another randomisation number and another treatment number, even if he/she should receive the 
same treatment. Subjects who leave the study early will not be replaced. 
The sponsor’s randomisation manager will keep the master lists. A copy of the list of treatment 
numbers (list B) will be confidentially supplied to the CMC Supply Chain (Beaufour Ipsen 
Industrie SAS, rue d’Ethe Virton, 28100 Dreux, France) and to the Contract Research 
Organisation (CRO) in charge of IRT. Similarly, a copy of the list of randomisation numbers 
(list A) will be also confidentially supplied to the CRO in charge of IRT. The master list(s) and 
the copy(ies) supplied to the CMC Supply Chain and CRO in charge of IRT will be kept 
confidential in a secure location. Access to the randomisation lists must be restricted until 
authorisation is given to release them for final analysis. 
3.4 
Maintenance of Randomisation and Blinding 
In an emergency situation, which requires the identification of the study treatment group, the 
investigator may break the treatment code immediately, or as quickly as possible, if he/she finds 
it is in the best interest of the trial subject. The investigators have direct and immediate access 
to break the treatment code through the IRT. At the earliest opportunity, the investigator is 


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D-FR-52120-237 
 
CONFIDENTIAL 
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requested to inform the blinded monitor in charge of his/her centre that the blind has been 
broken for an emergency. 
In addition, a set of hard copy sealed code break envelopes will be held by Global Patient Safety 
at Ipsen, in case of IRT failure (this set will be prepared by the Ipsen Randomisation manager). 
If code-break was performed using the IRT, the investigator must store the email notification 
revealing unblinded treatment in a sealed envelope. The investigator will then sign, date and 
provide the reason for the code break on the emergency code break form and on the sealed 
envelope. The date and reason for identifying the treatment group will be recorded in the eCRF.  
3.5 
Study Treatments and Dosage 
The term IMP refers to both active drugs and placebo. 
The study treatment, Dysport, will be provided as a white, lyophilised powder in vials 
containing 300 U or 500 U of BTX-A-HAC (abobotulinumtoxinA). Before each administration, 
the powder from the Dysport vial (300 U or 500 U) will be reconstituted at the investigational 
site with 0.9% sterile (preservative free) sodium chloride for injection, to a total volume of 
2.0 mL. Investigators will inject 0.5 mL of the reconstituted vial from a syringe into each of the 
four muscles in the study foot (i.e. the oblique head of the adductor hallucis muscle; the 
transverse head of the adductor hallucis muscle; flexor hallucis brevis muscle; and the extensor 
hallucis brevis muscle). Subjects assigned to receive 300 U of Dysport will be treated with 75 
U of Dysport per muscle (300 U dose divided equally among the four described muscle 
muscles). Subjects assigned to receive 500 U of Dysport will be treated with 125 U of Dysport 
per muscle (500 U dose divided equally among the described four muscles). 
A more detailed description of administration procedures is given in Section 6.2.  
The reference therapy in this study is a matching placebo for the DB period. Placebo will be 
provided as a white, lyophilised powder in vials containing only excipients of BTX-A-HAC 
and undistinguishable from the active BTX-A-HAC product. Reconstitution and administration 
of the placebo will be as described for the active BTX-A-HAC product. A more detailed 
description of administration procedures is given in Section 6.2.  
The study treatment will be packaged and released by Beaufour Ipsen Industrie and delivered 
to the investigational sites or interim storage facilities. A sufficient quantity of study treatment 
will be supplied as well as an acknowledgement of receipt form.  
The sponsor’s representative will receive; a Certificate of Analysis for which batch of IMP has 
been used under their study, and a Certificate of Compliance which reflects the product release 
statement and will provide them to sites according to local requirement.  
The core label texts for all packaging units will be translated or adjusted, to follow applicable 
regulatory requirements (e.g. Good Manufacturing Practice guidelines (Volume 4 Annex 13)), 
national laws in force and in accordance with the local regulations.  
The investigator, or designee, will only dispense IMPs to subjects included in this study. Each 
subject will only be given the IMP with his/her treatment number. The dispensing for each 
subject will be documented in the electronic case report form (eCRF). 
3.6 
Study Duration 
The duration of the study per subject will be up to 39 weeks. This study will consist of a 
screening period (up to 3 weeks), a DB single-dosing period (Cycle 1) followed by a repeated 
dose OL period where subjects can receive up to two additional cycles of Dysport (Cycles 2 
and 3) depending on retreatment eligibility (36 weeks). Each subject will receive up to three 
administrations (i.e. cycles) of study treatment with a 12-week follow up period after each 
treatment in the DB and OL periods. 


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The study will be considered to have started when the first subject has been screened/provided 
signed informed consent.  
The study will be considered complete after the last subject has completed 36 weeks in the 
study. 
3.7 
Stopping Rules and Discontinuation Criteria 
There are no formal rules for early termination of this study. During the conduct of the study, 
SAEs will be reviewed (see Section 8.1.5) as they are reported from the study centre to identify 
safety concerns. A specific site can be discontinued or the entire study may be terminated at 
any time if the sponsor judges it necessary for any reason. In that case, all scheduled procedures 
and assessments for subjects who are still in the study will be performed. 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 recruitment. 
A subject may discontinue participation in the study at any time for any reason (e.g. lack of 
efficacy, withdrawal of consent, AE). The investigator and/or sponsor can withdraw a subject 
from the study at any time for any reason (e.g. protocol violation or deviation as defined in 
Section 13.1.2, noncompliance with the protocol conditions, AE or if the investigator feels it is 
not in the best interest of the subject to continue in the study). All cases of discontinuation will 
be discussed between the investigator and the sponsor.  
3.8 
Source Data Recorded on the Case Report Form 
Data will be collected in the eCRF in compliance with FDA 21 CFR Part 11. As required by 
GCP, the sponsor assigned monitor will verify, by direct reference to the source documents, 
that the data required by the protocol are accurately reported on the eCRF.  
The source documents must, as a minimum, contain a statement that the subject is included in 
a clinical study, the date that informed consent was obtained prior to participation in the study, 
the identity of the study, diagnosis and eligibility criteria, visit dates (with subject status), IMP 
administration, and any AEs and associated concomitant medication. 
As required by ICH GCP Section 6.4.9, if some items are recorded directly on the eCRF and 
are considered as source data, the identification of these data must be documented and agreed 
between the investigator and the sponsor. 
Definition for source data and source documents are given below: 
• 
Source Data: All original records and certified copies of original records of clinical 
findings, observations, or other activities necessary for the reconstruction and evaluation 
of the study. Source data are contained in source documents (original records or certified 
copies). 
• 
Source Documents: Original documents, data and records (e.g. hospital records, clinical 
and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x rays, subject files, and records 
kept at the pharmacy, at the laboratories and at medicotechnical departments involved in 
the clinical study). 
The subject must have consented to their medical records being viewed by the sponsor’s 
authorised personnel, and by local, and possibly foreign, CAs. This information is included in 
the informed consent. 


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
All subjects must fulfil all the following criteria at Screening and Baseline to be included in the 
study: 
(1) 
Subjects must provide written informed consent prior to any study related procedures. 
(2) 
Male or female, aged 18 years or older 
(3) 
Clinical diagnosis of HAV as determined by the investigator based on evidence of lateral 
deviation of either great toe (left or right), as well as assessment of NPRS Pain scores for 
each foot (in bilateral subjects).  
(4) 
Subjects must present with a score of ≥4 on the NPRS in the study foot at Baseline 
(5) 
Subjects must present with a score of >27 on the mFFI Pain subscale in the study foot at 
Baseline 
(6) 
Subjects must present with a score of >27 on the mFFI Disability subscale in the study 
foot at Baseline 
(7) 
Subjects must present with HV angle ≤ 30° in the study foot great toe using radiographic 
measurements based on guidelines set forth by the AOFAS ad hoc Committee on 
Angular Measurements at Screening only 
(8) 
Subjects must present with an intermetatarsal angle of ≤ 18°, inclusive, in the study foot 
great toe using radiographic measurements based on guidelines set forth by the American 
Orthopedic Foot and Ankle Society Ad hoc Committee on Angular Measurements at 
Screening only 
(9) 
Subject's foot pain associated with HAV deformity is refractory to shoe modifications, 
nonsteroidal anti-inflammatory medications, and modification of activities 
(10) In the opinion of the investigator the subject's deformity is reducible following clinical 
evaluation including compression of the intermetatarsal angle or rotation of the proximal 
phalanx.  
(11) Female subjects of childbearing potential must have a negative pregnancy test result at 
Screening and be willing to use reliable contraceptive measures throughout study 
participation. 
a) 
Reliable forms of contraception include but are not limited to: 
▪ 
Hormonal contraceptives (e.g. oral, path, 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) 
b) 
Female subject 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 
(12) Ability to complete all study requirements in the opinion of the investigator 


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(13) Subject can read well enough to understand the informed consent form and other subject 
materials. 
Subjects must be willing and able to comply with study restrictions and to remain at the clinic 
for the required duration during the study period and willing to return to the clinic for the follow 
up evaluation as specified in the protocol. 
4.2 
Exclusion Criteria 
Subjects will not be included in the study if the subject: 
(1) 
Subject has an HV angle of >30° in the study foot 
(2) 
Evidence of cognitive impairment 
(3) 
Inability to walk unassisted 
(4) 
Subject presents with a flat or square metatarsal head in the study foot 
(5) 
Subject presents with metatarsus primus elevatus in the study foot 
(6) 
Subject presents with severe cavus/planus in the study foot 
(7) 
Subject suffers from any other podiatric or orthopaedic condition which, in the opinion 
of the investigator would interfere with the accurate evaluation of pain and/or function 
(8) 
Subject presents with medical history or clinical evidence of peripheral vascular disease 
(9) 
Subject has a body mass index greater than 40 kg/m2 or less than 18.5 kg/m2 
(10) Any medical history of a diabetic condition 
(11) Subject has a glycated haemoglobin level of ≥6.5% at Screening 
(12) Any history of ankle or foot surgery in the study foot 
(13) Subject is using an orthotic device (including over-the-counter toe-spacers) which could 
influence the functioning of the hallux of the study foot in any way, or any other device 
intended for this purpose. Over-the-counter shoe inserts for the study foot are permitted 
if used for at least 30 days prior to screening 
(14) Subject has medical history or clinical evidence of peripheral neuropathy or fibromyalgia 
(15) Subject has metatarsus adductus 
(16) Subject has a history of conditions or disease causing ligamentous laxity (e.g. Marfan’s 
syndrome, Ehlers-Danlos syndrome) 
(17) Subject has a history of allergic reaction or has a known or suspected sensitivity to any 
substance that is contained in the study treatment formulation (including cow's milk 
protein) 
(18) Any medical condition or disease that might interfere with neuromuscular function, e.g. 
diagnosed myasthenia gravis, Lambert-Eaton syndrome or amyotrophic lateral sclerosis. 
(19) Subject demonstrates evidence of inflammatory arthritis (including gout) in the study 
foot or osteoarthritis in the study foot based on either history or clinical evaluation 
(20) Subject demonstrates evidence of degenerative arthritis of the first metatarsophalangeal 
joint based on either history or clinical evaluation 
(21) Subject has an acute or chronic medical condition (other than HAV) that in the opinion 
of the investigator could confound clinical assessments or interfere with the ability of the 
subject to participate in the study. 
(22) Subject has a clinically significant abnormality on screening evaluation including 
physical examination, vital signs, or laboratory tests that the investigator considers to be 
inappropriate to allow participation in the study. 


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(23) Subject is currently participating or has participated in a clinical study within the last 90 
days or has participated in more than two clinical studies within the past year. This 
includes studies using marketed compounds or devices.  
(24) Subject is an investigational study site staff member or the relative of an investigational 
study site staff member. 
(25) Treatment with any preparation of botulinum toxin within 4 months prior to Screening 
for any condition, with the exception of glabellar lines or other aesthetic face applications 
of toxin. Subjects who have previously received an injection with botulinum toxin in the 
foot are not eligible to participate in the study.  
(26) Any concomitant therapy usage that, in the investigator's opinion, would interfere with 
the evaluation of safety or efficacy of the investigational medicinal product, and/or 
confound the study results. 
(27) Subject has planned or ongoing use of opioids; use of antipsychotics or antidepressants 
that are not stable for at least 30 days prior to Screening; use of anticholinergic therapies 
that are not stable for at least 6 weeks prior to randomisation; or requires continuous 
treatment with any medication restricted by this protocol. 
(28) Evidence of clinically significant chronic drug or alcohol abuse within the last year. 
(29) Use of medications that affect neuromuscular transmission, such as curare-like 
depolarising agents, lincosamides, polymyxins, anticholinesterases and aminoglycoside 
antibiotics within the last 3 months before Screening. 
(30) Subject is medically unable to discontinue treatment with medications with 
anticoagulant/antiplatelet effects (e.g. warfarin and other coumadin derivatives, 
acetylsalicylic acid and clopidogrel/ticlopidine) for at least 3 days before 
randomisation/injection 
of 
study 
treatment. 
Subjects 
are 
permitted 
restart 
anticoagulant/antiplatelet medications one day after injection of study treatment (or 
longer at the discretion of the investigator).  
(31) Any condition or situation which, in the investigator's opinion, puts the subject at 
significant risk, may confound the study results, or may interfere with the subject's 
participation in the study 
4.3 
Rationale for Inclusion / Exclusion Criteria 
The selection of the specific subject population defined by the inclusion/exclusion criteria 
above was based on the known aetiology and course of HAV in adult patients seeking treatment 
for this condition. The typical clinical presentation for HAV primarily includes clinically 
significant pain, mobility dysfunction and angular deviation of the hallux. As such, the entry 
criteria have been specifically chosen to allow for generalizability of this clinical study 
population to the larger adult HAV population. For the purposes of ensuring that variability is 
minimised and potential confounding factors are eliminated, the entry criteria include several 
provisions restricting subjects who have pre-existing medical conditions or are reliant upon 
treatments which will not be permitted in the study.  
4.4 
Subject Withdrawal Criteria and Procedures 
4.4.1 
Withdrawal from the Study 
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each subject is free to withdraw from the study at any time. The investigator also 
has the right to withdraw a subject from the study in the event of concurrent illness, AEs, or 
other reasons concerning the health or wellbeing of the subject, or in the case of lack of 
cooperation. In addition, a subject may be withdrawn from the study as described in 
Sections 3.7, 5.2.3, 6.3, 8.1.6 and 8.1.8.  


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If a subject decides to withdraw from the study after administration of IMP, or should the 
investigator decide to withdraw the subject, all efforts will be made to complete and report the 
observations 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 (see Sections 5.2.3) and an explanation 
given of why the subject is withdrawing or being withdrawn from the study. 
The reason for and date of withdrawal from the study must be recorded on the eCRF. If a subject 
withdraws consent, every attempt will be made to determine the reason. If the reason for 
withdrawal is an AE or a clinically significant laboratory test abnormality, monitoring will 
continue until the event has resolved or stabilised, until the subject is referred to the care of a 
local health care professional, or until a determination of a cause unrelated to the IMP or study 
procedure is made. The specific AE or test result(s) must be recorded on the eCRF. All 
evaluations should be performed, according to the protocol, on the last day the subject receives 
IMP, or as soon as possible thereafter. 
4.4.2 
Withdrawal from Study Treatment 
Discontinuation of the study treatment does not represent withdrawal from the study. However, 
a subject may permanently discontinue study treatment at any time. If a subject discontinues 
from the study treatment, the subject will continue to be followed up for efficacy and safety 
evaluations. Criteria for permanent discontinuation of study treatment include: 
• 
The subject requests to discontinue study treatment 
• 
The subject has a medical condition or personal circumstance which in the opinion of the 
investigator and/or Sponsor would place the participant at unnecessary risk from 
continued administration of study treatment. 
• 
The participant has a confirmed positive urine pregnancy test 
• 
Chronic failure to comply with dosing, evaluations, or other requirements of the study, 
despite documentation at the study site of repeated efforts to reinforce compliance. 
Discontinuation from the study treatment is permanent. Once a subject is discontinued, he/she 
will not be allowed to restart study treatment. 


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5 
STUDY PROCEDURES 
5.1 
Study Schedule 
The schedule of procedures and assessments during the double-blind and open-label periods of 
the study are summarised in Table 3 and Table 4, respectively. 


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PAGE 35/136 
 
Table 3 
Study Procedures and Assessments: Double-blind Period 
Procedures and Assessments 
Screening 1 
(Days -21 to 
Day -1)a 
Baseline 
Day 1 
Day 8 
Week 1 
Day 29 
Week 4 
Day 57 
Week 8 
Day 85b 
Week 12 
Additional 
Visit every 
4 weeksd 
End of Study 
or Early 
Withdrawale 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
- 
- 
Visit Window 
NA 
NA 
± 1 day 
± 3 days 
± 3 days 
+ 1 weekc 
± 7 days 
N/A 
Obtain informed 
consent/assent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
Demographicsf 
X 
 
 
 
 
 
 
 
Assessment of unilateral/ 
bilateral HAVg 
X 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
Injection of study treatment 
 
X 
 
 
 
 
 
 
Weight-bearing foot 
radiograph and measurement 
of HV and IM angles and 
tibial sesamoid positionh 
X 
 
 
X 
X 
X 
X 
X 
NPRS 
X 
Xi 
 
Xi 
Xi 
Xi 
Xi 
Xi 
mFFI 
X 
Xi 
 
Xi 
Xi 
Xi 
Xi 
Xi 
SF-36 
 
X 
 
 
X 
X 
 
X 
PGI-I for pain and PGI-I for 
disabilityn 
 
 
 
X 
X 
X 
 
X 
PGI-S for pain and PGI-S for 
disabilityn 
X 
X 
 
X 
X 
X 
 
X 
Prior/concomitant 
medications/non-drug 
therapies 
Xj 
X 
X 
X 
X 
X 
X 
X 
Adverse event monitoring 
X 
X 
X 
X 
X 
X 
X 
X 


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Procedures and Assessments 
Screening 1 
(Days -21 to 
Day -1)a 
Baseline 
Day 1 
Day 8 
Week 1 
Day 29 
Week 4 
Day 57 
Week 8 
Day 85b 
Week 12 
Additional 
Visit every 
4 weeksd 
End of Study 
or Early 
Withdrawale 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
- 
- 
Visit Window 
NA 
NA 
± 1 day 
± 3 days 
± 3 days 
+ 1 weekc 
± 7 days 
N/A 
Medical history 
X 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
 
 
X 
 
X 
Examination of injected footj 
 
X 
X 
X 
X 
X 
X 
X 
Height and weightk 
X 
 
 
 
 
X 
 
X 
Vital signsl  
X 
 
X 
 
 
X 
 
X 
Hematology and chemistry 
X 
 
 
 
 
X 
 
X 
Blood sampling for BTX-A 
Abs- testing 
 
X 
 
 
 
 
 
X 
Urine drug screen 
X 
X 
 
X 
 
X 
 
X 
Urine pregnancy test 
X 
X 
 
 
 
 
 
 
Eligibility for retreatment 
 
 
 
 
 
X 
X 
 
BTX-A-Abs=botulinum toxin type A antibodies; HV= hallux valgus; IM=intermetatarsal; mFFI=modified foot function index; NA=not applicable; NPRS=numeric pain rating scale; 
PGI-I=Patient Global Impression of Improvement; PGI-S=Patient Global Impression of Severity; SF-36=36-item short form survey 
a 
Screening assessments are to be performed at the study site, including NPRS, mFFI and PGI-S.  
b 
Assessments outlined for Day 85 are the same as those for Day 1 of the subsequent cycle and do not need to be repeated. 
c 
Repeat study treatment must not be administered any sooner than 12 weeks after the last dose. 
d Any subjects who are not eligible for retreatment will be evaluated every 4 weeks at additional follow-up visits until they are eligible for retreatment, or have completed the 
study. 
e A subject will be considered to have completed the study if he/she has completed a total of 36 weeks follow-up in the study from the first study treatment injection (Treatment 
Cycle 1, Day 1) and has completed the Day 85 visit following the last injection. 
f 
Demographic data will include sex, age/date of birth, ethnicity and race. 
g 
Subjects should be assessed for the presence of unilateral or bilateral HAV and the status recorded in the electronic case report form. 
h Subjects will record daily measurements for 7 consecutive days (preferably in the evening) using an electronic diary prior to Baseline (i.e.  Day -7 to Day -1) and prior to the 
following visits: Week 4, Week 8 and Week 12.  
i 
Prior and concomitant medications will include all medications administered within 30 days before the screening visit. 
j 
Assessment to include complete physical examination of the injection sites on the study foot specifically evaluating the foot for any dermatologic, neurologic or musculoskeletal 
abnormalities (see Section 8.4 for further details). 
k 
Height is to be collected at Screening only. 
l 
Vital signs will include sitting blood pressure and sitting heart rate. 


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Procedures and Assessments 
Screening 1 
(Days -21 to 
Day -1)a 
Baseline 
Day 1 
Day 8 
Week 1 
Day 29 
Week 4 
Day 57 
Week 8 
Day 85b 
Week 12 
Additional 
Visit every 
4 weeksd 
End of Study 
or Early 
Withdrawale 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
- 
- 
Visit Window 
NA 
NA 
± 1 day 
± 3 days 
± 3 days 
+ 1 weekc 
± 7 days 
N/A 
m 
The PGI-I and PGI-S assessments will be completed by the subject at the study site during the study visit. Subjects are to complete these self-assessments using the electronic 
diary which will be accessed at the site during the visit. Site staff should not help subjects answer questions but must ensure that the subject can access the eDiary to complete the 
assessment while at the site 


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Table 4 
Study Procedures and Assessments: Open-label Period 
Procedures and Assessments 
Cycle 2 to 3 
Day 1c 
Cycle 2 to 3 
Day 8  
Cycle 2 to 3 
Day 29 
Cycle 2 to 3  
Day 57 
Cycle 2 to 3  
Day 85d 
Additional  
Visit every 
4 weeksf 
End of Study or 
Early 
Withdrawalg 
Visit Number 
Visits 7 & 12 
Visits 8 & 13 
Visits 9 & 14 
Visits 10 & 15 
Visits 11 & 16 
- 
- 
Visit Window 
+ 2 days 
± 1 day 
± 3 days 
± 3 days 
+ 1 weeke 
± 7 days 
N/A 
Weight-bearing foot radiograph 
and measurement of HV and IM 
angles and tibial sesamoid 
position 
X 
 
X 
 
X 
 
X 
Injection of study treatment 
Xa, b 
 
 
 
 
 
 
NPRSh 
X 
 
X 
X 
X 
X 
X 
mFFIh 
X 
 
X 
X 
X 
X 
X 
SF-36 
X 
 
 
X 
X 
 
X 
PGI-I for pain and PGI-I for 
disabilityi, k 
X 
 
 
X 
 
 
X 
PGI-S for pain and PGI-S for 
disabilityi, k 
X 
 
 
X 
 
 
X 
Prior/concomitant medication 
review 
X 
X 
X 
X 
X 
X 
X 
Adverse event monitoring 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
X 
 
X 
Examination of injected footj 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
 
 
 
X 
Weight 
X 
 
 
 
 
 
X 
Hematology and chemistry 
X 
 
 
 
X 
 
X 
Blood sampling for BTX-A-Abs 
testing 
 
 
 
 
 
 
X 
Urine drug screen 
X 
 
X 
 
X 
 
X 


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Procedures and Assessments 
Cycle 2 to 3 
Day 1c 
Cycle 2 to 3 
Day 8  
Cycle 2 to 3 
Day 29 
Cycle 2 to 3  
Day 57 
Cycle 2 to 3  
Day 85d 
Additional  
Visit every 
4 weeksf 
End of Study or 
Early 
Withdrawalg 
Visit Number 
Visits 7 & 12 
Visits 8 & 13 
Visits 9 & 14 
Visits 10 & 15 
Visits 11 & 16 
- 
- 
Visit Window 
+ 2 days 
± 1 day 
± 3 days 
± 3 days 
+ 1 weeke 
± 7 days 
N/A 
Urine pregnancy test 
X 
 
 
 
 
 
 
Eligibility to retreatment 
 
 
 
 
X 
X 
 
BTX-A-Abs=botulinum toxin type A antibodies; HV= hallux valgus; IM=intermetatarsal; mFFI=modified foot function index; NPRS=numeric pain rating scale; U=units 
a 
Dysport 300 U or 500 U will be administered to eligible subjects based on investigator judgment and ONLY if the subject meets the protocol-specified retreatment criteria. 
b Treatment with Dysport in the open-label period will be administered in 12-week treatment cycles. All eligible subjects will receive open-label treatment with Dysport 300 U at the first 
retreatment cycle (Cycle 2) in the study foot. At the second retreatment cycle (Cycle 3), subjects will be treated with either Dysport 300 U or 500 U in the study foot based on investigator 
judgment following clinical evaluation of the subject at the time of retreatment. The decision to increase the dose at the beginning of Cycle 3 will be based on 1) evaluation of safety and 
tolerability (review of related AEs and consideration of any significant changes in the study foot) and 2) severity of pain (considering NPRS score) and disability (considering mFFI 
Disability subscale score) experienced by the subject at the time of evaluation. 
c 
This visit must occur on the same day as the last visit of the previous cycle. 
d 
Assessments outlined for Day 85 are the same as those for Day 1 of the subsequent cycle and do not need to be repeated. 
e 
Repeat study treatment must not be administered any sooner than 12 weeks after the last dose. 
f 
Any subject not eligible for retreatment will be evaluated every 4 weeks at additional follow-up visits until they are eligible for retreatment or have completed the study.  
g 
A subject will be considered to have completed the study if he/she has completed a total of 36 weeks follow-up in the study from the first study treatment injection (Treatment  Cycle 1, 
 
Day 1) and has completed the Day 85 visit following the last injection. 
h 
Subjects will record daily measurements for 7 consecutive days (preferably in the evening) for Cycles 2 and 3 during the open-label period prior to the following visits: Day 1, Week 4, 
 
Week 8 and Week 12 using an electronic diary. 
i 
The PGI-I and PGI-S assessments will be completed by the subject at the study site during the study visit. Subjects are to complete these self-assessments using the electronic diary 
which will be accessed at the site during the visit. Site staff should not help subjects answer questions but must ensure that the subject can access the eDiary to complete the assessment 
while at the site 
j 
Assessment to include a complete physical examination of the injection sites on the study foot specifically evaluating the foot for any dermatologic, neurologic or musculoskeletal 
 
abnormalities (see Section 8.4 for further details). 
k 
The PGI-I and PGI-S assessments will be completed by the subject at the study site during the study visit. Subjects are to complete these self-assessments using the electronic diary 
which will be accessed at the site during the visit. Site staff should not help subjects answer questions but must ensure that the subject can access the eDiary to complete the assessment 
while at the site 


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5.2 
Study Visits 
Activities to be performed at visits during the DB and OL periods are outlined in Table 3 and 
Table 4, respectively. Additional details for study visits are provided below as appropriate. 
5.2.1 
Screening and Enrolment  
A signed and dated informed consent form will be obtained before screening procedures during 
the DB period occur. 
After informed consent is obtained, subjects who are screened will be allocated a subject 
number. All screened subjects must be identifiable throughout the study. The investigator will 
maintain a list of subject numbers and names to enable records to be found at a later date if 
required. 
If the initial foot evaluated for study entry fails to meet the entry criteria, bilateral HAV subjects 
are allowed to be rescreened only once for entry in the study using the contralateral foot.  
Following confirmation of eligibility for the study, subjects will be given a 
randomisation/treatment allocation number and allocated to one of the dosing groups specified 
in Section 6.1. 
Each investigator will also maintain a record of all subjects screened into the study (i.e. who 
signed the informed consent form). Records up to the time of premature termination should be 
completed. In the event that the subject was not receiving IMP, the primary reason will be 
recorded.  
5.2.2 
Additional Follow-up Visits (Double-blind and Open-label Periods) 
Additional follow-up visits will be performed every 4 weeks after Visit 6 during the DB period, 
and after Visits 11 and 16 during the OL period to determine eligibility for retreatment.  
5.2.3 
End of Study or Early Withdrawal Visit 
Subjects who participate in the study in compliance with the protocol for at 36 weeks (DB and 
OL periods) will be considered to have completed the study.  
For subjects who complete the study, or for those who withdraw prematurely from the study, 
final evaluations will be performed on the last day the subject receives the study treatment, or 
as soon as possible afterwards. Subjects with ongoing AEs or clinically significant laboratory 
test abnormalities (as determined by the investigator) will be monitored as described in Section 
8.1.4 and Section 8.1.2.4, respectively. 


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6 
TREATMENT OF SUBJECTS 
6.1 
Investigational Medicinal Product Preparation Storage and Accountability 
6.1.1 
Investigational Medicinal Product Storage and Security 
The investigator, or an approved representative (e.g. pharmacist), will ensure that all IMP and 
any other study related material is stored in a secured area, under recommended temperature 
monitored storage conditions, in accordance with applicable regulatory requirements. 
To prevent theft or diversion, the IMP will be stored in a securely locked, substantially 
constructed cabinet or enclosure appropriate for the study treatment. Any actual or suspected 
theft or diversion must be reported immediately. 
6.1.2 
Investigational Medicinal Product Preparation 
The investigator, or an approved representative (e.g. pharmacist), will ensure that all IMP is 
reconstituted and dispensed by qualified staff members. Detailed instructions for the 
preparation before administration of study medication (Dysport and matching Placebo) will be 
provided in the study IMP Handling manual or similar documentation 
6.1.3 
Investigational Medicinal Product Accountability 
All IMP and any other study related material is to be accounted for on the IMP accountability 
log provided by the sponsor. It is essential that all used and unused supplies are retained for 
verification (by the sponsor or sponsor’s representative). The investigator should ensure 
adequate records are maintained in the IMP accountability log. 
All used and unused IMP and any other related material is to be destructed at the investigational 
sites and/or at the Interim Storage facility according to local procedures, regulations and laws. 
6.2 
Study Drugs Administered 
At Screening during the DB period, subjects will be allocated a subject number. Following 
confirmation of eligibility for the study, subjects will be allocated to treatment with Dysport 
300 U, Dysport 500 U or placebo during the DB period. 
A blinded kit will be used in this study to maintain the blinding of the study during the DB 
period. Each blinded kit will contain two vials regardless of treatment assignment: one vial 300 
U or placebo and one vial 500 U or placebo. The two vials in each kit will contain either a 
Dysport 300 U vial + a placebo vial, a Dysport 500 U vial + a placebo vial or two placebo vials, 
based on treatment assignment. Investigators will be blinded to which vial contains Dysport 
and which vial contains placebo. 
Before each administration, the powder in each vial in the blinded kit will be reconstituted at 
the investigational site with 1.0 mL of 0.9% sterile (preservative free) sodium chloride for 
injection. The contents of each vial will be combined for a total volume of 2.0 mL (150 U/mL 
for Dysport 300 U and 250 U/mL for Dysport 500 U). Investigators will inject 0.5 mL of the 
reconstituted solution (2.0 mL total volume) containing study treatment into each of the four 
targeted muscles. Subjects assigned to receive 300 U of Dysport will be treated with 75 U of 
Dysport per muscle (300 U dose divided equally among, 1) the oblique head of the adductor 
hallucis muscle; 2) the transverse head of the adductor hallucis muscle; 3) flexor hallucis brevis 
muscle; and 4) the extensor hallucis brevis muscle muscles); subjects assigned to receive 500 U 
of Dysport will be treated with 125 U of Dysport per muscle (500 U dose divided equally among 
the described four muscles); subjects treated with placebo will receive four injections of 
reconstituted product containing only the excipients described in Dysport, without the addition 
of toxin (see Section 6.2.2). 
During the OL period, subjects will receive treatment with Dysport 300 U or 500 U. At the first 
retreatment cycle (Cycle 2) during the OL period, subjects will receive Dysport 300 U in the 


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HAV study foot determined in the DB period. At the second retreatment cycle (Cycle 3), 
subjects will be treated with either Dysport 300 U or 500 U in the HAV study foot. The Dysport 
dose to be administered in the HAV study foot will be based on investigator judgment following 
clinical evaluation of the subject at the time of retreatment. The decision to increase the dose at 
the beginning of Cycle 3 will be based on 1) evaluation of safety and tolerability (related AEs 
and if any significant changes occurred in the injected foot) and 2) severity of pain (considering 
NPRS score) and disability (considering mFFI Disability subscale score) experienced by the 
subject at the time of evaluation. 
6.2.1 
Dysport 
Dysport is provided in glass vials containing 300 U or 500 U of BTX-A-HAC as a white 
lyophilised powder for reconstitution. The composition the Dysport 300 U and 500 U vials are 
provided in Table 5. 
Table 5 
Dysport Composition (300 U and 500 U Vial) 
Active Constituent Per Vial 
 
 
  Clostridium BTX-A-HAC 
500 U 
300 U 
Other Constituents Per Vial 
 
 
  Human Serum Albumin 
125 μg 
125 μg 
  Lactose monohydrate 
2.5 mg 
2.5 mg 
One unit (U) is defined as the median lethal intraperitoneal dose in mice. 
 
Dysport drug product should be stored at the recommended temperature, in a refrigerator 
between 2°C and 8°C (36 °F to 46°F). Dysport should not be frozen and protected from light. 
The drug product does not contain any microbial agent. Therefore, it is recommended that the 
product be used within 24 hours after reconstitution.  
6.2.2 
Placebo 
Placebo is provided in glass vials and will be undistinguishable from the active product. Placebo 
will contain only the excipient described in Dysport, without the addition of toxin, as white 
lyophilized powder for reconstitution. There will be two matching placebo vials: one matching 
the 500 U Dysport vial and one matching the 300 U Dysport vial. The constituents in both 
placebo vials are identical: 
• 
Constituent per vial: 
o Human Serum Albumin:  125 µg 
o Lactose monohydrate:  2.5 mg 
Placebo product should be stored at the recommended temperature (between 2°C and 8°C). 
The drug product does not contain any microbial agent. Dysport should not be frozen and 
protected from light. 
6.2.3 
Injection –Guided Technique 
To administer the study treatment, a peripheral electrical stimulator (with or without 
complementary techniques for identifying target muscles) will be used to locate the muscles in 
the foot. A Teflon coated, 22 to 30-gauge, open lumen needle will be used to stimulate the 
targeted muscle once per second (repetitive square wave pulses, 0.25 msec in duration). 
Injection will be performed when either a continuous or stretch of muscle has been induced by 
the electrical stimulator confirming the location of the targeted muscle. 
Further details of the use of electrical stimulator are provided in the study injection manual. 


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6.3 
Concomitant Medication/Therapy  
Any prior or concomitant therapy or medication given to a subject within 30 days before IMP 
administration or during IMP administration will be indicated on the eCRF. Dose and generic 
name or tradename will be indicated. 
The following concomitant medications are not permitted during this study: 
• 
Botulinum toxin for administration into any site of the body other than Dysport for HAV, 
with the exception of glabellar lines or other aesthetic face applications of toxin. 
• 
Any investigational new drug or device or off label use of any drug. 
• 
Aminoglycoside antibiotics or other drugs that interfere with neuromuscular 
transmission. 
• 
Opioids 
• 
Any medication not specifically permitted by the protocol which has antinociceptive 
(pain relieving) properties. This includes any and all narcotic pain relievers, as well as 
pregabalin and gabapentin. 
• 
Subjects who require treatment with antipsychotic (e.g. D2 antagonists) or antidepressant 
(e.g. selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake 
inhibitors) medications will need to demonstrate evidence of stable dose regimen in the 
30 days prior to Screening and will maintain that dose for the duration of the study. 
The following concomitant medications are permitted during this study but they must be 
monitored closely and every effort should be made to keep their dose and dose regimen constant 
throughout the course of the study.  
• 
Concomitant use of anticholinergic drugs (which may potentiate systemic 
anticholinergic effect) is permitted if the dosage has been stable for 6 weeks prior to 
study treatment and is expected to remain at this stable dose throughout the study. 
• 
Concomitant use of over-the-counter medications for the symptomatic treatment of 
minor ailments (e.g. common cold). Specifically, these include non-steroidal 
anti-inflammatory medications (e.g. aspirin, ibuprofen), anti-pyretic agents (e.g. 
acetaminophen), antihistamines (e.g. loratadine) and expectorants (e.g. guaifenesin). 
• 
After consultation with prescribing physician, anticoagulant medications must be 
stopped 3 days prior to administration of study treatment. These medications can be 
restarted one day after administration of study treatment and can be stopped for a longer 
period if deemed necessary in the opinion of the investigator, and in compliance with 
standard medical practice and the manufactures’ discontinuation recommendations for 
the medication. Anticoagulant medications permitted during the study include, but are 
not limited to: 
o 
warfarin and other coumadin derivatives 
o 
acetylsalicylic acid (including low-dose aspirin) 
o 
clopidogrel/ticlopidine 
If medically indicated, lower molecular weight heparins are permitted providing the last 
dose was within 24 hours prior to administration of study treatment, and may be restarted 
one day following administration of study treatment. 
• 
Topical or oral anaesthesia for pain management of the injection site. 
6.4 
Lifestyle Restrictions/Recommendations 
Besides restrictions already presented in the exclusion criteria, subjects should not use an 
orthotic device or 'over-the-counter shoe-insert' which could influence the functioning of the 
hallux of the study foot in any way during the study. This includes toe-spacers or any other 


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device intended for this purpose. Over-the-counter shoe inserts will be permitted during the 
study only for subjects who have used these for at least 30 days prior to screening. 
6.5 
Procedures for Monitoring Subject Compliance 
The study treatment will be administered at the investigational site; therefore, compliance is 
not likely to be an issue.  
6.6 
Priority Order on Study Procedures 
The following priority order should be followed in case study procedures are scheduled at the 
same time point: 
 
1. 
NPRS* 
2. 
mFFI* 
3. 
PGI-I and PGI-S (pain and disability) 
4. 
SF-36 
5. 
Weight-bearing radiographs 
*These assessments are assessed at home after baseline. 
 
7 
ASSESSMENT OF EFFICACY 
For the timing of assessments in this study, refer to the schedule in Table 3 and Table 4. 
7.1 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data 
Methods for assessing efficacy data is described below. Timing of efficacy assessments are 
discussed in Section 5. Procedures for recording efficacy data are discussed in Section 15.1, 
and methods of analyses are discussed in Section 11.4.3.  For all assessments related to pain, 
the subject is to be instructed by the investigator to report severity specifically for his/her 
study foot when completing the questionnaires using the e-diary. The Sponsor will provide a 
device (to complete the e-diary questionnaires) in the clinical trial if requested by subjects or 
in situations in which the subject is not willing or able to use their own device. The device 
will be returned to the site at the completion of the subjects' participation in the trial. Also, it 
is critical that investigators and site staff instruct and remind subjects to complete home-based 
self-assessments (eg, NPRS, mFFI) in the evening.  
7.1.1 
Numeric Pain Rating Scale 
The NPRS is a widely used and validated unidimensional measure of pain intensity in adults. 
Subjects will be asked to rate the intensity of their foot pain during physical activity (e.g. 
walking, standing or running) based on an 11-point scale ranging from 0 to 10, where 0 equals 
“no pain” and 10 equals “worst possible pain”. They will be asked to rate their daily pain 
intensity by responding directly to the following question: "Please rate the average intensity of 
the pain in your treated foot while performing physical activities (e.g. standing, walking or 
running) over the past 24 hours".  
Daily pain intensities will be recorded by the subject using an electronic diary for 7 consecutive 
days prior to the study visits as outlined in Section 5.1. The electronic diary should be completed 
by the subject at the same time each day, preferably in the evening.  The subject should be 
instructed by the investigator to focus on his/her study foot when completing the questionnaire.  
This instruction is critical in subjects with bilateral disease. 


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7.1.2 
Modified Foot Function Index 
The FFI was developed to assess foot-related pain, disability and activity limitations, and later 
revised to include foot-related health and quality of life [19; 20; 21]. A modified version of the 
FFI specific to this study is provided in Appendix 1. It is a self-administered specific patient-
reported outcome measure of foot pain plus evoked foot pain, and the impact of foot pathologies 
on disability and activity limitations. The mFFI consists of a total of 21 items grouped into three 
subscales: pain (seven questions), disability (nine questions), and activity limitation (five 
questions). The mFFI items are rated using numeric rating scales ranging from 0 to 10 and cover 
a period of the ‘past’ 24 hours. The poles are labelled “no pain” and “worst pain imaginable” 
(pain), “no difficulty” and “so difficult unable to do” (disability), and “none of the time” and 
“all of the time” (limitations). For each item, the subject is asked to record the number value 
which best corresponds to the effect of the foot complaints. To obtain a subscale score, the item 
scores for a given subscale (i.e. pain, disability or activity limitation subscales) are totalled and 
divided by the maximum total possible and then multiplied by 100. Each subscale score, as well 
as the total score, will range from 0 to 100. If a patient did not perform the task listed in the 
question, they will be instructed to mark the item as not applicable (N/A). 
Daily pain intensities, disability and activity limitations will be recorded by the subject using 
an electronic diary for 7 consecutive days prior to the study visits as outlined in Section 5.1. 
The electronic diary should be completed by the subject at the same time each day, preferably 
in the evening. The subject should be instructed by the investigator to focus on his/her study 
foot when completing the questionnaire.  This instruction is critical in subjects with bilateral 
disease.  In addition, all subjects should be educated on the proper use of the “not applicable” 
option.  For example, subjects that do not stand on their tiptoes in the course of their daily lives 
should mark “not applicable” for that particular item.  However, if the subject does not stand 
on his or her tiptoes due to their disease, then he or she should choose the option “so difficult 
unable to do”. 
7.1.3 
Intermetatarsal Angle, Hallux Valgus Angle and Sesamoid Position 
Intermetatarsal angle, HV angle and tibial sesamoid position will be measured directly on 
weight-bearing anteriorposterior radiographs, in which the X-ray beam is angled 15° towards 
the heel centered on the second tarsometatarsal joint with a source to image-receptor distance 
of 100 cm. Radiographic measurements will be conducted by following the General Acquisition 
Guidelines document provided to sites by the Sponsor to ensure accurate reproducibility of 
image acquisition across sites. Images should be taken by the same radiology technician. Angle 
measurements will be performed by a blinded central reader. 
7.1.4 
36-Item Short Form Health Survey 
The SF-36 is a 36-item questionnaire which measures the extent to which physical health 
impacts an individual's functional ability and perceived well-being in mental, social and 
physical aspects of life. The SF-36 has eight individual subscales divided across physical and 
psychological domains: physical function, role physical, bodily pain, global health, vitality, 
social function, role emotional and mental health. Scores on these subscales can be combined 
to form two higher-order summary scores, the Physical Component Summary and Mental 
Component Summary. The Physical Component Summary is calculated by positively 
weighting the four subscales in the physical domain (physical function, role physical, bodily 
pain and global health) and the remaining psychological domain subscales negatively. In 
contrast, the Mental Component Summary is calculated by positively weighting the four mental 
domain subscales (mental health, vitality, social function and role emotional), and negatively 
weighting the four physical domain subscales.  


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7.1.5 
Patient Global Impression of Improvement of Foot Pain 
An assessment of PGI-I of foot pain will be conducted by the subject using a 7-point Likert 
scale (from -3: very much worse to +3: very much improved). The PGI-I will be assessed by 
the subject answering the following question: “Compared to your foot pain prior to the study 
treatment initiation, your foot pain while performing physical activities (e.g. standing, walking 
or running) now is: +3=very much improved; +2=much improved; +1=minimally improved; 
0=no change; -1=minimally worse; -2=much worse; -3=very much worse”). Also, an additional 
question will be included in the PGI-I assessment which will ask patients the following: "If you 
experienced a change, was this change meaningful to you? (Yes/No)" 
The PGI-I of foot pain will be recorded by the subject using an electronic diary during the study 
visits at site as outlined in Section 5.1. The subject should be instructed by the investigator to 
focus on his/her study foot when completing the questionnaire.  This instruction is critical in 
subjects with bilateral disease. 
7.1.6 
Patient Global Impression of Severity of Foot Pain 
An assessment of PGI-S of foot pain will be conducted by the subject using a 4-point Likert 
scale (from 0: no pain to 3: severe pain). The PGI-S will be assessed by the subject by answering 
the following question: “How severe was your foot pain while performing physical activities 
(e.g. standing, walking or running) over the past week?” (0=no pain; 1=mild pain; 2=moderate 
pain; 3=severe pain). 
The PGI-S of foot pain will be recorded by the subject using an electronic diary during the 
study visits on site as outlined in Section 5.1. The subject should be instructed by the 
investigator to focus on his/her study foot when completing the questionnaire.  This instruction 
is critical in subjects with bilateral disease. 
7.1.7 
Patient Global Impression of Improvement of Disability 
An assessment of PGI-I of the subject's disability will be conducted by the subject using a 
7-point Likert scale (from -3: very much worse to +3: very much improved). The PGI-I will be 
assessed by the subject answering the following question: “Compared to your disability prior 
to the study treatment initiation, your disability while performing physical activities (e.g. 
standing, walking or running) now is: +3=very much improved; +2=much improved; 
+1=minimally improved; 0=no change from baseline; -1=minimally worse; -2=much worse; -
3=very much worse”). In addition, an additional question will be included in the PGI-I 
assessment which will ask patients the following: "If you experienced a change, was this change 
meaningful to you? (Yes/No)" 
The PGI-I of disability will be recorded by the subject using an electronic diary during the study 
visits on site as outlined in Section 5.1.   
7.1.8 
Patient Global Impression of Severity of Disability 
An assessment of PGI-S of disability will be conducted by the subject using a 4-point Likert 
scale (from 0: no disability to 3: severe disability). The PGI-S will be assessed by the subject 
by answering the following question: “How severe was your disability while performing 
physical activities (e.g. standing, walking or running) over the past week?” (0=no disability; 
1=mild disability; 2=moderate disability; 3=severe disability). 
The PGI-S of disability will be recorded by the subject using an electronic diary during the 
study visits on site outlined in Section 5.1.  
 


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8 
ASSESSMENT OF SAFETY 
8.1 
Adverse Events 
Adverse events will be monitored from the time that the subject gives informed consent and 
throughout the study until at least 14 days after the last dose of study treatment.  Information 
will be elicited by direct, nonleading questioning or by spontaneous reports. Further details for 
AE reporting can be found in Section 8.1.2. 
The investigator will be responsible for a clinical safety assessment of the study participants 
during the whole participation of the subjects in the study, from informed consent up to 
discharge from the study, and for the setup of a discharge plan if needed.  
The sponsor medical monitor and the global patient safety physician will monitor safety data 
throughout the course of the study. 
8.1.1 
Definition of an Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition 
can be symptoms (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g. laboratory findings, electrocardiogram). In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run in or washout periods, even if no IMP has been administered.  
This definition includes events occurring from the time of the subject giving informed consent 
until the end of the study (as defined in Section 3.6). 
8.1.2 
Categorisation of Adverse Events 
8.1.2.1 
Intensity Classification 
Adverse events will be classified as mild, moderate or severe according to the following criteria: 
• 
Mild: symptoms do not alter the subject’s normal functioning 
• 
Moderate: symptoms produce some degree of impairment to function, but are not 
hazardous, uncomfortable or embarrassing to the subject 
• 
Severe: symptoms definitely hazardous to wellbeing, significant impairment of function 
or incapacitation. 
8.1.2.2 
Causality Classification 
The relationship of an AE to IMP administration will be classified according to the following: 
• 
Related: reports including good reasons and sufficient information (e.g. plausible time 
sequence, dose response relationship, pharmacology, positive dechallenge and/or 
rechallenge) to assume a causal relationship with IMP administration in the sense that it 
is plausible, conceivable or likely. 
• 
Not related: reports including good reasons and sufficient information (e.g. implausible 
time sequence and/or attributable to concurrent disease or other drugs) to rule out a causal 
relationship with IMP administration. 
8.1.2.3 
Assessment of Expectedness 
The reference document for assessing expectedness of AEs/event in this study will be the 
current Dysport Therapeutics IB. 
8.1.2.4 
Laboratory Test Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the following 
apply:  


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• 
They result in a change in IMP schedule of administration (change in dosage, delay in 
administration, IMP discontinuation), 
• 
They require intervention or a diagnosis evaluation to assess the risk to the subject, 
• 
They are considered as clinically significant by the investigator. 
8.1.2.5 
Abnormal Physical Examination Findings  
Clinically significant changes, in the judgement of the investigator, in physical examination 
findings (abnormalities) will be recorded as AEs.  
8.1.2.6 
Other Investigation Abnormal Findings 
Abnormal test findings as judged by the investigator as clinically significant that result in a 
change in study drug dosage or administration schedule, or in discontinuation of the study drug, 
or require intervention or diagnostic evaluation to assess the risk to the subject, should be 
recorded as AEs.  
8.1.3 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) for Dysport are AEs that suggest a possible remote 
spread of effect of the toxin or events suggestive of hypersensitivity like reactions. The effects 
of Dysport and all BTX products may spread away from the area of injection to produce 
symptoms consistent with remote spread of BTX effects. These symptoms have been reported 
hours to weeks after injection. The events of remote spread of toxin maybe severe and 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.  
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 
remote spread of toxin or hypersensitivity like reactions. In order to perform the analysis, 
variables including alternative 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. 
8.1.4 
Recording and Follow up of Adverse Events 
At each visit, the subject should be asked a nonleading question such as: “How have you felt 
since starting the new treatment/the last assessment?” 
All observed or volunteered AEs, regardless of treatment group or suspected causal relationship 
to IMP, will be recorded on the AE page(s) of the eCRF. Events involving drug reactions, 
accidents, illnesses with onset during the treatment phase of the study, or exacerbations of pre-
existing illnesses should be recorded. 
Any AEs already recorded and designated as ‘continuing’ should be reviewed at each 
subsequent assessment. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a SAE 
requiring immediate notification to the sponsor or its designated representative. For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE (i.e. IMP or other illness). The investigator is required to assess causality and record that 
assessment on the eCRF. Follow up of the AE, after the date of IMP discontinuation, is required 
if the AE or its sequelae persist. Follow up is required until the event or its sequelae resolve or 


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stabilise at a level acceptable to the investigator and the sponsor’s clinical monitor or his/her 
designated representative. 
8.1.4.1 
Reporting of Adverse Events  
Any AE occurring during the study, from informed consent until 14 days after the end of 
study/early discontinuation must be reported to the Sponsor.  
Any AE considered related to IMP administration that the investigator becomes aware of after 
completion of the end of study/early discontinuation visit must be reported to the sponsor and 
will be recorded in the clinical database. 
8.1.5 
Reporting of Serious Adverse Events 
All SAEs (as defined below) regardless of treatment group or suspected relationship to IMP 
must be reported immediately (within 24 hours of the investigator’s knowledge of the event) 
using the e-mail address specified at the beginning of this protocol. If the immediate report is 
submitted by telephone, this must be followed by detailed written reports using the SAE report 
form. 
A SAE is any AE that: 
(1) 
Results in death, 
(2) 
Is life threatening, that is any event that places the subject at immediate risk of death 
from the event as it occurred. It does not include an event that, had it occurred in a more 
severe form, might have caused death, 
(3) 
Results in in-patient hospitalisation or prolongation of existing hospitalisation, excluding 
admission for social or administrative reasons (see further), 
(4) 
Results in a persistent or significant disability/incapacity, where disability is a substantial 
disruption of a person's ability to conduct normal life functions, 
(5) 
Results in congenital anomaly/birth defect in the offspring of a subject who received the 
IMP, 
(6) 
Is an important medical event that may not result in death, be life threatening, or require 
hospitalisation when, based upon appropriate medical judgement, may jeopardise the 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in in-patient hospitalisation, or the development of drug 
dependency or drug abuse. 
In addition to the above criteria, any additional AE that the sponsor or an investigator considers 
serious should be immediately reported to the sponsor and included in the corporate SAEs 
database system. 
• 
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 


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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. 
Any SAE must be reported immediately (within 24 hours), using the e-mail address specified 
at the beginning of this protocol, independent of the circumstances or suspected cause, if it 
occurs or comes to the attention of the investigator at any time during the study period. 
Any AE/SAE with a suspected causal relationship to IMP administration occurring at any other 
time after completion of the study must be promptly reported. 
The following information is the minimum that must be provided to the sponsor within 24 hours 
for each SAE: 
 
• 
Study number 
• 
Centre number 
• 
Subject number 
• 
AE 
• 
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. 
8.1.6 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP has interfered 
with a contraceptive method. If pregnancy occurs during the study, the outcome of the 
pregnancy will then need to be collected post study and it may be necessary to discontinue 
administration of the IMP.  
Information regarding pregnancies must be collected on the AE page of the eCRF. The sponsor 
will request further information from the investigator as to the course and outcome of the 
pregnancy using the Standard Pregnancy Outcome Report Form.  
The investigator must instruct all female subjects to inform them immediately should they 
become pregnant during the study. The investigator should counsel the subject, discuss the risks 
of continuing with the pregnancy and the possible effects on the foetus. Monitoring of the 
subject should continue until conclusion of the pregnancy, which may involve follow up after 
the subject’s involvement in the study has ended. 
Pregnancies with a conception date during the study period (or within 12 weeks of the subject 
being dosed with IMP, if early discontinuation) must also be reported to the investigator for 
onward reporting to the sponsor. 


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8.1.7 
Deaths 
All AEs resulting in death either during the study period or within 12 weeks (84 days) after the 
last dose of IMP, must be reported as an SAE within 24 hours of the investigator’s knowledge 
of the event.  
The convention for recording death is as follows:  
 
• 
Adverse event term: lead cause of death (e.g. multiple organ failure, pneumonia, 
myocardial infarction), 
• 
Outcome: fatal. 
 
The only exception is if the cause of death is unknown (i.e. sudden or unexplained death), in 
which case the AE term may be “death” or “sudden death”. 
8.1.8 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events 
Discontinuation/withdrawal 
due 
to 
AEs 
should 
be 
distinguished 
from 
discontinuation/withdrawal due to insufficient response to the IMP (see Section 4.4). 
If the IMP is discontinued due to a SAE, it must be reported immediately to the sponsor’s 
designated representative (see Section 8.1.5). 
In all cases, the investigator must ensure the subject receives appropriate medical follow up 
(see Section 8.1.4). 
8.1.9 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators 
The sponsor will ensure that processes are in place for submission of reports of Suspected 
Unexpected Serious Adverse Reactions (SUSARs) occurring during the study to the Competent 
Authorities (CA), IECs and other investigators concerned by the IMP. Reporting will be done 
in accordance with the applicable regulatory requirements. 
For study centres in the USA, Investigational New Drug Application Safety Reports will be 
submitted directly to the investigators. It is the investigators’ responsibility to notify their IRB 
in a timely manner. 
8.2 
Clinical Laboratory Tests 
Blood and urine samples will be collected during the DB and OL periods as described in the 
study procedures and assessments in Table 3 and Table 4 for the evaluation of haematology and 
serum chemistry and urine examination.  
The total volume of blood drawn for all evaluations throughout this study is approximately 
54 mL for each subject. 
The investigator will review the safety laboratory test results, document the review, and record 
any clinically relevant changes occurring or observed during the study in the AE section of the 
eCRF (see Section 8.1.2.4 for abnormal laboratory tests that should be recorded as AEs). 
8.2.1 
Haematology 
Blood samples will be collected in a potassium ethylenediamine tetra-acetic acid tube to assess 
the following variables: red blood cell count, haemoglobin, haematocrit, mean corpuscular 
volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, white 
blood cell count with differential (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils) and platelet count. 
8.2.2 
Blood Biochemistry 
Blood samples will be collected in an activator gel tube to assess the following parameters: 


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• 
urea, creatinine, total bilirubin, conjugated bilirubin 
• 
chloride, bicarbonate, sodium, potassium, calcium, phosphate 
• 
alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma 
glutamyl transferase 
• 
albumin total protein, total cholesterol, triglycerides, glycated haemoglobin 
Blood samples will be collected in a citrated tube to assess the following coagulation variables: 
activated partial thromboplastin time, prothrombin time and its derived measures of 
prothrombin ratio and international normalised ratio. 
8.2.3 
Pregnancy Test 
A human chorionic gonadotrophin urine test will be performed for all female subjects of 
childbearing potential at Screening (Visit 1), as well as at other timepoints as indicated in the 
study procedures and assessments (Table 3 and Table 4), and if clinically indicated thereafter. 
Any subject becoming pregnant during the study will be withdrawn. All pregnancies that occur 
during the study are to be reported as described in Section 8.1.6. 
8.2.4 
Drug of Abuse Testing 
Urine drug screen testing for opiates, cannabis, cocaine and amphetamines will be performed 
as specified in Table 3 and Table 4 at the study site, and at any time at the discretion of the 
investigator. 
8.2.5 
Immunogenicity 
Blood samples will be collected for the detection of antibodies to BTX-A (6 mL samples per 
timepoint). Each sample will be left to stand for 30 minutes at room temperature and the tubes 
should be centrifuged at approximately 1300 g for 10 minutes at 4°C. The serum will be 
removed and transferred into three aliquots in clean plastic tubes (approximately 0.5 mL, 
0.5 mL, 3 mL, respectively). This sample process has to be made in the most sterile possible 
conditions. The resulting serum will be stored at -20°C or below. Each tube should be labelled 
with the sample identification, study number, site number, subject number and initials, and visit 
number (when applicable). Serum samples will be sent to the central laboratory for storage up 
to analysis by the bioanalytical CRO. 
Batch shipping to the bioanalytical CRO will be arranged by the central laboratory at 
appropriate interval. 
All samples will be tested initially for the presence of binding antibodies using a validated 
immunoassay. Samples found positive for the presence of binding antibodies will be analysed 
for the presence of neutralising antibodies using a functional assay. Additional aliquots (i.e. 
back-up samples) will be archived at the central laboratory. Archived samples will be destroyed 
at the end of the study. 
Full details regarding required the processing, labelling and shipment processes for these 
samples are provided in the Study Manual. 
The determination of antibodies against BTX-A will be evaluated using a validated method: 
• 
RS16-077-IP: Validation of the ECLA method for the detection of binding antibodies to 
Dysport in human serum samples by KYMOS PHARMA SERVICES, S.L. 
• 
RS15-574-IP: Validation of a Cell Based Assay (CBA) for the detection of neutralising 
antibodies to BoNT/A in human serum samples by KYMOS PHARMA SERVICES, S.L. 
8.3 
Physical Examination 
Physical examinations, including body weight, will be conducted as outlined in Table 3 and 
Table 4 and height will be measured at Baseline. 


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Any new clinically significant physical examination findings (abnormalities) observed during 
the study will be reported as AEs. Any physical examination findings (abnormalities) persisting 
at the end of the study will be followed by the investigator until resolution or until reaching a 
clinically stable endpoint. 
8.4 
Examination of the Study Foot 
A complete physical examination of the study foot will be conducted as outlined in Table 3 and 
Table 4 for the DB and OL periods. The examination will include evaluation of the a) 
dermatologic, b) neurologic and c) musculoskeletal condition of the study foot. For 
dermatologic and musculoskeletal foot examinations, the Investigator will record whether a 
given abnormality or deformity is present. For neurological examinations, the Investigator will 
record whether the specified neurological parameters are "normal" or "abnormal" based on 
clinical presentation.  
Any findings that were not present at Baseline based on examination of the study will be 
recorded as AEs. As for all AEs reported during the study, the investigator should use his/her 
medical judgment to determine if treatment of the study foot is required based on an abnormal 
finding, and/or if the subject should be withdrawn from the study due to an abnormal finding 
in the study foot. 
Details for each of the study foot examination parameters required during the study are provided 
in the sections below. 
8.4.1 
Dermatologic Examination 
The dermatologic examination will consist of a global inspection of the study foot and injection 
sites for injection site irritations, ulcerations, bleeding, discolorations, calluses, wounds, 
fissures, lesions, macerations, nail dystrophy, hyperpigmentation, erythema, oedema or 
paronychia. Inspection of the toes should include a search for fungal, ingrown or elongated 
nails, as well as areas between the toes for the presence of deeper lesions. The investigator will 
evaluate and record whether these or other dermatological conditions are present in the study 
foot and will record new findings as AEs that were not present at Baseline resulting from the 
dermatologic examination. 
8.4.2 
Neurologic Examination 
The neurological examination will consist of the evaluation of protective sensation using the 
Ipswich Touch Test [22], as subjects who develop neuropathies with loss of sensation at are 
increased risk for unrecognized injury. The subject will be instructed to close their eyes while 
the investigator lightly rests his/her finger on each of the subject’s first, third and fifth toes of 
the study foot for 1 to 2 seconds. Subjects will be instructed to respond “yes” when they feel 
the investigator’s touch. The investigator will evaluate and record whether the neurological 
condition of the study foot is “normal” or “abnormal” based on their medical judgment 
regarding the degree of loss of sensation in the study foot and will record new findings as AEs 
that were not present at Baseline resulting from the neurological examination. 
8.4.3 
Musculoskeletal Examination 
The musculoskeletal examination will include a visual inspection of the study foot, as well as 
direct evaluation via palpation, range of motion (ie, dorsiflexion, plantar flexion), motor 
strength and muscle tone to identify the presence of abnormalities or foot deformities (except 
for HAV). The investigator will specifically look for the presence of bony prominences, 
asymmetry, wasting, fasciculations or the presence of foot deformities (except for HAV) 
including but not limited to hammer toe, claw toe, Charcot’s neuroarthropathy, pes planus, 
cavus planus, Morton’s neuroma, or hallux limitus. The investigator will evaluate and record 
whether these or other musculoskeletal conditions of the study foot are present and will record 


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new findings as AEs that were not present at Baseline resulting from the musculoskeletal 
examination. 
8.5 
Vital Signs 
Blood pressure and heart rate will be assessed with an automated device so that measurements 
are independent of the observer. Blood pressure and heart rate will be recorded after five 
minutes’ rest in sitting position. Absolute values and change from Baseline will be analysed. 
Respiratory rate and temperature oral will be recorded. 
 


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


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10 
EXPLORATORY BIOMARKERS AND BIOBANKING 
No exploratory biomarkers or biobanking will be performed during this study. 


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11 
STATISTICS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a SAP, which will be dated and completed before the interim analysis. 
The SAP may modify the plans outlined in the protocol; however, any major modifications of 
the primary endpoint and/or its analysis will also be reflected in a protocol amendment. 
Statistical evaluation will be performed using Statistical Analysis System (SAS)® (version 9.1 
or higher) 
11.1 
Analyses Populations 
The following populations will be used during statistical analyses: 
• 
Screened population: All subjects screened (i.e. who signed the informed consent). 
• 
Safety population: All subjects who received at least one dose of IMP administration 
(including only partial administration). 
• 
Intention-to-treat (ITT) population: All randomised subjects (i.e. who were randomly 
allocated to a treatment group by IRT). 
• 
Per protocol (PP) population: All subjects in the ITT population for whom no major 
protocol deviations (which may interfere with efficacy evaluation) occurred until Week 8 
of the DB period. 
• 
Open-label (OL) population: All randomised subjects who received at least one dose 
of Dysport (including only partial administration) during the OL period. 
• 
Active Treatment population: All randomised subjects who received at least one dose 
of Dysport (including only partial administration) during the DB or OL period 
11.1.1 
Populations Analysed 
The primary analysis based on the primary efficacy endpoint will be performed on the ITT 
population. In addition, PP analysis will be performed as confirmatory. Secondary analyses 
based on secondary efficacy endpoints will be performed on the ITT population (for the DB 
period) and on the Active Treatment population (for analysis by active treatment cycle).  
The analyses of safety data will be performed based on the safety population. 
11.1.2 
Reasons for Exclusion from the Analyses 
Any major protocol deviation (see Section 13.1.2 for definition) will be described and its impact 
on inclusion in PP population for any subject will be specified. The final list of protocol 
deviations impacting the PP population will be reviewed prior to database lock, before any 
unblinding of treatment groups. The list may be updated, up to the point of database lock. 
11.2 
Sample Size Determination 
Several lines of evidence have established that a reduction of approximately 2 points or 10% to 
30% on the NPRS represents a clinically important difference for evaluations of pain intensity 
in numerous musculoskeletal disorders [23; 24; 25; 26; 27; 28], as well as specifically in HAV 
patients following treatment [13; 29]. Several interventional studies have demonstrated 
treatment-placebo differences in the NPRS ranging from 1.5 to 2.0 points in HAV patients [13; 
30]. Based on these findings, a difference of 1.5 points between Dysport and Placebo is 
anticipated in the change from baseline in the mean daily NPRS score averaged for the 
7 consecutive days prior to the Week 8 DB visit. 
A sample size of 165 subjects (55 subjects per treatment group) is required to demonstrate the 
superiority of each of the two Dysport doses (300 U and 500 U) over placebo. This calculation 
is based on the following assumptions: 


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• 
a mean difference of 1.5 points observed between the Dysport and placebo groups in the 
mean daily NPRS score averaged for the 7 consecutive days prior to the Week 8 visit in 
the DB period;  
• 
a common standard deviation of 2.5, 
• 
a treatment group ratio of 1:1:1, 
• 
a Hochberg procedure is implemented to control the family-wise Type 1 error rate at one-
sided 2.5% level for comparisons of two Dysport doses versus placebo, 
• 
a minimal power of 80%, corresponding for a comparison based on power using a Type I 
error rate from a one-sided test at 1.25% level. 
 
An interim analysis will be conducted after the first 110 randomised subjects have been 
followed up for at least 12 weeks. To account for this interim analysis, the overall type I error 
for each comparison is controlled at the one-sided 0.025 level using O’Brien Fleming spending 
per Lan-DeMets spending function specification. Treatment comparison with an O’Brien 
Fleming spending corresponds to a nominal one-sided alpha of 0.0062 at the interim and 0.0231 
at the final analysis. 
 
To implement the Hochberg procedure, decision rules are the following: 
• At interim look: 
Compare larger p-value to 0.0062 
• if <larger of 2 p-values> <0.0062 then stop and declare evidence of effect for 
each arm, 
• If not, compare <smaller of 2 p-values> to 0.0062/2. If <smaller of 2 p-values> 
<0.0062/2, then conclude evidence of effect for arm with the smallest p-value 
• At final look (if outcome of interim analysis is to continue): 
Compare larger p-value to 0.0231 
• if <larger of 2 p-values> <0.0231 then stop and declare evidence of effect for 
each arm 
• If not, compare <smaller of 2 p-values> to 0.0231/2. If <smaller of 2 p-values> 
<0.0231/2, then conclude evidence of effect for arm with the smallest p-value 
 
The non-binding futility boundary is set to declare futility if the one-sided p-value for a 
comparison is above 0.30.   
Considering the Hochberg adjustment for two experimental arms, this interim analysis plan 
results in a minimal power of at least 80 % to detect a treatment effect of 1.5 units in a Dysport 
arm.  
Details regarding operational aspects of the interim analysis are described in an Interim 
Analysis Charter. 
 
 


IPSEN GROUP 
D-FR-52120-237 
 
CONFIDENTIAL 
PROTOCOL: FINAL: 03 JULY 2019 
 
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11.3 
Significance Testing and Estimations 
The primary efficacy hypotheses are as follow: 
• 
H0: there is no difference between treatment with Dysport 300 U and Dysport 500 U 
versus treatment with Placebo with respect to the change from baseline in the mean daily 
NPRS score averaged for the 7 consecutive days prior the DB Week 8 visit. 
• 
H1: There is a difference between treatment with Dysport 300 U or Dysport 500 U and 
treatment with Placebo with respect to the change from baseline in the mean daily NPRS 
score averaged for the 7 consecutive days prior the DB Week 8 visit. 
For the primary efficacy analysis, a Hochberg procedure will be applied to control the global 
type I error at one-sided 2.5% significance level. 
For other efficacy analyses, all statistical tests will be performed one-sided with a type I error 
rate set at 2.5%. For safety analyses, no formal statistical analyses will be carried out; only 
descriptive statistics will be provided. 
11.4 
Statistical/Analytical Methods 
Statistical analyses will be performed by an external CRO, managed by the sponsor’s biometry 
department. 
11.4.1 
Demographic and Other Baseline Characteristics 
In order to assess balance of treatment groups, descriptive summary statistics (n, mean, standard 
deviation (SD), median, minimum, maximum) or frequency counts of demographic and 
baseline data (medical history, concomitant disease, etc.) will be presented by treatment group 
and overall. 
11.4.2 
Subject Disposition and Withdrawals 
The numbers and percentages of subjects enrolled and included in each analysis populations 
will be tabulated by centre. The reasons for subject exclusions from each of the populations 
will also be tabulated. In addition, the numbers of subjects who discontinued and completed at 
each of the study periods (DB and OL period) will be tabulated. Primary reasons for 
discontinuation of study treatment will be tabulated. 
11.4.3 
Efficacy Evaluation 
11.4.3.1 Analysis of the Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline in foot pain as measured by the daily 
NPRS score averaged over the 7 consecutive days prior to the Week 8 DB visit. Baseline is 
defined as the daily NPRS score averaged over the 7 consecutive days prior to the baseline visit. 
The NPRS score data collected over the 7 consecutive days prior to a visit will be retrieved 
using an electronic diary (see Section 7.1.1).  
The estimate of the treatment effect will be the difference in mean change from baseline in the 
daily NPRS score averaged over the 7 consecutive days prior to the Week 8 DB visit between 
each Dysport dose group and the placebo group.  
The primary 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. 
Potential intercurrent events are the following: 
(1) 
Use of prohibited pain medication, 
(2) 
Surgery for HAV. 
No treatment switch or interruption is possible as the primary efficacy endpoint is evaluated 
following a single injection of study treatment. Intercurrent event (1) is unlikely to occur, as 
the evaluation period for the primary efficacy endpoint is up to Week 8 (short period). 


IPSEN GROUP 
D-FR-52120-237 
 
CONFIDENTIAL 
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Intercurrent event (2) is also unlikely to occur. All subjects with this level of pain severity and 
angular displacement are considered surgical candidates theoretically. However, the upper limit 
on HV angle (30 degrees) will likely limit the need for a “rescue” surgery. 
Subjects are expected to continue follow-up assessments regardless of these two intercurrent 
events. NPRS scores will be used as observed.  
A mixed model for repeated measures (MMRM) on change from baseline in foot pain as 
measured by the daily NPRS score averaged over the 7 consecutive days prior to each scheduled 
assessment timepoint of the DB period (up to Week 12) will be used to evaluate the estimand 
and compare treatment groups.   
This model will include the fixed categorical effects of treatment group, visit, treatment-group-
by-visit interaction, the stratification parameter as fixed categorical covariates and the baseline 
value as fixed continuous covariate. The treatment group factor will have three levels (Dysport 
300 U, Dysport 500 U and placebo), the factor visit three levels (Week 4, Week 8 and Week 12) 
and the stratification parameter two levels (unilateral and bilateral HAV).  
Average scores will be calculated if there is at least 5-day e-diary completed. No missing 
baseline is expected as NPRS assessment is part of the inclusion criteria. Subjects will have 
reminders to complete the electronic diary, and site staff will be alerted if they miss a day. 
Therefore, the risk of having missing days is minimized. However, if subjects have no post-
baseline efficacy assessment, Week 8 score will be imputed (imputation method will be 
described in the SAP). Other missing data will be considered missing at random (MAR). 
Sensitivity analysis 
Two sensitivity analyses will be performed to investigate the robustness of the primary efficacy 
analysis. First, the primary efficacy analysis will be re-run imputing missing data as described 
in Table 6. 
Table 6 
Rules for Missing Data Associated with the NPRS 
Reason for missing data 
Imputation of the missing NPRS score 
More than 2 days missing in the 7-day NPRS e-diary 
assessment 
Multiple imputation based on subject with similar 
characteristics on the same treatment group. 
Subject withdrawal before Week 8 of the DB period due 
to lack of efficacy 
NPRS score imputed as the mean of placebo value at 
Week 8 
Subject withdrawal before Week 8 of the DB period due 
to other reason 
Multiple imputation based on subject with similar 
characteristics in the same treatment group 
Subjects not withdrawn before Week 8 of the DB period 
with a missing NPRS at Week 8 
Multiple imputation based on subject with similar 
characteristics within the same treatment group 
DB=double blind; e-diary=electronic diary; NPRS=numeric pain rating scale 
 
Then, a tipping point analysis will be performed (analysis will be detailed in the Statistical 
Analysis Plan).  
 
Supplementary analyses 
Supplementary analyses will be performed in order to complement the primary estimand. The 
primary efficacy analysis will be first re-run on the PP population. In addition, two other 
estimands will be considered: 
• 
Proportion of responders in the NPRS pain score at Week 8 DB. A responder is defined 
as a subject with at least a 20% decrease from baseline (30%, 40% and 50% cut-off will 
also be considered). 
• 
The mean change in the area under the curve of the daily NPRS score averaged over the 
7 consecutive days prior to each visit up to Week 8 of the DB period. 


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11.4.3.2 Analysis of Secondary Efficacy Endpoints 
Double-blind Period 
Table 7 summarises the secondary efficacy endpoints, their associated estimates and estimands 
during the DB period. 
Table 7 
Analysis of Secondary Efficacy Endpoints (Double-blind Period) 
Secondary Efficacy Endpoints 
Estimate of Treatment Effect 
Estimand 
The change from baseline in the daily 
NPRS score averaged over the 7 
consecutive days prior to Week 4 and 
Week 12 DB visits. 
Difference between each Dysport doses 
and the placebo group, in the mean 
change from baseline in the mean daily 
NPRS 
score 
averaged 
for 
the 
7 consecutive days prior to Week 4 and 
Week 12 DB visits. 
 
 
 
 
 
 
 
 
 
For each estimate, the 
associated 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 change from baseline in the daily 
mFFI disability subscale score averaged 
over the 7 consecutive days prior to Week 
4, Week 8 and Week 12 DB visits. 
Difference between each Dysport doses 
and the placebo group in the mean 
change from baseline in the mean daily 
mFFI disability subscale score averaged 
for the 7 consecutive days prior to Week 
4, Week 8 and Week 12 DB visits. 
The change from baseline in the daily 
mFFI pain subscale score averaged over 
the 7 consecutive days prior to Week 4, 
Week 8 and Week 12 DB visits. 
Difference between each Dysport dose 
and the placebo group in the mean 
change from baseline in the mean daily 
mFFI pain subscale score averaged for 
the 7 consecutive days prior to Week 4, 
Week 8 and Week 12 DB visits. 
The change from baseline in the daily 
mFFI total score averaged over the 7 
consecutive days prior to Week 4, Week 
8 and Week 12 DB visits. 
Difference between each Dysport doses 
and the placebo group in the mean 
change from baseline in the mean daily 
mFFI total score averaged for the 
7 consecutive days prior to Week 4, 
Week 8 and Week 12 DB visits. 
The change from baseline in the daily 
mFFI activity limitation subscale score 
averaged over the 7 consecutive days 
prior to Week 4, Week 8 and Week 12 
DB visits. 
 
Difference between each Dysport doses 
and the placebo group in the mean 
change from baseline in the mean daily 
mFFI activity limitation subscale score 
averaged for the 7 consecutive days 
prior to Week 4, Week 8 and Week 12 
DB visits. 
The change from baseline in the PGI-S 
pain and disability scores, respectively, 
averaged over the 7 consecutive days 
prior to Week 4, Week 8 and Week 12 
DB visits. 
Difference between each Dysport doses 
and the placebo group in the change 
from baseline in the mean daily PGI-S 
pain and disability scores, respectively, 
averaged for the 7 consecutive days 
prior to Week 4, Week 8 and Week 12 
DB visits. 
PGI-I 
pain 
and 
disability 
scores, 
respectively, at Week 4, Week 8 and 
Week 12 DB visits. 
Difference between each Dysport doses 
and the placebo group in the mean daily 
PGI-I pain and disability scores, 
respectively, 
averaged 
for 
the 
7 consecutive days prior to Week 4, 
Week 8 and Week 12 DB visits. 
The change from baseline in HV angle as 
measured directly by weight-bearing 
Difference between each Dysport doses 
and the placebo group in then mean 
change from baseline in HV angle at 


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PAGE 62/136 
 
Secondary Efficacy Endpoints 
Estimate of Treatment Effect 
Estimand 
anterior-posterior radiographs at Week 4, 
Week 8 and Week 12 DB visits. 
Week 4, Week 8 and Week 12 DB 
visits. 
The change from baseline in 
intermetatarsal angle as measured 
directly by weight-bearing anterior-
posterior radiographs at Week 4, Week 8 
and Week 12 DB visits. 
Difference between each Dysport doses 
and the placebo group in then mean 
change from baseline in intermetatarsal 
angle at Week 4, Week 8 and Week 12 
DB visits. 
The change from baseline in quality of 
life as measured by the SF-36 at Week 8 
and Week 12 DB visits. 
 
Difference between each Dysport doses 
group and the placebo group in the 
SF-36 scores to Week 8 and Week 12 
DB visits (analysis will be detailed in 
the statistical analysis plan) 
Time to retreatment 
Difference between each Dysport doses 
group and the placebo group in the 
median time to retreatment between the 
first and the second injection. 
DB=double blind; HV=hallux valgus; mFFI=modified foot function index; NPRS=numeric pain rating scale; 
PGI-I=patient global impression of improvement; PGI-S=patient global impression of severity; SF-36=36-item 
short form 
 
Subjects are expected to continue follow-up assessments regardless of the intercurrent events 
define above. Scores will be used as observed. No imputation of missing data will be done. 
According to the scale, an MMRM model or a mixed-linear-generalized model on change from 
baseline including each scheduled timepoint up to Week 12 will be used to evaluate the 
estimands and compare treatment groups.  Missing data will be considered as MAR. 
Only descriptive statistics will be used to present the estimands after Week 12 visit. 
Active Treatment Cycles 
Table 8 summarises the secondary efficacy endpoints, their associated estimates and estimands 
during the active treatment cycles. 
Table 8 
Analysis of Secondary Efficacy Endpoints (active treatment cycles) 
Secondary Efficacy Endpoints 
Estimate of Treatment Effect 
Estimand 
The change from baseline as measured by 
the daily NPRS score averaged over 
7 consecutive 
days 
prior 
to 
each 
scheduled assessment timepoint. 
The mean change from baseline in the 
mean daily NPRS score averaged for 
the 7 consecutive days prior to each 
scheduled assessment timepoint. 
 
 
 
 
 
 
 
 
 
For each estimate, the 
associated estimand will 
be based on "treatment 
policy" strategy, which 
is the estimate of the 
treatment 
effect 
The change from baseline in the daily 
mFFI Disability subscale score averaged 
over the 7 consecutive days prior each 
scheduled assessment timepoint. 
 
The mean change from baseline in the 
mean daily mFFI disability subscales 
score averaged for the 7 consecutive 
days prior to each scheduled assessment 
timepoint. 
The change from baseline in the daily 
mFFI Pain subscale score averaged over 
the 7 consecutive days prior to each 
scheduled assessment timepoint. 
 
The mean change from baseline in the 
mean daily mFFI pain subscale score 
averaged for the 7 consecutive days 
prior to each scheduled assessment 
timepoint. 
The change from baseline in the daily 
mFFI total score averaged over the 
The mean change from baseline in the 
mean daily mFFI total score averaged 


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11.7 
Primary Analyses 
A primary analysis will be conducted once all subjects have completed the Week 12 of the DB 
period. At this point, all subjects will have completed the Week 8 visit and had adequate safety 
follow-up. 
 


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


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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Protocol Amendments and Protocol Deviations 
13.1.1 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favourable opinion of a written amendment by the IEC/IRB, except when necessary 
to eliminate immediate safety concerns to the subjects or when the change involves only 
logistics or administration. The principal investigator and the sponsor will sign the protocol 
amendment. 
13.1.2 
Protocol Deviations and Exceptions 
All protocol deviations will be identified and recorded by the sponsor or sponsor’s 
representative. 
A major protocol deviation is any significant divergence from the protocol, i.e. nonadherence 
on the part of the subject, the investigator, or the sponsor to protocol specific 
inclusion/exclusion criteria, primary objective evaluation criteria, and/or GCP guidelines. 
Generally, a protocol deviation qualifies as major if: 
(1) 
The deviation has harmed or posed a significant or substantive risk of harm to the 
research subject 
(2) 
The deviation compromises the scientific integrity of the data collected for the study 
(3) 
The deviation is a wilful or knowing breach of human subject protection regulations, 
policies, or procedures on the part of the investigator(s) 
(4) 
The deviation involves a serious or continuing noncompliance with any applicable 
human subject protection regulations, policies, or procedures 
(5) 
The deviation is inconsistent with Ipsen’s research, medical, and ethical principles. 
See also Section 11.1.2 for details on the impact of major protocol deviations on the inclusion 
of subjects in each analysis population. 
A minor protocol deviation is any significant divergence from the protocol that does not impact 
the study results. 
As a matter of policy, the sponsor will not grant exceptions to protocol specific entry criteria to 
allow subjects to enter a study. If under extraordinary circumstances such action is considered 
ethically, medically, and scientifically justified for a particular subject, prior approval from the 
sponsor and the responsible IRB/IEC, in accordance with the Standard Operating Procedure 
(SOP), is required before the subject will be allowed to enter the study. If investigative centre 
personnel learn that a subject who did not meet protocol eligibility criteria was entered in a 
study (a protocol violation), they must immediately inform the sponsor. Such subjects will be 
discontinued from the study, except in an exceptional instance following review and written 
approval by the sponsor and the responsible IRB/IEC, according to the applicable SOP. 
13.2 
Information to Study Personnel 
To ensure accurate, complete and reliable data, the sponsor or its representatives will provide 
instructional material to the study sites, as appropriate. A study initiation visit will be conducted 
prior to screening start to instruct the investigators and study coordinators. This session will 
give instruction on the protocol, the completion of the eCRF and all study procedures. The 
investigator is responsible for giving information about the study to all staff members involved 
in the study or in any element of subject management, both before starting any study procedures 
and during the course of the study (e.g. when new staff become involved). The investigator 
must assure that all study staff members are qualified by education, experience, and training to 
perform their specific responsibilities. These study staff members must be listed on the study 


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centre authorisation form, which includes a clear description of each staff member’s 
responsibilities. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including the 
investigator, and for ensuring their compliance with the protocol. Additional information will 
be made available during the study when new staff become involved in the study and as 
otherwise agreed upon with either the investigator or the study monitor. 
13.3 
Study Monitoring 
The investigator is responsible for the validity of all data collected at the site. 
The sponsor is responsible for monitoring these data to verify that the rights and wellbeing of 
subjects are protected, that study data are accurate (complete and verifiable to source data) and 
that the study is conducted in compliance with the protocol, GCP and regulatory requirements. 
Sponsor assigned monitors will conduct regular site visits. The investigator will allow direct 
access to all relevant files (for all subjects) and clinical study supplies (dispensing and storage 
areas) for the purpose of verifying entries made in the eCRF, and assist with the monitor’s 
activities, if requested. Adequate time and space for monitoring visits should be made available 
by the investigator. 
The site must complete the eCRFs on an ongoing basis to allow regular review by the study 
monitor, both remotely by the internet and during site visits. The CRO study monitor will use 
functions of the electronic data capture 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 initials 
visible, and annotated with the subject number as identification. 
13.4 
Investigator’s Regulatory Obligations 
All clinical work under this protocol will be conducted according to GCP rules. This includes 
that the study may be audited at any time by a quality assurance personnel designated by the 
sponsor, or by regulatory bodies. The investigator must adhere to the GCP principles in addition 
to any applicable local regulations. 
If requested, the investigator will provide the sponsor, applicable regulatory agencies, and 
applicable 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. 
13.5 
Audit and Inspection 
Authorised personnel from external CAs and the sponsor’s authorised Quality Assurance 
personnel may carry out inspections and audits (see Section 12). 
13.6 
Data Quality Assurance 
Monitored eCRFs shared between the investigational site and Data Management CRO will be 
reviewed (Data Review) for completeness, consistency, legibility and protocol compliance. 
Reasons should be given on the relevant eCRF for any missing data and other protocol 
deviations. Any electronic queries and items not adequately explained will require additional 
electronic manual queries to be raised to the investigator by the monitor for 
clarification/correction. The investigator must ensure that queries are dealt with promptly. All 
data changes and clarifications can be viewed in the audit trail function of the eCRF. 


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14 
ETHICS 
14.1 
Compliance with Good Clinical Practice and Ethical Considerations 
This study will be conducted in compliance with IECs/IRBs, informed consent regulations, the 
Declaration of Helsinki and ICH GCP Guidelines (Section 1.7). 
In addition, this study will adhere to all local regulatory requirements.  
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject emergency study contact cards, 
subject recruitment procedures (e.g. advertisements), any written information to be provided to 
subjects and a statement from the IEC/IRB that they comply with GCP requirements. The 
IEC/IRB approval must identify the protocol version as well as the documents reviewed. 
After IEC/IRB approval, changes will require a formal amendment. Once the study has started, 
amendments should be made only in exceptional circumstances. Changes that do not affect 
subject safety or data integrity are classified as administrative changes and generally do not 
require ethical approval. If ethically relevant aspects are concerned, the IEC/IRB must be 
informed and, if necessary, approval sought prior to implementation. Ethical approval on 
administrative changes will be obtained if required by local/site IEC/IRB. 
14.2 
Informed Consent for Participation in the Study 
Prior to study entry, the investigator, or a person designated by the investigator, will explain 
the nature, purpose, benefits and risks of participation in the study to each subject, subject’s 
legally acceptable representative or impartial witness. Written informed consent must be 
obtained prior to the subject entering the study (before initiation of any study-related procedure 
and administration of the IMP). Sufficient time will be allowed to discuss any questions raised 
by the subject. 
The sponsor will provide a sample informed consent form. The final version-controlled form 
must be agreed to by the sponsor, and the IEC/IRB and must contain all elements included in 
the sample form, in language readily understood by the subject. Each subject’s original consent 
form, personally signed and dated by the subject or by the subject’s legally acceptable 
representative, and by the person who conducted the informed consent discussion, will be 
retained by the investigator. The investigator will supply subjects with a copy of their signed 
informed consent. 
The consent form may need to be revised during the study should important new information 
become available that may be relevant to the safety of the subject or as a result of protocol 
amendments. In this instance approval should always be given by the IEC/IRB. It is the 
investigator’s responsibility to ensure that all subjects subsequently entered into the study and 
those currently in the study sign the amended form. This is documented in the same way as 
previously described. Subjects who have completed the study should be informed of any new 
information that may impact on their welfare/wellbeing. 
The investigator should, with the consent of the subject, inform the subject’s primary physician 
about their participation in the clinical study. 
14.3 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards 
As required by local regulations, the sponsor’s Regulatory Affairs group will ensure all legal 
regulatory aspects are covered, and obtain approval of the appropriate regulatory bodies, prior 
to study initiation in regions where an approval is required. 


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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. 
14.4 
Confidentiality Regarding Study Subjects 
The investigator must assure that the privacy of the subjects, including their personal identity 
and all personal medical information, will be maintained at all times. In CRFs and other 
documents or image material submitted to the sponsor, subjects will be identified not by their 
names, but by an identification code (e.g. initials and identification number). 
Personal medical information may be reviewed for the purpose of verifying data recorded on 
the eCRF. This review may be conducted by the study monitor, properly authorised persons on 
behalf of the sponsor, the quality assurance unit, or regulatory authorities. Personal medical 
information will always be treated as confidential. 


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


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For screen failure subjects, at least the Unique Subject Identifier, the date of informed consent 
signature and the potential AEs which occurred during the screening phase will be reported in 
the eCRFs and collected in the sponsor’s database. 
15.3 
Record Archiving and Retention 
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 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications 
in an ICH region (that is at least 15 years) or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the product. However, these documents should be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. The investigator should take measures to prevent accidental or 
premature destruction of these documents. The final archiving arrangements will be confirmed by 
the monitor when closing out the site. The sponsor will inform the investigator, in writing, as to 
when these documents no longer need to be retained. 
If the principal investigator relocates or retires, or otherwise withdraws his/her responsibility 
for maintenance and retention of study documents, the sponsor must be notified (preferably in 
writing) so that adequate provision can be made for their future maintenance and retention. 


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


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


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18 
REFERENCES 
1. 
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Coughlin MJ, Jones CP. Hallux Valgus: demographics, etiology, and radiographic 
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Pinsker E, Daniels TR. AOFAS position statement regarding the future of the AOFAS 
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4. 
Ferrari J, Higgins JPT, Prior TD. Interventions for treating hallux valgus (abductovalgus) 
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5. 
Schuh R, Hofstaetter SG, Adams SB et al. Rehabilitation after hallux valgus surgery: 
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Perera AM, Mason L, Stephens MM. The pathogenesis of hallux valgus, J Bone Joint 
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7. 
Arinci IN, Genc H, Erdem HR et al. Muscle imbalance in hallux valgus: an 
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8. 
Radovic, PA, Shah E. Nonsurgical treatment for hallux abducto valgus with botulinum 
toxin A. J Am Pod Med Assoc. 2008;98:61-5. 
9. 
Haines RW, McDougall A. The anatomy of hallux valgus. J Bone Joint Surg Br. 1954;36 
B(2):272-93. 
10. 
Wu KPH, Chen CK, Lin SC et al. Botulinum toxin type A injections for patients with 
painful hallux valgus: a double-blind, randomized controlled study. Clin Neurol and 
Neurosurg. 2015;129 S1:S58-S62. 
11. 
Babcock MS, Foster L, Pasquina P et al. Treatment of pain attributed to plantar fasciitis 
with botulinum toxin a: a short-term, randomized, placebo-controlled, double-blind 
study. Am J Phys Med Rehabil. 2005;84:649-54. 
12. 
Schrier JC, Palmen LN, Verheyen CC et al. Patient-reported outcome measures in hallux 
valgus surgery. A review of literature. Foot Ankle Surg. 2015;21(1):11-5. 
13. 
Riff DS, Duckor S, Gottlieb I et al. Diclofenac potassium liquid-filled soft gelatin 
capsules in the management of patients with postbunionectomy pain: a phase III, 
multicentre, randomized, double-blind, placebo-controlled study conducted over 5 days. 
Clin Ther. 2009;31(10):2072-85. 
14. 
Daniels SE, Baum DR, Francis C et al. Diclofenac potassium liquid-filled soft gelatin 
capsules for the treatment of postbunionectomy pain. Curr Med Res Opin. 
2010;26(10):2375-84. 
15. 
Golf M, Daniels SE, Onel E. A phase 3, randomized, placebo-controlled trial of 
DepoFoam® 
bupivacaine 
(extended-release 
bupivacaine 
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bunionectomy. Adv Ther. 2011;28(9):776-88. 
16. 
Shimazaki K, Takebe K. Investigations on the origin of hallux valgus by 
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17. 
Saltzman CL, Aper RL, Brown TD. Anatomic determinants of first metatarsophalangeal 
flexion movements in hallux valgus. Clin Orthop Rel Res. 1997;339:261-69. 
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Hoffmeyer P, Cox JN, Blanc Y et al. Muscle in hallux valgus. Clin Orthop Relat Res. 
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Budiman-Mak E, Conrad KJ, Roach KE. The foot function index: a measure of foot pain 
and disability. J Clin Epidemlol. 1991;44(6):561-70. 


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20. 
Budiman-Mak E, Conrad KJ, Stuch R et al. Theoretical model and rasch analysis to 
develop a revised foot function index. Foot Ankle Int. 2006;27(7):519-27. 
21. 
Budiman-Mak E, Conrad KJ, Mazza J et al. A review of the foot function index and the 
foot function index – revised. J Foot Ankle Res. 2013;6(1):5. 
22. 
Raymond G, Prashanth R, Baker N et al. The Ipswich Touch Test: a simple and novel 
method to identify in patients with diabetes at risk of foot ulceration. Diabetes Care. 
2011;34(7):1517-8. 
23. 
Dworkin RH, Turk DC, Wyrwich KW et al. Interpreting the clinical importance of 
treatment outcomes in chronic pain trials: IMMPACT recommendations. Pain. 
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24. 
Farrar JT, Young JP, LaMoreaux L et al. Clinical importance of changes in chronic pain 
intensity measured on an 11-point numerical pain rating scale. Pain. 2001;94(2):149-58. 
25. 
Hanley MA, Jensen MP, Ehde DM et al. Clinically significant change in pain intensity 
ratings in persons with spinal cord injury or amputation. Clin J Pain. 2006;22(1):25-31. 
26. 
Kendrick DB, Stout TD. The minimum clinically significant difference in 
patient-assigned numeric scores for pain. Am J Emerg Med. 2005;23(7):828-32. 
27. 
Salaffi F, Stancati A, Silvestri CA et al. Minimal clinically important changes in chronic 
musculoskeletal pain intensity measured on a numerical rating scale. Eur J Pain. 
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28. 
Childs JD, Piva SR, Fritz JM. Responsiveness of the numeric pain rating scale in patients 
with low back pain. Spine (Phila Pa 1976). 2005;30(11):1331-4. 
29. 
van der Swaard BC, van der Horst HE, Knol DL et al. Treatment of forefoot problems in 
older people: a randomized clinical trial comparing podiatric treatment with standardized 
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30. 
Halstead J, Chapman GJ, Gray JC et al. Foot orthoses in the treatment of symptomatic 
midfoot osteoarthritis using clinical and biochemical outcomes: a randomised feasibility 
study. Clin Rheum. 2016;35(4):987-96. 


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19 
LIST OF APPENDICES 
Appendix 1 Modified Foot Function Index ..........................................................78 
Appendix 2 : Protocol Amendment Forms ...........................................................80 
 


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Appendix 1 Modified Foot Function Index 


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Appendix 2 : Protocol Amendment Forms 


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STUDY NUMBER: 
D-FR-52120-237 
PROTOCOL TITLE: 
A MULTIPLE-DOSE, DOUBLE-BLIND, RANDOMISED, PLACEBO-CONTROLLED STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF DYSPORT FOR THE TREATMENT OF PAIN 
ASSOCIATED WITH HALLUX ABDUCTO VALGUS 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Protocol Version 5.0 (Amendment 4) 
15 February 2019 
THE FOLLOWING AMENDMENTS ARE PROPOSED: 
Version Date 
15 FEBRUARY 2019 
03 JULY 2019 
Page  
Section 
WAS 
IS 
10 & 
64/65 
Synopsis: 
sample size 
calculation 
Sections 
11.6 
 
An interim analysis will be conducted after the first 110 
randomized subjects have been followed up for at least 12 
weeks. The aim of this interim analysis is to both assess futility 
and the potential for early stopping due to efficacy for each 
Dysport group as compared to the Placebo group. A decision to 
continue with an arm will be determined by an independent 
Data Monitoring Committee (DMC) based on the outcome of 
the interim analysis. No interruption to recruitment will occur 
whilst the decision-making process is ongoing. 
A primary analysis will be conducted once all subjects have 
completed the Week 12 of the DB period. At this point, all 
subjects will have completed the Week 8 visit and had 
adequate safety follow-up. 
38 
Table 4 
Study 
Procedures 
and 
Assessment
s: Open-
label Period 
 
 


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39 
 
 
 
 
39 
Table 4 
Footnotes 
h 
Radiographic assessments should be performed using a 
standard foot positioner. 
 
 
57 
Section 11 
Statistics 
Detailed methodology for summary and statistical 
analyses of the data collected in this study will be 
documented in a SAP, which will be dated and completed 
before the unblinding for the primary analysis at the latest. 
The SAP may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint 
and/or its analysis will also be reflected in a protocol 
amendment. 
Detailed methodology for summary and statistical analyses of the 
data collected in this study will be documented in a SAP, which will 
be dated and completed before the interim analysis. The SAP may 
modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint and/or its analysis will also 
be reflected in a protocol amendment. 
 


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58 
Section 
11.2 
Sample size 
Determinati
on 
• 
a Hochberg procedure to apply to control the family-
wise Type 1 error rate at 5% as comparing two 
Dysport doses versus placebo, 
• 
a type I error rate two-sided test of 2.5%, 
corresponding to the second step of the Hochberg 
procedure, 
• 
a power of 80% 
• 
a Hochberg procedure is implemented to control the family-
wise Type 1 error rate at one-sided 2.5% level for 
comparisons of two Dysport doses versus placebo, 
• 
a minimal power of 80%, corresponding for a comparison 
based on power using a Type I error rate from a one-
sided test at 1.25% level. 
 
An interim analysis will be conducted after the first 110 
randomized subjects have been followed up for at least 12 
weeks. To account for this interim analysis, the overall type I 
error for each comparison is controlled at the one-sided 0.025 
level using O’Brien Fleming spending per Lan-DeMets 
spending function specification. Treatment comparison with an 
O’Brien Fleming spending corresponds to a nominal one-sided 
alpha of 0.0062 at the interim and 0.0231 at the final analysis. 
 
To implement the Hochberg procedure, decision rules are the 
following: 
• 
At interim look: 
Compare larger p-value to 0.0062 
• 
if <larger of 2 p-values> <0.0062 then stop and 
declare evidence of effect for each arm, 
• 
If not, compare <smaller of 2 p-values> to 
0.0062/2. If <smaller of 2 p-values> <0.0062/2, 
then conclude evidence of effect for arm with 
the smallest p-value 
• 
At final look (if outcome of IA is to continue): 
Compare larger p-value to 0.0231 
• 
if <larger of 2 p-values> <0.0231 then stop and 
declare evidence of effect for each arm 
• 
If not, compare <smaller of 2 p-values> to 
0.0231/2. If <smaller of 2 p-values> <0.0231/2, 


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then conclude evidence of effect for arm with 
the smallest p-value 
 
The non-binding futility boundary is set to declare futility if the 
one-sided p-value for a comparison is above 0.30. 
Considering the Hochberg adjustment for two experimental 
arms, this interim analysis plan results in a minimal power of 
at least 80 % to detect a treatment effect of 1.5 units in a 
Dysport arm.  
Details regarding operational aspects of the interim analysis 
are described in the Interim Analysis Charter. 
59 
Section 
11.3 
Significanc
e Testing 
and 
Estimations 
For the primary efficacy analysis, a Hochberg 
procedure will be applied to control the global type I 
error at 5% significance level. 
For other efficacy analyses, all statistical tests will be 
performed two sided with a type I error rate set at 5%. 
For safety analyses, no formal statistical analyses will 
be carried out; only descriptive statistics will be 
provided. 
 
For the primary efficacy analysis, a Hochberg procedure will 
be applied to control the global type I error at one-sided 2.5% 
significance level. 
For other efficacy analyses, all statistical tests will be 
performed one-sided with a type I error rate set at 2.5%. For 
safety analyses, no formal statistical analyses will be carried 
out; only descriptive statistics will be provided. 
 
 
Section 
11.6 
Interim 
Analyses 
 
An interim analysis will be conducted after the first 110 
randomised subjects have been followed up for at least 12 
weeks. The aim of this interim analysis is to both assess 
futility and the potential for early stopping due to efficacy of 
one of the Dysport group as compared to the Placebo group. 
A decision to continue with the study will be determined by 
an independent DMC based on the outcome of the interim 
analysis. No interruption to recruitment will occur whilst the 
decision-making process is ongoing. 
 


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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
D-FR-52120-237 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Protocol Version 5.0 (Amendment 4) 
15 February 2019 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON(S) FOR CHANGES 
 
Implementation of an interim analysis plan 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
STATISTICAL ANALYSIS PLAN (SAP) UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 


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STUDY NUMBER: 
D-FR-52120-237 
PROTOCOL TITLE: 
A MULTIPLE-DOSE, DOUBLE-BLIND, RANDOMISED, PLACEBO-CONTROLLED 
STUDY TO EVALUATE THE EFFICACY AND SAFETY OF DYSPORT FOR THE 
TREATMENT OF PAIN ASSOCIATED WITH HALLUX ABDUCTO VALGUS 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Protocol Version 4.0 (Amendment 3) 
07 September 2018 
 
 
THE FOLLOWING AMENDMENTS ARE PROPOSED: (deleted text is indicated with strikethrough; new text is indicated in bold) 
Version Date 
07 SEPTEMBER 2018 
15 FEBRUARY 2019 
Page  
Section 
WAS 
IS 
1 
n/a 
FINAL Version 4.0: 7 September 2018 (Amendment 3) 
FINAL Version 5.0: 15 February 2019 (Amendment 4) 
3 
Table 1 
 
 
 
 
4 
15 February 2019 
Appendix 2 
 
5 & 30 
Synopsis 
& 4.1 
Inclusion 
Criteria 
(3) 
Clinical diagnosis of HAV as determined by the 
investigator based on evidence of lateral deviation of 
either great toe (left or right), as well as assessment of 
NPRS scores for each foot 
Clinical diagnosis of HAV as determined by the investigator 
based on evidence of lateral deviation of either great toe (left 
or right), as well as assessment of NPRS scores for each foot 
(in bilateral subjects). 
6 & 30 
Synopsis 
& 4.1 
Inclusion 
Criteria 
(7) 
Subjects must present with hallux valgus (HV) angle 
between ≥ 15° and <30° in the study foot great toe using 
radiographic measurements based on guidelines set 
forth by the AOFAS ad hoc Committee on Angular 
Measurements at Screening only 
 
Subjects must present with hallux valgus (HV) angle ≤ 30° in 
the study foot great toe using radiographic measurements 
based on guidelines set forth by the AOFAS ad hoc 
Committee on Angular Measurements at Screening only 
 


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Version Date 
07 SEPTEMBER 2018 
15 FEBRUARY 2019 
Page  
Section 
WAS 
IS 
6 & 30 
Synopsis 
& 4.1 
Inclusion 
Criteria 
(8) 
Subjects must present with an intermetatarsal angle of 
9° to 18°, inclusive in the study foot great toe using 
radiographic measurements based on guidelines set 
forth by the American Orthopedic Foot and Ankle 
Society ad hoc Committee on Angular Measurements at 
Screening only 
 
Subjects must present with an intermetatarsal angle of ≤ 18°, 
inclusive in the study foot great toe using radiographic 
measurements based on guidelines set forth by the American 
Orthopedic Foot and Ankle Society ad hoc Committee on 
Angular Measurements at Screening only 
 
6 & 32 
Synopsis 
& 4.2.1 
Exclusion 
Criteria 
(1) 
Subject has an HV angle of <15° or ≥30° in the study 
foot 
 
Subject has an HV angle of >30° in the study foot 
 
7 & 31 
Synopsis 
& 4.2 
Exclusion 
Criteria 
(13) 
 
Subject is using an orthotic device of any kind 
(including over-the-counter toespacers) which could 
influence the functioning of the hallux of the study 
foot in any way, or any other device intended for this 
purpose. 
Subject is using an orthotic device (including over-the-
counter toespacers) which could influence the functioning of 
the hallux of the study foot in any way, or any other device 
intended for this purpose. 
8 & 32 
Synopsis 
& 4.2.28 
Exclusion 
Criteria 
(28) 
History of chronic drug or alcohol abuse. 
Evidence of clinically significant chronic drug or alcohol 
abuse within the last year. 
25 
3.1.2.1 
Retreat
ment 
Criteria 
• 
Subject's foot pain is clinically significant as 
evidenced by an NPRS score ≥3 for the 24-hour 
period immediately prior to the retreatment visit.  
 
• 
Subject's foot pain is clinically significant as evidenced 
by an NPRS score ≥3 within 24-48 hours immediately 
prior to the retreatment visit.  
 


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Version Date 
07 SEPTEMBER 2018 
15 FEBRUARY 2019 
Page  
Section 
WAS 
IS 
36 
Table 3 
Footnote
s 
h 
Radiographic assessments should be performed 
using a standard foot positioner.  
* note footnotes reordered due to deletion 
 
 
43 
6.4 
Lifestyle 
Restrictio
ns/Recom
mendatio
ns 
Besides restrictions already presented in the exclusion 
criteria, subjects should not use an orthotic device or 
'over-the-counter shoe-insert' of any kind which could 
influence the functioning of the hallux of the study foot 
in any way during the study 
Besides restrictions already presented in the exclusion 
criteria, subjects should not use an orthotic device or 'over-
the-counter shoe-insert' which could influence the functioning 
of the hallux of the study foot in any way during the study 
44 
7.1 
Methods 
and 
Timing of 
Assessing, 
Recording
, and 
Analysing 
Efficacy 
Data 
For all assessments related to pain, the subject is to be 
instructed by the investigator to report severity 
specifically for his/her study foot when completing the 
questionnaires. Also, it is critical that investigators and 
site staff instruct and remind subjects to complete 
home-based self-assessments (eg, NPRS, mFFI) in the 
evening. 
For all assessments related to pain, the subject is to be 
instructed by the investigator to report severity specifically for 
his/her study foot when completing the questionnaires using 
the e-diary. The Sponsor will provide a device (to complete 
the e-diary questionnaires) in the clinical trial if requested 
by subjects or in situations in which the subject is not 
willing or able to use their own device. The device will be 
returned to the site at the completion of the subjects' 
participation in the trial. 
Also, it is critical that investigators and site staff instruct and 
remind subjects to complete home-based self-assessments 
(eg, NPRS, mFFI) in the evening. 


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Version Date 
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15 FEBRUARY 2019 
Page  
Section 
WAS 
IS 
46 
7.1.5 
Patient 
Global 
Impressio
n of 
Improve
ment of 
Foot Pain 
The PGI-I will be assessed by the subject answering the 
following question: “Compared to your foot pain prior 
to the study treatment initiation, your foot pain while 
performing physical activities (e.g. standing, walking or 
running) now is: +3=very much improved; +2=much 
improved; +1=minimally improved; 0=no change; -
1=minimally worse; -2=much worse; -3=very much 
worse”). 
 
The PGI-I will be assessed by the subject answering the 
following question: “Compared to your foot pain prior to the 
study treatment initiation, your foot pain while performing 
physical activities (e.g. standing, walking or running) now is: 
+3=very much improved; +2=much improved; +1=minimally 
improved; 0=no change; -1=minimally worse; -2=much 
worse; -3=very much worse”). Also, an additional question 
will be included in the PGI-I assessment which will ask 
patients the following: "If you experienced a change, was 
this change meaningful to you? (Yes/No)" 
 
46 
7.1.7 
Patient 
Global 
Impressio
n of 
Improve
ment of 
Disability 
The PGI-I will be assessed by the subject answering the 
following question: “Compared to your disability prior 
to the study treatment initiation, your disability while 
performing physical activities (e.g. standing, walking or 
running) now is: +3=very much improved; +2=much 
improved; +1=minimally improved; 0=no change from 
baseline; -1=minimally worse; -2=much worse; -3=very 
much worse”). 
The PGI-I will be assessed by the subject answering the 
following question: “Compared to your disability prior to the 
study treatment initiation, your disability while performing 
physical activities (e.g. standing, walking or running) now is: 
+3=very much improved; +2=much improved; +1=minimally 
improved; 0=no change from baseline; -1=minimally worse; 
-2=much worse; -3=very much worse”). In addition, an 
additional question will be included in the PGI-I 
assessment which will ask patients the following: "If you 
experienced a change, was this change meaningful to you? 
(Yes/No)" 
 
 
 


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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
D-FR-52120-237 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Protocol Version 4.0 (Amendment 3) 
07 September 2018 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON FOR CHANGES 
 
Additional questions are being included and an e-diary device will be now available to the subject upon request. The 
minimum HV and IM angle criteria have also been further amended.” 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
EPRO UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
REPORTING & ANALYSIS PLAN (RAP) UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 


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STUDY NUMBER: 
D-FR-52120-237 
PROTOCOL TITLE: 
A MULTIPLE-DOSE, DOUBLE-BLIND, RANDOMISED, PLACEBO-CONTROLLED STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF DYSPORT FOR THE TREATMENT OF PAIN 
ASSOCIATED WITH HALLUX ABDUCTO VALGUS 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Protocol Version 4.0 (Amendment 3) 
7 September 2018 
 
 
THE FOLLOWING AMENDMENT(S) IS/ARE PROPOSED: (DELETED TEXT IS INDICATED WITH STRIKETHROUGH; NEW TEXT IS INDICATED IN BOLD) 
Version Date 
25 MAY 2018 
7 SEPTEMBER 2018 
Pag
e  
Section 
WAS 
IS 
4 & 
22 
Synopsis 
Objectives 
And 
2.2.2 
Secondary 
Objectives 
• 
To evaluate the clinical safety and efficacy of Dysport 
following repeated treatment cycles in adult subjects with HAV. 
• 
To evaluate the clinical safety and efficacy of Dysport 
following repeated treatment cycles. 
5 & 
24 
3.1.1 
Double-
blind 
Period 
(Cycle 1): 
For subjects presenting with bilateral HAV at Screening, the 
investigator will determine which foot is of greater severity 
based on the clinical judgment of the investigator following 
clinical evaluation of the degree of pain (including assessment of 
the NPRS scores for each foot during Screening), degree of 
disability and angular deviation of the hallux, and meeting all 
other study entry criteria. In these subjects, the foot with the 
greatest severity of HAV, based on clinical evaluation by the 
investigator (and meeting all other study entry criteria), will be 
selected for treatment with DB study treatment in this study. 
For subjects presenting with bilateral HAV at Screening, the 
investigator will determine which foot is of greater severity 
based on the clinical judgment of the investigator following 
clinical evaluation of the degree of pain (including assessment of 
the NPRS scores for each foot during Screening), degree of 
disability and angular deviation of the hallux, and meeting all 
other study entry criteria. In these subjects, the foot with the 
greatest severity of HAV will be selected for treatment with DB 
study treatment in this study. 


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Version Date 
25 MAY 2018 
7 SEPTEMBER 2018 
Pag
e  
Section 
WAS 
IS 
6 & 
31 
Synopsis 
& 
Section 
4.1 
Inclusion 
Criteria 
(8) 
Subjects must present with an intermetatarsal angle of 
12° to 18°, inclusive in the study foot great toe using 
radiographic measurements based on guidelines set forth by the 
American Orthopedic Foot and Ankle Society ad hoc Committee 
on Angular Measurements at Screening only 
(8) 
Subjects must present with an intermetatarsal angle of 9° 
to 18°, inclusive in the study foot great toe using radiographic 
measurements based on guidelines set forth by the American 
Orthopedic Foot and Ankle Society ad hoc Committee on 
Angular Measurements at Screening only 
9 
Synopsis 
 
Secondary 
Efficacy 
Evaluatio
ns and 
Endpoints 
• 
Patient Global Impression of Improvement of foot pain 
score averaged over the 7 consecutive days prior to Week 4, 
Week 8 and Week 12 DB visits and at each scheduled visit in the 
OL period 
• 
Patient Global Impression of Improvement in disability 
score averaged over the 7 consecutive days prior to Week 4, 
Week 8 and Week 12 DB visits and at each scheduled visit in the 
OL period. 
• 
The change from baseline in the Patient Global 
Impression of Severity of foot pain score averaged over the 7 
consecutive days prior to Week 4, Week 8 and Week 12 DB 
visits and each scheduled visit in the OL period. 
• 
The change from baseline in the Patient Global 
Impression of Severity disability score averaged over the 7 
consecutive days prior to Week 4, Week 8 and Week 12 DB 
visits and at each scheduled visit in the OL period. 
• 
Patient Global Impression of Improvement of foot pain 
score at the Week 4, Week 8 and Week 12 DB visits and at each 
scheduled visit in the OL period 
• 
Patient Global Impression of Improvement in disability 
score at the Week 4, Week 8 and Week 12 DB visits and at each 
scheduled visit in the OL period. 
• 
The change from baseline in the Patient Global 
Impression of Severity of foot pain score to Week 4, Week 8 and 
Week 12 DB visits at each scheduled visit in the OL period. 
• 
The change from baseline in the Patient Global 
Impression of Severity disability score to Week 4, Week 8 and 
Week 12 DB visits and at each scheduled visit in the OL period. 
16 
Abbrev 
iations 
mITT: modified Intention-to-treat 
ITT: Intention-to-treat 


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Pag
e  
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WAS 
IS 
22 
2.2.2 
Secondary 
Objectives 
The secondary objectives of the study are:  
• 
To assess functional improvement Dysport (300 U and 
500 U) as compared with placebo using the mFFI disability 
subscale. 
 
The secondary objectives of the study are:  
• 
To assess functional improvement in Dysport (300 U 
and 500 U) as compared with placebo using the mFFI disability 
subscale. 
23 
3.1 
Figure 2 
Study 
Design 
footnote 
Subjects who meet the protocol-defined retreatment criteria will 
be administered injections of Dysport 300 U (Cycle 2) in open-
label fashion. Subsequent treatment with Dysport (Cycle 3) will 
also be based on subjects’ meeting the retreatment criteria and 
will occur at least 12 weeks after receiving the prior injection of 
Dysport.  
Subjects who meet the protocol-defined retreatment criteria will 
be administered injections of Dysport 300 U (Cycle 2) in an 
open-label fashion. Subsequent treatment with Dysport (Cycle 3) 
will also be based on subjects’ meeting the retreatment criteria 
and will occur at least 12 weeks after receiving the prior 
injection of Dysport.  
24 
3.1.1 
Double-
blind 
Period 
(Cycle 1): 
In these subjects, the foot with the greatest severity of HAV, 
based on clinical evaluation by the investigator (and meeting all 
other study entry criteria), will be selected for treatment with DB 
study treatment in this study. 
In these subjects, the foot with the greatest severity of HAV will 
be selected for treatment with DB study treatment in this study. 
24 
3.1.2 
Open-
label 
Period 
(Cycles 2 
to 3): 
Following completion of all protocol-specified procedures for 
the DB period (i.e. completion of Cycle 1), subjects who meet 
retreatment criteria (see Section 3.1.2.1) will be treated with 
Dysport (300 U) in the HAV study foot determined in the DB 
period during the OL period.  
Following completion of all protocol-specified procedures for 
the DB period (i.e. completion of Cycle 1), subjects who meet 
retreatment criteria (see Section 3.1.2.1) will be treated with 
Dysport (300 U) in the HAV study foot determined in the DB 
period.. 
24 
3.1.2 
Open-
label 
Period 
(Cycles 2 
to 3 
At the second retreatment cycles (Cycle 3), subjects will be 
treated with either Dysport 300 U or 500 U in the HAV study 
foot based on investigator judgment following clinical 
evaluation of the subject at the time of retreatment. 
At the second retreatment cycle (Cycle 3), subjects will be 
treated in the HAV study foot with either Dysport 300 U or 500 
U based on investigator judgment following clinical evaluation 
of the subject at the time of retreatment. 


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7 SEPTEMBER 2018 
Pag
e  
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WAS 
IS 
24 
3.1.2 
Open-
label 
Period 
(Cycles 2 
to 3 
• 
Week 12 (Day 85) (clinic visit*) 
(*Note: Subjects will be evaluated for retreatment with 
Dysport (300 U or 500 U) in an OL fashion.) 
 
Week 12 (Day 85) (clinic visit) 
25 
Figure 3 
 
Alignment of ‘D1’ in cycle 2 and arrows replaced => signs 
36 
Table 3 
SF-36 
 In End of 
Study or 
Early 
Withdraw
alColumn 
 
Xi 
 
X 


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Version Date 
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7 SEPTEMBER 2018 
Pag
e  
Section 
WAS 
IS 
36 
Table 3 
PGI-I for 
pain and 
PGI-I for 
disabilityn 
All 
timepoints 
including 
Early 
Withdraw
ale 
Column  
 
PGI-S for pain and PGI-S for disability 
Xi 
PGI-S for pain and PGI-S for disabilityn 
X 
36 
Table 3 
PGI-S for 
pain and 
PGI-S for 
disability 
(All 
timepoints
) 
PGI-S for pain and PGI-S for disability 
Xi 
PGI-S for pain and PGI-S for disabilityn 
X 


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Version Date 
25 MAY 2018 
7 SEPTEMBER 2018 
Pag
e  
Section 
WAS 
IS 
36 
Table 3 
PGI-S for 
pain and 
PGI-S for 
disability 
Screening 
1 
(Days -21 
to Day -
1)a 
 
 
X 
38 
Table 3 
Footnote 
 
n 
The PGI-I and PGI-S assessments will be completed 
by the subject at the study site during the study visit. 
Subjects are to complete these self-assessments using the 
electronic diary which will be accessed at the site during the 
visit. Site staff should not help subjects answer questions but 
must ensure that the subject can access the eDiary to 
complete the assessment while at the site 
39 
Table 4 
PGI-I for pain and PGI-I for disabilityj 
PGI-I for pain and PGI-I for disabilityj, l 
39 
Table 4 
PGI-S for pain and PGI-S for disabilityj 
PGI-S for pain and PGI-S for disabilityj, l 
39 
Table 4 
footnote 
b The decision to increase the dose at the beginning of Cycle 3 
will be based on 1) evaluation of safety and tolerability (review 
related AEs and consideration of any significant changes in the 
study foot) and 2) severity of pain (considering NPRS score) and 
disability (considering mFFI Disability subscale score) 
experienced by the subject at the time of evaluation. 
 
b The decision to increase the dose at the beginning of Cycle 3 
will be based on 1) evaluation of safety and tolerability (review 
of related AEs and consideration of any significant changes in 
the study foot) and 2) severity of pain (considering NPRS score) 
and disability (considering mFFI Disability subscale score) 
experienced by the subject at the time of evaluation. 


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7 SEPTEMBER 2018 
Pag
e  
Section 
WAS 
IS 
39 
Table 3 
& 
footnote 
 
n  
The PGI-I and PGI-S assessments will be completed 
by the subject at the study site during the study visit. 
Subjects are to complete these self-assessments using the 
electronic diary which will be accessed at the site during the 
visit. Site staff should not help subjects answer questions but 
must ensure that the subject can access the eDiary to 
complete the assessment while at the site 
39 
Table 4 
footnote 
j 
To be recorded by the subject daily for 7 consecutive 
days prior to Week 8 using an electronic diary. These 
assessments are assessed at home after baseline 
 
j 
The PGI-I and PGI-S assessments will be completed 
by the subject at the study site during the study visit. 
Subjects are to complete these self-assessments using the 
electronic diary which will be accessed at the site during the 
visit. Site staff should not help subjects answer questions but 
must ensure that the subject can access the eDiary to 
complete the assessment while at the site 
43 
6.2.3 
Injection –
Guided 
Technique 
A Teflon coated, 27 to 30-gauge, open lumen needle will be 
used to stimulate the targeted muscle once per second (repetitive 
square wave pulses, 0.25 msec in duration). Injection will be 
performed when either a continuous or stretch of muscle has 
been induced by the electrical stimulator confirming the location 
of the targeted muscle. 
A Teflon coated, 22 to 30-gauge, open lumen needle will be 
used to stimulate the targeted muscle once per second (repetitive 
square wave pulses, 0.25 msec in duration). Injection will be 
performed when either a continuous or stretch of muscle has 
been induced by the electrical stimulator confirming the location 
of the targeted muscle. 
44 
6.3 
Concomit
ant 
Medicatio
n/Therapy 
Subjects who require treatment with antipsychotic (e.g. D2 
antagonists) or antidepressant (e.g. selective serotonin reuptake 
inhibitors, serotonin and norepinephrine reuptake inhibitors) will 
need to demonstrate evidence of stable dose regimen in the 30 
days prior to Screening and will maintain that dose for the 
duration of the study. 
• 
Subjects who require treatment with antipsychotic (e.g. D2 
antagonists) or antidepressant (e.g. selective serotonin 
reuptake inhibitors, serotonin and norepinephrine reuptake 
inhibitors) medications will need to demonstrate evidence 
of stable dose regimen in the 30 days prior to Screening 
and will maintain that dose for the duration of the study. 


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7 SEPTEMBER 2018 
Pag
e  
Section 
WAS 
IS 
44 
6.4 
Lifestyle 
Restrictio
ns/Recom
mendation
s 
This includes toe-spacers or any other device intended for this 
purpose. Over-the counter shoe will be permitted during the 
study only for subjects who have used these for at least 30 days 
prior to screening. 
This includes toe-spacers or any other device intended for this 
purpose. Over-the counter shoe inserts will be permitted during 
the study only for subjects who have used these for at least 30 
days prior to screening. 
45 
6.6 
Priority 
Order on 
Study 
Procedure
s 
The following priority order should be followed in case study 
procedures are scheduled at the same time point: 
 
1. 
NPRS 
2. 
mFFI 
3. 
PGI-I and PGI-S (pain and disability) 
4. 
SF-36 
5. 
Weight-bearing radiographs 
 
The following priority order should be followed in case study 
procedures are scheduled at the same time point: 
 
1. 
NPRS* 
2. 
mFFI* 
3. 
PGI-I and PGI-S (pain and disability) 
4. 
SF-36 
5. 
Weight-bearing radiographs 
*These assessments are assessed at home after baseline. 
45 
7.1 
Methods 
and 
Timing of 
Assessing, 
Recording
, and 
Analysing 
Efficacy 
Data 
Methods for assessing efficacy data is described below. Timing 
of efficacy assessments are discussed in Section 5. Procedures 
for recording efficacy data are discussed in Section 15.1, and 
methods of analyses are discussed in Section 11.4.4. 
Methods for assessing efficacy data is described below. Timing 
of efficacy assessments are discussed in Section 5. Procedures 
for recording efficacy data are discussed in Section 15.1, and 
methods of analyses are discussed in Section 11.4.4.  For all 
assessments related to pain, the subject is to be instructed by 
the investigator to report severity specifically for his/her 
study foot when completing the questionnaires.  Also, it is 
critical that investigators and site staff instruct and remind 
subjects to complete home-based self-assessments (eg, NPRS, 
mFFI) in the evening. 


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7.1.1 
 
Numeric 
Pain 
Rating 
Scale 
The NPRS is a widely used, and validated unidimensional 
measure of pain intensity in adults. Subjects will be asked to rate 
the intensity of their foot pain during physical activity (e.g. 
walking, standing or running) based on an 11-point scale ranging 
from 0 to 10, where 0 equals “no pain” and 10 equals “worst 
possible pain” in which they will be asked to rate their daily pain 
intensity by responding directly to the following question: 
"Please rate the average intensity of the pain in your treated foot 
while performing physical activities (e.g. standing, walking or 
running) over the past 24 hours". 
The NPRS is a widely used and validated unidimensional 
measure of pain intensity in adults. Subjects will be asked to rate 
the intensity of their foot pain during physical activity (e.g. 
walking, standing or running) based on an 11-point scale ranging 
from 0 to 10, where 0 equals “no pain” and 10 equals “worst 
possible pain”. They will be asked to rate their daily pain 
intensity by responding directly to the following question: 
"Please rate the average intensity of the pain in your treated foot 
while performing physical activities (e.g. standing, walking or 
running) over the past 24 hours". 
45 
7.1.1 
 
Numeric 
Pain 
Rating 
Scale 
Daily pain intensities will be recorded by the subject using an 
electronic diary for 7 consecutive days prior to the study visits as 
outlined in Section 5.1. The electronic diary should be 
completed by the subject at the same time each day, preferably 
in the evening. 
Daily pain intensities will be recorded by the subject using an 
electronic diary for 7 consecutive days prior to the study visits as 
outlined in Section 5.1. The electronic diary should be 
completed by the subject at the same time each day, preferably 
in the evening.  The subject should be instructed by the 
investigator to focus on his/her study foot when completing 
the questionnaire.  This instruction is critical in subjects with 
bilateral disease. 
45 
7.1.2 
Foot 
Function 
Index 
7.1.2 Foot Function Index 
7.1.2 Modified Foot Function Index 


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7.1.2 
Foot 
Function 
Index 
The mFFI items are rated using numeric rating scales ranging 
from 0 to 10. The poles are labelled “no pain” and “worst pain 
imaginable” (pain), “no difficulty” and “so difficult unable” 
(disability), and “none of the time” and “all of the time” 
(limitations). For each item, the subject is asked to record the 
number value which best corresponds to the effect of the foot 
complaints. To obtain a subscale score, the item scores for a 
given subscale (i.e. pain, disability or activity limitation 
subscales) are totalled and divided by the maximum total 
possible multiplied by 100 for all of the subscale items. Each 
subscale score, as well as the total score will range from 0 to 
100. 
Daily pain intensities, disability and activity limitations will be 
recorded by the subject using an electronic diary for 7 
consecutive days prior to the study visits as outlined in Section 
5.1. The electronic diary should be completed by the subject at 
the same time each day, preferably in the evening. 
The mFFI items are rated using numeric rating scales ranging 
from 0 to 10 and cover a period of the ‘past’ 24 hours. The 
poles are labelled “no pain” and “worst pain imaginable” (pain), 
“no difficulty” and “so difficult unable to do” (disability), and 
“none of the time” and “all of the time” (limitations). For each 
item, the subject is asked to record the number value which best 
corresponds to the effect of the foot complaints. To obtain a 
subscale score, the item scores for a given subscale (i.e. pain, 
disability or activity limitation subscales) are totalled and 
divided by the maximum total possible and then multiplied by 
100. Each subscale score, as well as the total score, will range 
from 0 to 100. If a patient did not perform the task listed in 
the question, they will be instructed to mark the item as not 
applicable (N/A). 
Daily pain intensities, disability and activity limitations will be 
recorded by the subject using an electronic diary for 7 
consecutive days prior to the study visits as outlined in Section 
5.1. The electronic diary should be completed by the subject at 
the same time each day, preferably in the evening.  The 
subject should be instructed by the investigator to focus on 
his/her study foot when completing the questionnaire.  This 
instruction is critical in subjects with bilateral disease.  In 
addition, all subjects should be educated on the proper use of 
the “not applicable” option.  For example, subjects that do 
not stand on their tiptoes in the course of their daily lives 
should mark “not applicable” for that particular item.  
However, if the subject does not stand on his or her tiptoes 
due to their disease, then he or she should choose the option 
“so difficult unable to do”. 


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7.1.5 
Patient 
Global 
Impressio
n of 
Improvem
ent of 
Foot Pain 
An assessment of PGI-I of foot pain will be conducted by the 
subject using a 7-point Likert scale (from -3: very much worse to 
+3: very much improved). The PGI-I will be assessed by the 
subject answering the following question: “Compared to your 
foot pain at Baseline (Cycle 1 Day 1) i.e. prior to the study 
treatment initiation, your foot pain while performing physical 
activities (e.g. standing, walking or running over the past 24 
hours is: +3=very much improved; +2=much improved; 
+1=minimally improved; 0=no change from baseline; -
1=minimally worse; -2=much worse; -3=very much worse”).# 
The PGI-S of foot pain will be recorded by the subject using an 
electronic diary for 7 consecutive days prior to the study visits as 
outlined in Section 5.1. The electronic diary should be 
completed by the subject at the same time each day, preferably 
in the evening. 
An assessment of PGI-I of foot pain will be conducted by the 
subject using a 7-point Likert scale (from -3: very much worse to 
+3: very much improved). The PGI-I will be assessed by the 
subject answering the following question: “Compared to your 
foot pain prior to the study treatment initiation, your foot pain 
while performing physical activities (e.g. standing, walking or 
running) now is: +3=very much improved; +2=much improved; 
+1=minimally improved; 0=no change; -1=minimally worse; -
2=much worse; -3=very much worse”). 
The PGI-I of foot pain will be recorded by the subject using an 
electronic diary during the study visits at site as outlined in 
Section 5.1. The subject should be instructed by the 
investigator to focus on his/her study foot when completing 
the questionnaire.  This instruction is critical in subjects with 
bilateral disease. 
47 
Section 
7.1.6 
Patient 
Global 
Impressio
n of 
Severity 
of Foot 
Pain 
The PGI-S will be assessed by the subject by answering the 
following question: “How severe was your foot pain while 
performing physical activities (e.g. standing, walking or running) 
over the past 24 hours?” (0=no pain; 1=mild pain; 2=moderate 
pain; 3=severe pain). 
The PGI-S of foot pain will be recorded by the subject using an 
electronic diary for 7 consecutive days prior to the study visits as 
outlined in Section 5.1. The electronic diary should be completed 
by the subject at the same time each day, preferably in the 
evening. 
 
The PGI-S will be assessed by the subject by answering the 
following question: “How severe was your foot pain while 
performing physical activities (e.g. standing, walking or 
running) over the past week?” (0=no pain; 1=mild pain; 
2=moderate pain; 3=severe pain). 
The PGI-S of foot pain will be recorded by the subject using an 
electronic diary during the study visits on site as outlined in 
Section 5.1. The subject should be instructed by the 
investigator to focus on his/her study foot when completing 
the questionnaire.  This instruction is critical in subjects with 
bilateral disease. 
 


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47 
7.1.7 
Patient 
Global 
Impressio
n of 
Improvem
ent of 
Disability 
The PGI-I will be assessed by the subject answering the following 
question: “Compared to your disability at Baseline (Cycle 1 Day 
1) i.e. prior to the study treatment initiation, your disability while 
performing physical activities (e.g. standing, walking or running 
over the past 24 hours is: +3=very much improved; +2=much 
improved; 
+1=minimally 
improved; 
0=no 
change 
from 
baseline; -1=minimally worse; -2=much worse; -3=very much 
worse”). 
The PGI-I of disability will be recorded by the subject using an 
electronic diary for 7 consecutive days prior to the study visits as 
outlined in Section 5.1. 
The PGI-I will be assessed by the subject answering the following 
question: “Compared to your disability prior to the study 
treatment 
initiation, 
your 
disability 
while 
performing 
physical activities (e.g. standing, walking or running) now is: 
+3=very much improved; +2=much improved; +1=minimally 
improved; 0=no change from baseline; -1=minimally worse; -
2=much worse; -3=very much worse”). 
The PGI-I of disability will be recorded by the subject using an 
electronic diary during the study visits on site as outlined in 
Section 5.1. 
47 
7.1.8 
Patient 
Global 
Impressio
n of 
Severity 
of 
Disability 
The PGI-S will be assessed by the subject by answering the 
following question: “How severe was your disability while 
performing physical activities (e.g. standing, walking or running) 
over the past 24 hours?” (0=no disability; 1=mild disability; 
2=moderate disability; 3=severe disability). 
The PGI-S of disability will be recorded by the subject using an 
electronic diary for 7 consecutive days prior to the study visits as 
outlined in Section 5.1. The electronic diary should be completed 
by the subject at the same time each day, preferably in the 
evening. 
 
The PGI-S will be assessed by the subject by answering the 
following question: “How severe was your disability while 
performing physical activities (e.g. standing, walking or running) 
over the past week?” (0=no disability; 1=mild disability; 
2=moderate disability; 3=severe disability). 
The PGI-S of disability will be recorded by the subject using an 
electronic diary during the study visits on site outlined in Section 
5.1.  
 


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58 
11.1 
Analyses 
Populatio
ns 
The following populations will be used during statistical 
analyses: 
• 
Screened population: All subjects screened (i.e. who 
signed the informed consent). 
• 
Randomised population: All subjects randomised (i.e. 
who were randomly allocated to a treatment group by IRT). 
• 
Safety population: All subjects who received at least one 
dose of IMP administration (including only partial 
administration). 
• 
Intention-to-treat (ITT) population: All randomised 
subjects. 
• 
Per protocol (PP) population: All subjects in the ITT 
population for whom no major protocol deviations (which may 
interfere with efficacy evaluation) occurred until Week 8 of the 
DB period. 
• 
Open-label (OL) population: All randomised subjects 
who received at least one dose of Dysport (including only partial 
administration) during the OL period. 
The following populations will be used during statistical 
analyses: 
• 
Screened population: All subjects screened (i.e. who 
signed the informed consent). 
• 
Safety population: All subjects who received at least one 
dose of IMP administration (including only partial 
administration). 
• 
Intention-to-treat (ITT) population: All randomised 
subjects (i.e. who were randomly allocated to a treatment 
group by IRT). 
• 
Per protocol (PP) population: All subjects in the ITT 
population for whom no major protocol deviations (which may 
interfere with efficacy evaluation) occurred until Week 8 of the 
DB period. 
• 
Open-label (OL) population: All randomised subjects 
who received at least one dose of Dysport (including only partial 
administration) during the OL period. 
• 
Active Treatment population: All randomised 
subjects who received at least one dose of Dysport (including 
only partial administration) during the DB or OL period 
58 
11.1.1 
Populatio
ns 
Analysed 
In addition, PP analysis will be performed as confirmatory. 
Secondary analysis based on secondary efficacy endpoints will 
be performed on the ITT population (for the DB period) and on 
the OL population (for the OL period).  
 
In addition, PP analysis will be performed as confirmatory. 
Secondary analyses based on secondary efficacy endpoints will 
be performed on the ITT population (for the DB period) and on 
the Active Treatment population (for analysis by active 
treatment cycle).  


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11.3 
Significan
ce Testing 
and 
Estimatio
ns 
For other efficacy analysis, all statistical tests will be performed 
two sided with a type I error rate set at 5%. For safety analysis, 
no format statistical will be carried out, only descriptive 
statistics will be provided. 
For other efficacy analyses, all statistical tests will be performed 
two sided with a type I error rate set at 5%. For safety analyses, 
no formal statistical analyses will be carried out; only 
descriptive statistics will be provided. 
59 
11.4.3.1 
Efficacy 
Evaluatio
n 
The NPRS score data collected over the 7 consecutive days prior 
to a visit, will be retrieve using an electronic diary (see Section 
7.1.1). No missing baseline is expected as NPRS assessment is 
part of the inclusion criteria. Subjects will have reminders to 
complete the electronic diary, and site staff will be alerted if they 
miss a day. Therefore, the risk of have missing days is 
minimised. However, as described in Table 6, any cases of 
possible missing data will be considered. 
 
 
The NPRS score data collected over the 7 consecutive days prior 
to a visit will be retrieved using an electronic diary (see Section 
7.3.1). 
 


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60 
11.4.3 
Efficacy 
Evaluatio
n 
(2) 
Surgery for HAV. 
No treatment switch or interruption is possible as the primary 
efficacy endpoint is evaluated following a single injection of 
study treatment. Intercurrent event (1) is unlikely to occur, as the 
evaluation period for the primary efficacy endpoint is up to 
Week 8 (short period). Intercurrent event (2) is also unlikely to 
occur. All subjects with this level of pain severity and angular 
displacement are considered surgical candidates theoretically. 
However, the upper limit on HV angle (30 degrees) will likely 
limit the need of a “rescue” surgery. 
Subjects are expected to continue follow-up assessments 
regardless of these two intercurrent events. NPRS scores will be 
used as observed.  
A mixed model for repeated measures (MMRM) on change from 
baseline in foot pain as measured by the daily NPRS score 
averaged over the 7 consecutive days prior to each scheduled 
assessment timepoint of the DB period (up to Week 12) will be 
used to evaluate the estimand and compare treatment groups.  
Missing data will be considered missing at random (MAR). 
This model will include the fixed categorical effects of treatment 
group, visit, treatment group-by-visit interaction, the 
stratification parameter as fixed categorical covariates and the 
baseline value as fixed continuous covariate. The treatment 
group factor will have three levels (Dysport 300 U, Dysport 500 
U and placebo), the factor visit three levels (Week 4, Week 8 
and Week 12) and the stratification parameter two level 
(unilateral and bilateral HAV). No missing baseline is expected 
as NPRS assessment is part of the inclusion criteria. Subjects 
will have reminders to complete the electronic diary, and site 
staff will be alerted if they miss a day. 
(2) 
Surgery for HAV. 
No treatment switch or interruption is possible as the primary 
efficacy endpoint is evaluated following a single injection of 
study treatment. Intercurrent event (1) is unlikely to occur, as the 
evaluation period for the primary efficacy endpoint is up to 
Week 8 (short period). Intercurrent event (2) is also unlikely to 
occur. All subjects with this level of pain severity and angular 
displacement are considered surgical candidates theoretically. 
However, the upper limit on HV angle (30 degrees) will likely 
limit the need for a “rescue” surgery. 
Subjects are expected to continue follow-up assessments 
regardless of these two intercurrent events. NPRS scores will be 
used as observed.  
A mixed model for repeated measures (MMRM) on change from 
baseline in foot pain as measured by the daily NPRS score 
averaged over the 7 consecutive days prior to each scheduled 
assessment timepoint of the DB period (up to Week 12) will be 
used to evaluate the estimand and compare treatment groups.  
This model will include the fixed categorical effects of treatment 
group, visit, treatment group-by-visit interaction, the 
stratification parameter as fixed categorical covariates and the 
baseline value as fixed continuous covariate. The treatment 
group factor will have three levels (Dysport 300 U, Dysport 500 
U and placebo), the factor visit three levels (Week 4, Week 8 
and Week 12) and the stratification parameter two levels 
(unilateral and bilateral HAV).  
Average scores will be calculated if there is at least 5-day e-
diary completed. No missing baseline is expected as NPRS 
assessment is part of the inclusion criteria. Subjects will have 
reminders to complete the electronic diary, and site staff will 
be alerted if they miss a day. Therefore, the risk of having 
missing days is minimised. However, if subjects have no post-
baseline efficacy assessment, Week 8 score will be imputed 


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(imputation method will be described in the SAP). Other 
missing data will be considered missing at random (MAR). 
 
60 
Table 6 
 
 
 
62 
Table 7 
Difference between each Dysport doses and the placebo group in 
the mean change from baseline in the mean daily mFFI pain 
subscale score averaged for the 7 consecutive days prior to 
Week 4, Week 8 and Week 12 DB visits. 
Difference between each Dysport dose and the placebo group in 
the mean change from baseline in the mean daily mFFI pain 
subscale score averaged for the 7 consecutive days prior to 
Week 4, Week 8 and Week 12 DB visits. 
63 
Table 7 
PGI-I pain and disability scores, respectively, averaged over the 
7 consecutive days prior to Week 4, Week 8 and Week 12 DB 
visits. 
PGI-I pain and disability scores, respectively, at Week 4, Week 
8 and Week 12 DB visits. 
63 
11.4.3.2 
Analysis 
of 
Secondary 
Efficacy 
Endpoints 
Double-
blind 
Period 
A MMRM model on change from baseline including each 
scheduled timepoint up to Week 12 will be used to evaluate the 
estimands and compare treatment groups.  Missing data will be 
considered at MAR. 
According to the scale, an MMRM model or a mixed-linear-
generalized model on change from baseline including each 
scheduled timepoint up to Week 12 will be used to evaluate the 
estimands and compare treatment groups.  Missing data will be 
considered as MAR. 


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64 
11.4.3.2 
Analysis 
of 
Secondary 
Efficacy 
Endpoints 
Open 
label 
Period 
Open-Label period 
Table 8 summarises the secondary efficacy endpoints, their 
associated estimates and estimands during the OL period. 
Active Treatment Cycles 
Table 8 summarises the secondary efficacy endpoints, their 
associated estimates and estimands during the active treatment 
cycles. 
64 
Table 8 
Table 8 Analysis of Secondary Efficacy Endpoints (Open-label 
Period) 
Table 8 Analysis of Secondary Efficacy Endpoints (active 
treatment cycles) 
65 
11.4.3.2 
Analysis 
of 
Secondary 
Efficacy 
Endpoints 
Only descriptive statistics will be performed for the open-label 
period. 
Only descriptive statistics will be performed for the active 
treatment cycles. 
 
11.5 
Subgroup 
analysis 
Descriptive statistics for the primary efficacy endpoints will be 
provided on the stratification parameter (unilateral or bilateral 
HAV) on the ITT population. Other subgroup analyses may be 
planned according to clinical interest and will be detailed in the 
SAP. 
Descriptive statistics for the primary efficacy endpoint will be 
provided on the stratification parameter (unilateral or bilateral 
HAV) on the ITT population. Other subgroup analyses may be 
planned according to clinical interest and will be detailed in the 
SAP. 
 
Appendix 
1 
Modified 
Foot 
Function 
Index 
 
New version appended  


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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
D-FR-52120-237 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Protocol Version 4.0 (Amendment 3) 
7 September 2018 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON(S) FOR CHANGES 
 
Changes: 
After internal and external consultation the following changes were made to update the protocol: 
• 
Incorporate the items from the administrative letter sent in July (attached the admin letter). 
o assessment of the PGI-S for pain and PGI-S for disability at the Screening visit need to be added 
back into Table 3 (they inadvertently removed in the last amendment). 
o gauge sizes were expanded to 22 to 30. 
• 
adding an N/A option to the mFFI questionnaire and providing written guidance within protocol for 
administering the questionnaire to the sites. Text to be included which reminds the PI to instruct the patient 
on the following: 
o Complete assessments always on study foot 
o Complete assessments in the evening 
o Finish assessment completely (eg, do not start then finish later)  
o Explain the “NA” option  
• 
Update the IM angle minimum entry criteria from 12° to 18° to 9° to 18°. 
• 
modify the frequency of the PGI-I and PGI-S. 
o change administration from performing at home to completing the assessment at the site on site 
computer. 
• 
mFFI Instrument changes: 
o Add a “not applicable” option to the mFFI questionnaire (all items). 


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o addition of the word “study” to three areas of the questionnaire to focus the subject’s attention on 
their treated study foot when answering questions. 
o updating “therapist” to “clinician” in the initial instructions. 
 
• 
Update/add instructions to the site regarding importance of instructing subjects to focus on their treated 
study foot when completing modified FFI, NRS, and PGI assessments 
o additional subject take-home instructions on this topic. 
• 
Update SF-36 superscript at early termination instructing that the assessment should be done every day for 
seven days. 
Statistical Sections: 
• 
- 
Clarification regarding missing data handling 
• 
- 
Replace ‘open-label’ analysis by ‘active treatment analysis’. 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
STATISTICAL ANALYSIS PLAN (SAP) UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 
 


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5, 25, 26, 
42 & 45 
Synopsis  
Methodology 
3.1 
Fig 2 footnotes 
3.1.2  
Open-label Period 
(Cycles 2 to 3) 
 
Table 4 footnotes 
6.2 
Study Drugs 
Administered 
Following completion of the DB period (i.e. 
completion of Cycle 1), subjects who meet 
retreatment criteria will be eligible to participate in 
the OL period. All retreatment-eligible subjects will 
receive OL treatment with Dysport 300 U at the 
first retreatment cycle (Cycle 2) in the HAV study 
foot selected during the DB period. At the second 
retreatment cycle (Cycle 3), subjects will be treated 
with either Dysport 300 U or 500 U in the HAV 
study foot based on investigator judgment and 
following clinical evaluation at the time of 
retreatment. The muscles to be injected and 
procedures for injection are identical to those 
targeted in the DB period.  
 
Following completion of the DB period (i.e. completion of 
Cycle 1), subjects who meet retreatment criteria will be 
eligible to participate in the OL period. All retreatment-
eligible subjects will receive OL treatment with Dysport 300 
U at the first retreatment cycle (Cycle 2) in the HAV study 
foot selected during the DB period. At the second retreatment 
cycle (Cycle 3), subjects will be treated with either Dysport 
300 U or 500 U in the HAV study foot based on investigator 
judgment and following clinical evaluation at the time of 
retreatment. The decision to increase the dose at the 
beginning of Cycle 3 will be based on 1) evaluation of 
safety and tolerability (review related AEs and 
consideration of any significant changes in the study foot) 
and 2) severity of pain (considering NPRS score) and 
disability (considering mFFI Disability subscale score) 
experienced by the subject at the time of evaluation. The 
muscles to be injected and procedures for injection are 
identical to those targeted in the DB period.  
 
5 & 32 
Synopsis 
Diagnosis and criteria 
for inclusion 
4.1 
Inclusion Criteria 
 
 
(2) Male or female, aged 18 years to 75, years 
inclusive 
 
(2) Male or female, aged 18 years or older 
 


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9 & 10 
Synopsis 
Criteria for 
evaluation 
(endpoints) 
 
Efficacy: 
Primary Endpoint: the change from baseline in foot 
pain as measured by the daily NPRS score averaged 
over the 7 consecutive days prior to the Week 8 DB 
visit. 
Secondary Endpoints:  
• 
The change from baseline as measured by the 
daily NPRS score averaged over the 
7 consecutive days prior to each scheduled 
assessment timepoint (except at Week 8 
DB). 
• 
The change from baseline in the daily mFFI 
Disability subscale score averaged over the 7 
consecutive days prior each scheduled 
assessment timepoint. 
• 
The change from baseline in the daily mFFI 
Pain subscale score averaged over the 
7 consecutive days prior to each scheduled 
assessment timepoint. 
• 
The change from baseline in the daily mFFI 
total score averaged over the 7 consecutive 
days prior to each scheduled assessment 
timepoint. 
• 
The change from baseline in the daily mFFI 
activity limitation subscale score averaged 
over the 7 consecutive days prior to each 
scheduled assessment timepoint. 
 
 
Efficacy: 
Primary Endpoint: the change from baseline in foot pain 
as measured by the daily NPRS score averaged over the 
7 consecutive days prior to the Week 8 DB visit. 
Secondary Endpoints:  
• 
The change from baseline as measured by the daily 
NPRS score averaged over the 7 consecutive days prior 
to Week 4 and Week 12 DB visits and at each 
scheduled visit in the OL period. 
 
• 
The change from baseline in the daily mFFI Disability 
subscale score averaged over the 7 consecutive days 
prior to Week 4, Week 8 and Week 12 DB visits and 
at each scheduled visit in the OL period.  
 
• 
The change from baseline in the daily mFFI Pain 
subscale score averaged over the 7 consecutive days 
prior to Week 4, Week 8 and Week 12 DB visits and 
at each scheduled visit in the OL period. 
 
• 
The change from baseline in the daily mFFI total score 
averaged over the 7 consecutive days prior to Week 4, 
Week 8 and Week 12 DB visits and at each scheduled 
visit in the OL period. 
 
• 
The change from baseline in the daily mFFI activity 
limitation subscale score averaged over the 7 
consecutive days prior to Week 4, Week 8 and Week 
12 DB visits and at each scheduled visit in the OL 
period. 


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• 
The change from baseline in quality of life 
as measured by the SF-36 at each scheduled 
assessment timepoint. 
 
• 
The change from baseline in HV angle as 
measured directly by weight-bearing 
anterior-posterior radiographs at each 
scheduled assessment timepoint. 
 
• 
The change from baseline in intermetatarsal 
angle as measured directly by 
weight-bearing anterior-posterior 
radiographs at each scheduled assessment 
timepoint. 
 
• 
Time to retreatment 
 
• 
Patient Global Impression of Improvement 
of foot pain score averaged over the 
7 consecutive days prior to each scheduled 
assessment timepoint. 
 
• 
Patient Global Impression of Improvement 
in disability score averaged over the 
7 consecutive days prior to each scheduled 
assessment timepoint. 
 
• 
The change from baseline in quality of life as measured 
by the SF-36 at Week 8 and Week 12 DB visits and 
at each scheduled visit in the OL period. 
 
• 
The change from baseline in HV angle as measured 
directly 
by 
weight-bearing 
anterior-posterior 
radiographs at Week 4 and Week 12 DB visits and at 
each scheduled visit in the OL period. 
 
 
• 
The change from baseline in intermetatarsal angle as 
measured directly by weight-bearing anterior-posterior 
radiographs at Week 4, Week 8 and Week 12 DB 
visits and at each scheduled visit in the OL period. 
 
 
• 
Time to retreatment 
 
 
• 
Patient Global Impression of Improvement of foot pain 
score averaged over the 7 consecutive days prior to 
Week 4, Week 8 and Week 12 DB visits and at each 
scheduled visit in the OL period. 
 
• 
Patient Global Impression of Improvement in disability 
score averaged over the 7 consecutive days prior to 
Week 4, Week 8 and Week 12 DB visits and at each 
scheduled visit in the OL period. 
 


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• 
The change from baseline in the Patient 
Global Impression of Severity of foot pain 
score averaged over the 7 consecutive days 
prior 
to 
each 
scheduled 
assessment 
timepoint. 
 
• 
The change from baseline in the Patient 
Global Impression of Severity disability 
score averaged over the 7 consecutive days 
prior 
to 
each 
scheduled 
assessment 
timepoint. 
 
 
• 
The change from baseline in the Patient Global 
Impression of Severity of foot pain score averaged over 
the 7 consecutive days prior to Week 4, Week 8 and 
Week 12 DB visits and at each scheduled visit in the 
OL period. 
 
• 
The change from baseline in the Patient Global 
Impression of Severity disability score averaged over 
the 7 consecutive days prior to Week 4, Week 8 and 
Week 12 DB visits and at each scheduled visit in the 
OL period. 
 
22 
1.8  
Population to be 
studies 
The study will enrol adult male and female subjects 
aged 18 years to 75, inclusive, suffering from 
clinically significant HAV who have not undergone 
surgery for their condition. 
The study will enrol adult male and female subjects aged 
18 years or older suffering from clinically significant 
HAV who have not undergone surgery for their 
condition. 
26 
 
3.2.1 
Primary Efficacy 
Endpoint 
The primary efficacy endpoint is the change from 
baseline in the daily NPRS score averaged over the 
7 consecutive days prior to the Week 8 assessment 
timepoint. 
The primary efficacy endpoint is the change from 
baseline in the daily NPRS score averaged over the 7 
consecutive days prior to the Week 8 DB visit. 


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27 & 62 
3.2.2 
Secondary Efficacy 
Endpoints 
Table 2  
 
Secondary Efficacy Endpoints 
The change from baseline in the daily NPRS score 
averaged over the 7 consecutive days prior to each 
scheduled assessment timepoint (except Week 8 DB). 
The change from baseline in the daily mFFI disability 
subscale score averaged over the 7 consecutive days 
prior to each scheduled assessment timepoint. 
 
The change from baseline in the daily mFFI pain 
subscale score averaged over the 7 consecutive days 
prior to each scheduled assessment timepoint. 
 
The change from baseline in the daily mFFI total score 
averaged over the 7 consecutive days prior to each 
scheduled assessment timepoint. 
The change from baseline in the daily mFFI activity 
limitation subscale score averaged over the 7 
consecutive days prior to each scheduled assessment 
timepoint. 
The change from baseline in HV angle as measured 
directly by weight-bearing anterior-posterior 
radiographs at each scheduled assessment timepoint. 
The change from baseline in intermetatarsal angle as 
measured directly by weight-bearing anterior-posterior 
radiographs at each scheduled assessment timepoint. 
 
 
The time to retreatment 
The change from baseline in PGI-S of foot pain score 
averaged over the 7 consecutive days prior each 
scheduled assessment timepoint.  
 
Secondary Efficacy Endpoints 
The change from baseline in the daily NPRS score averaged over 
the 7 consecutive days prior to Week 4 and Week 12 DB visits 
and each scheduled visit in the OL period. 
The change from baseline in the daily mFFI disability subscale 
score averaged over the 7 consecutive days prior to Week 4, 
Week 8 and Week 12 DB visits and each scheduled visit in the 
OL period. 
The change from baseline in the daily mFFI pain subscale score 
averaged over the 7 consecutive days prior to Week 4, Week 8 
and Week 12 DB visits and each scheduled visit in the OL 
period. 
The change from baseline in the daily mFFI total score averaged 
over the 7 consecutive days prior to Week 4, Week 8 and Week 
12 DB visits and each scheduled visit in the OL period. 
The change from baseline in the daily mFFI activity limitation 
subscale score averaged over the 7 consecutive days prior to 
Week 4, Week 8 and Week 12 DB visits at each scheduled visit 
in the OL period. 
The change from baseline in HV angle as measured directly by 
weight-bearing anterior posterior radiographs at Week 4, Week 
8 and Week 12 DB visits and each scheduled visit in the OL 
period. 
The change from baseline in intermetatarsal angle as measured 
directly by weight bearing anterior-posterior radiographs at 
Week 4, Week 8 and Week 12 DB visits and each scheduled 
visit in the OL period. 
 
The time to retreatment 
The change from baseline in PGI-S of foot pain score averaged 
over the 7 consecutive days prior to Week 4, Week 8 and 
Week 12 DB visits and each scheduled visit in the OL period.  


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The change from baseline in PGI-S disability score 
averaged over the 7 consecutive days prior each 
scheduled assessment timepoint. 
The PGI-I foot pain score averaged over the 7 
consecutive days prior to each scheduled assessment 
timepoint 
The PGI-I disability score averaged over the 7 
consecutive days prior to each scheduled assessment 
timepoint 
The change from baseline in quality of life as measured 
by the SF-36 at each scheduled assessment timepoint. 
 
 
 
The change from baseline in PGI-S disability score averaged 
over the 7 consecutive days prior to Week 4, Week 8 and 
Week 12 DB visits and each scheduled visit in the OL period. 
The PGI-I foot pain score averaged over the 7 consecutive days 
prior to Week 4, Week 8 and Week 12 DB visits and each 
scheduled visit in the OL period. 
The PGI-I disability score averaged over the 7 consecutive days 
prior to Week 4, Week 8 and Week 12 DB visits and each 
scheduled visit in the OL period. 
The change from baseline in quality of life as measured by the 
SF-36 at Week 8 and Week 12 DB visits and each scheduled 
visit in the OL period. 
27 
3.2.4 
Safety Endpoints and 
Evaluations 
• 
The incidence of AEs, serious AEs (SAEs), 
AEs leading to discontinuations and AEs of 
special interest (AESIs) (i.e. remote effects of 
toxin) 
 
• 
The incidence of AEs, serious AEs (SAEs), AEs 
leading to discontinuations and AEs of special interest 
(AESIs) (i.e. remote effects of toxin and 
hypersensitivity like reactions) 
 
30 
3.7 
Stopping Rules and 
Discontinuation 
Criteria 
• 
failure of the investigator staff to comply with 
the protocol or with the GCP guidelines; 
• 
safety concerns; 
• 
inadequate subject recruitment. 
 
• 
failure of the investigator staff to comply with the 
protocol or with the GCP guidelines; 
• 
New and significant safety concerns; 
• 
inadequate subject recruitment. 
 
38 
Table 3 
Study Procedures and 
Assessments: 
Double-blind Period 
 
 
 
 


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43 
6.2 
Study Drugs 
Administered 
A blinded kit will be used in this study to maintain 
the blinding of the study during the DB period. Each 
blinded kit will contain two vials regardless of 
treatment assignment. The two vials in each kit will 
contain either a Dysport 300 U vial + a placebo vial, 
a Dysport 500 U vial + a placebo vial or two placebo 
vials, based on treatment assignment. Investigators 
will be blinded to which vial contains Dysport and 
which vial contains placebo. 
 
A blinded kit will be used in this study to maintain the 
blinding of the study during the DB period. Each blinded kit 
will contain two vials regardless of treatment assignment: 
one vial 300 U or placebo and one vial 500 U or placebo. 
The two vials in each kit will contain either a Dysport 300 U 
vial + a placebo vial, a Dysport 500 U vial + a placebo vial or 
two placebo vials, based on treatment assignment. 
Investigators will be blinded to which vial contains Dysport 
and which vial contains placebo. 
 
53 
8.2 
Clinical Laboratory 
Tests 
Blood and urine samples will be collected during the 
DB and OL periods as described in the study 
procedures and assessments in Table 3 and Table 4 
for the evaluation of haematology and serum 
chemistry.  
 
Blood and urine samples will be collected during the DB and 
OL periods as described in the study procedures and 
assessments in Table 3 and Table 4 for the evaluation of 
haematology and serum chemistry and urine examination.  
 
55 
8.4.1 
Dermatological 
examination 
The investigator will evaluate and record whether 
these or other dermatological conditions are present 
in the study foot and will record any AEs that were 
not present at Baseline resulting from the 
dermatologic examination. 
The investigator will evaluate and record whether these or 
other dermatological conditions are present in the study foot 
and will record new findings as AEs that were not present at 
Baseline resulting from the dermatologic examination. 
55 
8.42 
Neurological 
Examination 
The investigator will evaluate and record whether the 
neurological condition of the study foot is “normal” 
or “abnormal” based on their medical judgment 
regarding the degree of loss of sensation in the study 
foot and will record any AEs that were not present at 
Baseline 
resulting 
from 
the 
neurological 
examination. 
The investigator will evaluate and record whether the 
neurological condition of the study foot is “normal” or 
“abnormal” based on their medical judgment regarding the 
degree of loss of sensation in the study foot and will record 
new findings as AEs that were not present at Baseline 
resulting from the neurological examination. 


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56 
8.4.3 
Musculoskeletal  
Examination 
The investigator will evaluate and record whether 
these or other musculoskeletal conditions of the 
study foot are present and will record any AEs that 
were not present at Baseline resulting from the 
musculoskeletal examination. 
 
The investigator will evaluate and record whether these or 
other musculoskeletal conditions of the study foot are present 
and will record new findings as AEs that were not present at 
Baseline resulting from the musculoskeletal examination. 
 
60 
11.4.3 
Efficacy evaluation 
Sensitivity analysis 
Two sensitivity analyses will be performed. First, 
the primary efficacy analysis will be re-run 
imputing missing data as described in Table 6. 
 
Then, the primary efficacy analysis will be re-run 
on the PP population. 
 
Sensitivity analysis 
Two sensitivity analyses will be performed to investigate the 
robustness of the primary efficacy analysis. First, the 
primary efficacy analysis will be re-run imputing missing 
data as described in Table 6. 
Then, a tipping point analysis will be performed (analysis 
will be detailed in the Statistical Analysis Plan). 
 
60 
11.4.3 
Efficacy evaluation 
Supplementary analyses 
Supplementary analyses will be performed in order 
to complement the primary estimand considering 
two other estimands: 
Supplementary analyses 
Supplementary analyses will be performed in order to 
complement the primary estimand. The primary efficacy 
analysis will be first re-run on the PP population. In 
addition, two other estimands will be considered: 
 


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60 
11.4.3 
Table 7 
Column 1 
Secondary Efficacy Endpoints 
The change from baseline as measured by the 
daily NPRS score averaged over 7 consecutive 
days prior to each scheduled assessment 
timepoint (except at Week 8 DB). 
The change from baseline in the daily mFFI 
Disability subscale score averaged over the 7 
consecutive 
days 
prior 
each 
scheduled 
assessment timepoint. 
The change from baseline in the daily mFFI Pain 
subscale score averaged over the 7 consecutive 
days prior to each scheduled assessment 
timepoint. 
The change from baseline in the daily mFFI total 
score averaged over the 7 consecutive days prior 
to each scheduled assessment timepoint. 
The change from baseline in the daily mFFI 
activity limitation subscale score averaged over 
the 7 consecutive days prior to each scheduled 
assessment timepoint. 
The change from baseline in the PGI-S pain and 
disability scores, respectively, averaged over the 
7 consecutive days prior to each scheduled 
assessment timepoint. 
PGI-I pain and disability scores, respectively, 
averaged over the 7 consecutive days prior to 
each scheduled assessment timepoint. 
 
Secondary Efficacy Endpoints 
The change from baseline in the daily NPRS score averaged 
over the 7 consecutive days prior to Week 4 and Week 12 
DB visits. 
 
The change from baseline in the daily mFFI disability 
subscale score averaged over the 7 consecutive days prior 
to Week 4, Week 8 and Week 12 DB visits. 
 
The change from baseline in the daily mFFI pain subscale 
score averaged over the 7 consecutive days prior to Week 
4, Week 8 and Week 12 DB visits. 
The change from baseline in the daily mFFI total score 
averaged over the 7 consecutive days prior to Week 4, 
Week 8 and Week 12 DB visits. 
 
The change from baseline in the daily mFFI activity 
limitation subscale score averaged over the 7 consecutive 
days prior to Week 4, Week 8 and Week 12 DB visits. 
 
The change from baseline in the PGI-S pain and disability 
scores, respectively, averaged over the 7 consecutive days 
prior to Week 4, Week 8 and Week 12 DB visits. 
 
PGI-I pain and disability scores, respectively, averaged 
over the 7 consecutive days prior to Week 4, Week 8 and 
Week 12 DB visits. 
 


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The change from baseline in HV angle as 
measured 
directly 
by 
weight-bearing 
anterior-posterior radiographs at each scheduled 
assessment timepoint. 
 
The change from baseline in intermetatarsal angle as 
measured directly by weight-bearing anterior-posterior 
radiographs at each scheduled assessment timepoint. 
 
The change from baseline in quality of life as measured 
by the SF-36 at each scheduled assessment 
timepoint. 
 
Time to retreatment 
 
 
 
 
 
 
 
 
 
The change from baseline in HV angle as measured directly 
by weight-bearing anterior-posterior radiographs at Week 
4, Week 8 and Week 12 DB visits. 
 
 
The change from baseline in intermetatarsal angle as 
measured directly by weight-bearing anterior-posterior 
radiographs at Week 4, Week 8 and Week 12 DB visits. 
 
The change from baseline in quality of life as measured by 
the SF-36 at Week 8 and Week 12 DB visits. 
 
Time to retreatment 
 


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60 
11.4.3 
Table 7 
Column 2 
Estimate of Treatment Effect 
Difference between each Dysport doses and the 
placebo group, in the mean change from baseline 
in the mean daily NPRS score averaged for the 
7 consecutive days prior to each scheduled 
assessment timepoint. 
Difference between each Dysport doses and the 
placebo group in the mean change from baseline in 
the mean daily mFFI disability subscale score 
averaged for the 7 consecutive days prior to each 
scheduled assessment timepoint 
Difference between each Dysport doses and the 
placebo group in the mean change from baseline 
in the mean daily mFFI pain subscale score 
averaged for the 7 consecutive days prior to each 
scheduled assessment timepoint 
Difference between each Dysport doses and the 
placebo group in the mean change from baseline in 
the mean daily mFFI total score averaged for the 
7 consecutive days prior to each scheduled 
assessment timepoint 
Difference between each Dysport doses and the 
placebo group in the mean change from baseline 
in the mean daily mFFI activity limitation 
subscale score averaged for the 7 consecutive 
days prior to each scheduled assessment 
timepoint 
Difference between each Dysport doses and the 
placebo group in the change from baseline in the 
mean daily PGI-S pain and disability scores, 
Estimate of Treatment Effect 
Difference between each Dysport doses and the placebo 
group, in the mean change from baseline in the mean daily 
NPRS score averaged for the 7 consecutive days prior to 
Week 4 and Week 12 DB visits. 
Difference between each Dysport doses and the placebo 
group in the mean change from baseline in the mean daily 
mFFI disability subscale score averaged for the 7 
consecutive days prior to Week 4 and Week 12 DB visits. 
Difference between each Dysport doses and the placebo 
group in the mean change from baseline in the mean daily 
mFFI pain subscale score averaged for the 7 consecutive 
days prior to Week 4 and Week 12 DB visits. 
Difference between each Dysport doses and the placebo 
group in the mean change from baseline in the mean daily 
mFFI total score averaged for the 7 consecutive days prior 
to Week 4 and Week 12 DB visits. 
Difference between each Dysport doses and the placebo 
group in the mean change from baseline in the mean daily 
mFFI activity limitation subscale score averaged for the 7 
consecutive days prior to Week 4 and Week 12 DB 
visits. 
Difference between each Dysport doses and the placebo 
group in the change from baseline in the mean daily PGI-S 
pain and disability scores, respectively, averaged for the 7 
consecutive days prior to Week 4 and Week 12 DB visits. 
Difference between each Dysport doses and the placebo 
group in the mean daily PGI-I pain and disability scores, 
respectively, averaged for the 7 consecutive days prior to 
Week 4 and Week 12 DB visits. 


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respectively, averaged for the 7 consecutive days 
prior to each scheduled assessment timepoint 
Difference between each Dysport doses and the 
placebo group in the mean daily PGI-I pain and 
disability scores, respectively, averaged for the 
7 consecutive days prior to each scheduled 
assessment timepoint 
Difference between each Dysport doses and the 
placebo group in then mean change from baseline 
in HV angle at each scheduled assessment 
timepoint 
Difference between each Dysport doses and the 
placebo group in then mean change from baseline 
in intermetatarsal angle at each scheduled 
assessment timepoint 
Difference between each Dysport doses group and 
the placebo group in the SF-36 scores to each 
scheduled assessment timepoint (analysis will be 
detailed in the statistical analysis plan) 
Difference between each Dysport doses group and 
the placebo group in the median time to 
retreatment between the first and the second 
injection. 
 
Difference between each Dysport doses and the 
placebo group in then mean change from baseline in 
HV angle at Week 4 and Week 12 DB visits. 
Difference between each Dysport doses and the placebo 
group in then mean change from baseline in intermetatarsal 
angle at Week 4 and Week 12 DB visits. 
Difference between each Dysport doses group and the 
placebo group in the SF-36 scores to Week 4 and Week 
12 DB visits (analysis will be detailed in the statistical 
analysis plan) 
Difference between each Dysport doses group and the 
placebo group in the median time to retreatment between 
the first and the second injection. 
 
 
 
 
 


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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
D-FR-52120-237 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Protocol Version 3.0 (Amendment 2) 
25 May 2018 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON FOR CHANGES 
 
Follow-up on FDA advice/information re: IND 136332 Dysport - Reference ID: 4259336 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
REPORTING & ANALYSIS PLAN (RAP) UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 


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STUDY NUMBER: 
D-FR-52120-237 
PROTOCOL TITLE: 
A MULTIPLE-DOSE, DOUBLE-BLIND, RANDOMISED, PLACEBO-CONTROLLED 
STUDY TO EVALUATE THE EFFICACY AND SAFETY OF DYSPORT FOR THE 
TREATMENT OF PAIN ASSOCIATED WITH HALLUX ABDUCTO VALGUS 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Protocol Version 2.0 (Amendment 1) 
22 May 2018 
 
 
THE FOLLOWING AMENDMENTS ARE PROPOSED: (deleted text is indicated with strikethrough; new text is indicated in bold) 
Version Date 
06 MARCH 2018 
22 MAY 2018 
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7 & 33 
Synopsis & 
4.2 
Subject presents with metatarsus primus elevates in the 
study foot 
Subject presents with metatarsus primus elevatus in 
the study foot 
7 & 33 
Synopsis & 
4.2 
(8) Subject presents with medical history or clinical evidence 
of any vascular disease 
(8) Subject presents with medical history or clinical 
evidence of peripheral vascular disease 
7 & 33 
Synopsis & 
4.2 
 (13) Subject is using orthotic inserts or devices on the study 
foot 
 
(13) Subject is using an orthotic device of any kind 
(including over-the-counter toe-spacers) which could 
influence the functioning of the hallux of the study foot in 
any way, or any other device intended for this purpose. 
Over-the-counter shoe inserts for the study foot are 
permitted if used for at least 30 days prior to screening. 
7 & 33 
Synopsis & 
4.2 
(14) Subject has medical history or clinical evidence of 
peripheral neuropathy 
(14) Subject has medical history or clinical evidence of 
peripheral neuropathy or fibromyalgia 
7 & 33 
Synopsis & 
4.2 
(19) Subject demonstrates evidence of inflammatory arthritis 
(including gout) or osteoarthritis based on either history or 
clinical evaluation 
(19) Subject demonstrates evidence of inflammatory 
arthritis (including gout) in the study foot or osteoarthritis 
in the study foot based on either history or clinical 
evaluation 


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8 & 34 
Synopsis & 
4.2 
(30) 
Subject is medically unable to discontinue treatment 
with medications with anticoagulant/antiplatelet effects for at 
least 3 days before Screening. Subjects who are medically 
unable to stop these medications for the duration of the 
study (in the opinion of the investigator) will not be 
eligible to participate in the study. 
(30) 
Subject is medically unable to discontinue 
treatment with medications with anticoagulant/antiplatelet 
effects (e.g. warfarin and other coumadin derivatives, 
acetylsalicylic acid and clopidogrel/ticlopidine) for at 
least 3 days before randomisation/injection of study 
treatment. Subjects are permitted restart 
anticoagulant/antiplatelet medications one day after 
injection of study treatment (or longer at the discretion 
of the investigator). 
8 & 43 
Synopsis 
& 
6.2 
Investigators will inject 0.5 mL of the reconstituted solution 
containing study treatment into each of four specified 
muscles of the foot 
Investigators will inject 0.5 mL of the reconstituted solution 
containing study treatment into each of four specified 
muscles of the foot (2.0 mL total volume) 
9, 27 & 
63 
Throughout 
document 
The change from baseline in functional outcome as 
measured by the SF-36 at each scheduled assessment 
timepoint. 
• 
The change from baseline in quality of life as 
measured by the SF-36 at each scheduled assessment 
timepoint. 
26 
3.1.2.1 
Retreatment 
Criteria 
Prior to receiving retreatment with Dysport in each of the two 
retreatment cycles in the OL period (Cycles 2 and 3), subjects 
will be required to meet the following retreatment criteria: 
• 
Subject is willing to receive a new treatment cycle 
with Dysport 
• 
Retreatment with Dysport is in the best interest of 
the subject based on the investigator's clinical 
judgment. 
Prior to receiving retreatment with Dysport in each of the two 
retreatment cycles in the OL period (Cycles 2 and 3), subjects 
will be required to meet all the following retreatment criteria: 
• 
Subject is willing to receive a new treatment cycle 
with Dysport 
• 
Treatment with Dysport is in the best interest of the 
subject based on the investigator's clinical judgment. 
 


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26 
3.2.1 
Primary 
Efficacy 
Endpoint 
 
The primary efficacy endpoint is the change from baseline in 
the daily NPRS score averaged over the 7 consecutive days 
prior to each scheduled assessment timepoint. 
The baseline is defined as the daily NPRS score averaged 
over the 7 consecutive days prior to the baseline visit (Day 
1). 
 
The primary efficacy endpoint is the change from baseline in 
the daily NPRS score averaged over the 7 consecutive days 
prior to the Week 8 assessment timepoint. 
The baseline is defined as the daily NPRS score averaged 
over the 7 consecutive days prior to the baseline visit (Day 
1). 
 
38 & 39 
5.1 
Study 
Schedule 
Table 2 
Was: 
 
 
 
k 
Assessment to include examination of the injection sites on the study foot specifically evaluating the foot for the 
presence of injection site irritation or emergence of other foot  
deformities or dysfunctions (e.g. hammer toe, 
claw toe, neuropathy). Assessment to include evaluation of sensation of the study foot and, any the development of skin 
irritations  
or ulcerations on the study foot. 
 
 


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Is:  
 
 
 
k 
Assessment to include complete physical examination of the injection sites on the study foot specifically evaluating 
the foot for any dermatologic, neurologic or musculoskeletal abnormalities (see Section 8.4 for further details). 
 
40 & 41 
5.1 
Study 
Schedule 
Table 3 
Was: 
 
k 
Assessment to include examination of the injection sites on the study foot specifically evaluating the foot for 
the presence of injection site irritation or emergence of other foot deformities  
or dysfunctions (e.g. hammer 
toe, claw toe, neuropathy). Assessment to include evaluation of sensation of the study foot and, any the development 
of skin irritations or ulcerations on the  
study foot. 
Is: 
 
k 
Assessment to include a complete physical examination of the injection sites on the study foot specifically 
evaluating the foot for any dermatologic, neurologic or musculoskeletal abnormalities (see Section 8.4 for further 
details). 


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45 
6.3 
Concomitant 
Medication/ 
Therapy 
• 
Opioids 
• 
Anticoagulants, with the exception of over the 
counter pain medications (i.e. low dose aspirin) for 
short-term treatment of minor ailments (e.g. 
common cold) 
• 
Subjects who require treatment with antipsychotic 
(e.g. D2 antagonists) or antidepressant (e.g. selective 
serotonin reuptake inhibitors, serotonin and 
norepinephrine reuptake inhibitors) will need to 
demonstrate evidence of stable dose regimen in the 30 
days prior to Screening and will maintain that dose for 
the duration of the study. 
 
• 
Opioids 
• 
Any medication not specifically permitted by the 
protocol which has antinociceptive (pain relieving) 
properties. This includes any and all narcotic pain 
relievers, as well as pregabalin and gabapentin. 
• 
Subjects who require treatment with antipsychotic 
(e.g. D2 antagonists) or antidepressant (e.g. selective 
serotonin reuptake inhibitors, serotonin and norepinephrine 
reuptake inhibitors) will need to demonstrate evidence of 
stable dose regimen in the 30 days prior to Screening and will 
maintain that dose for the duration of the study. 
 
• 
After consultation with prescribing physician, 
anticoagulant medications must be stopped 3 days 
prior to administration of study treatment. These 
medications can be restarted one day after 
administration of study treatment and can be stopped 
for a longer period if deemed necessary in the opinion 
of the investigator, and in compliance with standard 
medical 
practice 
and 
the 
manufactures’ 
discontinuation recommendations for the medication. 
Anticoagulant medications permitted during the study 
include, but are not limited to: 
o 
warfarin and other coumadin derivatives 
o 
acetylsalicylic 
acid 
(including 
low-dose 
aspirin) 
o 
clopidogrel/ticlopidine 
If medically indicated, lower molecular weight heparins are 
permitted providing the last dose was within 24 hours prior 
to administration of study treatment, and may be restarted 
one day following administration of study treatment. 


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46 
6.4 Lifestyle 
Restrictions/
Recommenda
tions 
Besides restrictions already presented in the exclusion 
criteria, subjects should not use orthotic inserts or devices on 
the study foot at any time during the study. 
Besides restrictions already presented in the exclusion 
criteria, subjects should not use an orthotic device or 'over-
the-counter shoe-insert' of any kind which could 
influence the functioning of the hallux of the study foot in 
any way during the study. This includes toe-spacers or 
any other device intended for this purpose. Over-the 
counter shoe inserted will be permitted during the study 
only for subjects who have used these for at least 30 days 
prior to screening. 
46 
7.1.2 
 Foot 
Function 
Index 
To obtain a subscale score, the item scores for a given 
subscale (i.e. pain, disability or activity limitation 
subscales) are totalled and divided by the maximum total 
possible multiplied by 100 for all of the subscale items 
which the subject indicated were applicable. Each 
subscale score, as well as the total score will range from 
0 to 100. 
 
To obtain a subscale score, the item scores for a given 
subscale (i.e. pain, disability or activity limitation 
subscales) are totaled and divided by the maximum 
total possible multiplied by 100 for all of the subscale 
items. Each subscale score, as well as the total score will 
range from 0 to 100. 
 
47 
7.1.3 
Intermetatars
al Angle, 
Hallux 
Valgus Angle 
and 
Sesamoid 
Position 
Intermetatarsal angle, HV angle and tibial sesamoid position 
will be measured directly on weight-bearing anteriorposterior 
radiographs, in which the X-ray beam is angled 15° towards 
the heel centered on the second tarsometatarsal joint with a 
source to image-receptor distance of 100 cm. Radiographs 
should be done using a foot positioner. Images should be 
taken by the same radiology technician. Angle measurements 
will be performed by a blinded central reader.  
 
Intermetatarsal angle, HV angle and tibial sesamoid position 
will 
be 
measured 
directly 
on 
weight-bearing 
anteriorposterior radiographs, in which the X-ray beam is 
angled 15° towards the heel centered on the second 
tarsometatarsal joint with a source to image-receptor distance 
of 100 cm. Radiographic measurements will be conducted 
by following the General Acquisition Guidelines 
document provided to sites by the Sponsor to ensure 
accurate reproducibility of image acquisition across sites. 
Images should be taken by the same radiology technician. 
Angle measurements will be performed by a blinded central 
reader. 


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48 
7.1.8 
Patient 
Global 
Impression of 
Severity of 
Disability 
The PGI-S will be assessed by the subject by answering the 
following question: “How severe was your disability while 
performing physical activities (e.g. standing, walking or 
running) over the past 24 hours?” (0=no pain; 1=mild pain; 
2=moderate pain; 3=severe pain). 
 
The PGI-S will be assessed by the subject by answering the 
following question: “How severe was your disability while 
performing physical activities (e.g. standing, walking or 
running) over the past 24 hours?” (0=no disability; 1=mild 
disability; 2=moderate disability; 3=severe disability). 
49 
8.1 
Adverse 
Events 
The investigator will be responsible for a clinical assessment 
of the study participants during the whole participation of the 
subjects in the study, from informed consent up to discharge 
from the study, and for the setup of a discharge plan if 
needed. 
The investigator will be responsible for a clinical safety 
assessment of the study participants during the whole 
participation of the subjects in the study, from informed 
consent up to discharge from the study, and for the setup of 
a discharge plan if needed. 


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50 
8.1.3 
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.  
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 alternative 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. 
Adverse events of special interest (AESIs) for Dysport are 
AEs that suggest a possible remote spread of effect of the 
toxin or events suggestive of hypersensitivity like 
reactions. The effects of Dysport and all BTX products 
may spread away from the area of injection to produce 
symptoms consistent with remote spread of BTX effects. 
These symptoms have been reported hours to weeks after 
injection. The events of remote spread of toxin maybe 
severe and 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. 
 
 
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 remote 
spread of toxin or hypersensitivity like reactions. In order 
to perform the analysis, variables including alternative 
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. 


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52 
8.1.6 
Pregnancy 
Information regarding pregnancies must be collected on the 
AE page of the eCRF and reported to the sponsor as an 
SAE. The sponsor will request further information from the 
investigator as to the course and outcome of the pregnancy 
using the Standard Pregnancy Outcome Report Form.  
 
Information regarding pregnancies must be collected on the 
AE page of the eCRF. The sponsor will request further 
information from the investigator as to the course and 
outcome of the pregnancy using the Standard Pregnancy 
Outcome Report Form.  
 
53 
8.1.9 
Reporting to 
Competent 
Authorities/I
ECs/IRBs/Ot
her 
Investigators 
The sponsor will ensure that processes are in place for 
submission of reports of Suspected Unexpected Serious 
Adverse Reactions (SUSARs) occurring during the study to 
the Competent Authorities (CA), IECs and other investigators 
concerned by the 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 7 calendar days, with another 8 days for 
completion of the report. 
For study centres in the USA, Investigational New Drug 
Application Safety Reports will be submitted directly to the 
investigators. It is the investigators’ responsibility to notify 
their IRB in a timely manner. 
 
The sponsor will ensure that processes are in place for 
submission of reports of Suspected Unexpected Serious 
Adverse Reactions (SUSARs) occurring during the study to 
the Competent Authorities (CA), IECs and other 
investigators concerned by the IMP. Reporting will be done 
in accordance with the applicable regulatory requirements. 
For study centres in the USA, Investigational New Drug 
Application Safety Reports will be submitted directly to the 
investigators. It is the investigators’ responsibility to notify 
their IRB in a timely manner. 
 


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55 
8.4 
Examination 
of the Study 
Foot 
(8.3.1) An examination of the study foot will be conducted as 
outlined in Table 3 and Table 4. The examination will 
include assessment of the injection sites on the study foot 
specifically evaluating the foot for the presence of injection 
site irritation or emergence of other foot deformities or 
dysfunctions (e.g., hammer toe, claw toe, neuropathy). The 
assessment will also include evaluation of sensation of the 
study foot and any development of skin irritations or 
ulcerations on the study foot. Any findings will be reported 
as AEs. 
 
(8.4) A complete physical examination of the study foot 
will be conducted as outlined in Table 3 and Table 4 for 
the DB and OL periods. The examination will include 
evaluation of the a) dermatologic, b) neurologic and c) 
musculoskeletal condition of the study foot. For 
dermatologic and musculoskeletal foot examinations, 
the Investigator will record whether a given 
abnormality or deformity is present. For neurological 
examinations, the Investigator will record whether the 
specified neurological parameters are "normal" or 
"abnormal" based on clinical presentation.  
Any findings that were not present at Baseline based on 
examination of the study will be recorded as AEs. As for 
all AEs reported during the study, the investigator 
should use his/her medical judgment to determine if 
treatment of the study foot is required based on an 
abnormal finding, and/or if the subject should be 
withdrawn from the study due to an abnormal finding 
in the study foot. 
Details for each of the study foot examination 
parameters required during the study are provided in 
the sections below. 


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55 
8.4.1 
Dermato 
logical 
Examination 
 
The dermatologic examination will consist of a global 
inspection of the study foot and injection sites for 
injection site irritations, ulcerations, bleeding, 
discolorations, calluses, wounds, fissures, lesions, 
macerations, nail dystrophy, hyperpigmentation, 
erythema, oedema or paronychia. Inspection of the toes 
should include a search for fungal, ingrown or elongated 
nails, as well as areas between the toes for the presence 
of deeper lesions. The investigator will evaluate and 
record whether these or other dermatological conditions 
are present in the study foot and will record any AEs 
that were not present at Baseline resulting from the 
dermatologic examination. 
55 
8.4.2 
Neurological 
Examination 
 
The neurological examination will consist of the 
evaluation of protective sensation using the Ipswich 
Touch Test [22], as subjects who develop neuropathies 
with loss of sensation at are increased risk for 
unrecognized injury. The subject will be instructed to 
close their eyes while the investigator lightly rests 
his/her finger on each of the subject’s first, third and 
fifth toes of the study foot for 1 to 2 seconds. Subjects 
will be instructed to respond “yes” when they feel the 
investigator’s touch. The investigator will evaluate and 
record whether the neurological condition of the study 
foot is “normal” or “abnormal” based on their medical 
judgment regarding the degree of loss of sensation in the 
study foot and will record any AEs that were not 
present at Baseline resulting from the neurological 
examination. 


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56 
8.4.3 
Musculo 
skeletal 
Examination 
 
The musculoskeletal examination will include a visual 
inspection of the study foot, as well as direct evaluation 
via palpation, range of motion (ie, dorsiflexion, plantar 
flexion), motor strength and muscle tone to identify the 
presence of abnormalities or foot deformities (except for 
HAV). The investigator will specifically look for the 
presence of bony prominences, asymmetry, wasting, 
fasciculations or the presence of foot deformities (except 
for HAV) including but not limited to hammer toe, claw 
toe, Charcot’s neuroarthropathy, pes planus, cavus 
planus, Morton’s neuroma, or hallux limitus. The 
investigator will evaluate and record whether these or 
other musculoskeletal conditions of the study foot are 
present and will record any AEs that were not present 
at Baseline resulting from the musculoskeletal 
examination. 
65 
11.4.5 
Safety 
Evaluation 
 
Descriptive statistics will be provided for study foot 
examination (i.e. dermatological, neurological and 
musculoskeletal). Results of these assessments will 
include whether a given dermatologic or 
musculoskeletal deformity is present in the study foot, 
or whether the neurological foot evaluation domain 
evaluated is “normal” or “abnormal”. For each of the 
three parameters summaries will be provided by 
treatment group for both the DB and OL periods.  
78 
18 
References 
 
22. 
Raymond G, Prashanth R, Baker N et al. The 
Ipswich Touch Test: a simple and novel method to 
identify in patients with diabetes at risk of foot 
ulceration. Diabetes Care. 2011;34(7):1517-8. 


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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
D-FR-52120-237 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Protocol Version 2.0 (Amendment 1) 
22 May 2018 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON FOR CHANGES 
 
Changes made based on FDA recommendation to expand and clarify required examination of the study foot following 
injection; use of anticoagulants and pain relieving medications during the study. In addition, the IRB requested for the 
clarification for discontinuation of anticoagulants. 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
REPORTING & ANALYSIS PLAN (RAP) UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 
 

SAP_001.pdf: 
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$SSURYHG
&OLQLFDO
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&OLQLFDO
*07
PPD
PPD
PPD


SAP Final: Version 1.0 20 September 2019 
1/38 
 
CONFIDENTIAL  
 
STATISTICAL ANALYSIS PLAN 
 
PROTOCOL TITLE: A MULTIPLE-DOSE, DOUBLE-BLIND, RANDOMISED, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
DYSPORT FOR THE TREATMENT OF PAIN ASSOCIATED WITH HALLUX 
ABDUCTO VALGUS 
D-FR-52120-237 
 
 
This statistical analysis plan is based on: 
PROTOCOL VERSION AND DATE: FINAL VERSION 6.0 – 03 JULY 2019 
 
 
 
 
SAP Version 
Date 
Final Version 1.0 
20 September 2019 
 
 
 
 
 
 


PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


SAP Final: Version 1.0 20 September 2019 
3/38 
 
CONFIDENTIAL  
 
HISTORY OF CHANGES 
 
Version Number Date
Description/Rational for change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


SAP Final: Version 1.0 20 September 2019 
4/38 
 
CONFIDENTIAL  
 
TABLE OF CONTENTS 
APPROVAL PAGE .................................................................................................................. 2 
HISTORY OF CHANGES ...................................................................................................... 3 
TABLE OF CONTENTS ......................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................... 6 
1 
INTRODUCTION .......................................................................................................... 8 
2 
PROTOCOL OVERVIEW ............................................................................................ 8 
2.1 
Study Objectives and Hypotheses ................................................................................. 8 
2.1.1 
Primary objective ........................................................................................... 8 
2.1.2 
Secondary objectives ..................................................................................... 8 
2.1.3 
Exploratory objectives ................................................................................... 8 
2.1.4 
Primary efficacy hypotheses ......................................................................... 8 
2.2 
Overall Study Design and Investigational Plan ........................................................... 9 
2.3 
Sample Size Determination and Power ......................................................................... 9 
2.4 
Randomization and Blinding ......................................................................................... 9 
2.5 
Schedule of Assessments ............................................................................................... 10 
3 
PLANNED ANALYSES ............................................................................................... 10 
3.1 
Safety Monitoring ......................................................................................................... 10 
3.2 
Interim Analysis / Primary Analysis ........................................................................... 10 
3.2.1 
Interim Analysis .......................................................................................... 10 
3.2.2 
Primary Analysis ......................................................................................... 10 
3.3 
Final Analysis ................................................................................................................ 10 
4 
ANALYSIS POPULATIONS ...................................................................................... 10 
4.1 
Safety population .......................................................................................................... 10 
4.2 
Intention-To-Treat (ITT) population .......................................................................... 11 
4.3 
Per Protocol (PP) population ....................................................................................... 11 
4.4 
Active Treatment population ....................................................................................... 11 
4.5 
Mis-Stratification .......................................................................................................... 11 
5 
STATISTICAL METHODS/ANALYSES .................................................................. 11 
5.1 
General Considerations ................................................................................................ 11 
5.1.1 
Outputs Presentation................................................................................... 11 
5.1.1.1 
Tables Header .............................................................................................. 11 
5.1.1.2 
Presentation of Treatment Group ................................................................ 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 
Randomization, Disposition and Population .............................................................. 13 
5.3 
Protocol Deviations ....................................................................................................... 14 
5.4 
Demography and Other baseline characteristics ....................................................... 14 
5.5 
Medical history, non-drug therapies, medications and surgical procedures .......... 14 
5.6 
Compliance .................................................................................................................... 15 


SAP Final: Version 1.0 20 September 2019 
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CONFIDENTIAL  
 
5.7 
Efficacy .......................................................................................................................... 15 
5.7.1 
General Considerations .............................................................................. 15 
5.7.1.1 
Significance Testing and Estimations .......................................................... 15 
5.7.1.2 
Statistical/analytical issues .......................................................................... 16 
5.7.2 
Analysis of Primary Efficacy Endpoint ...................................................... 17 
5.7.2.1 
Endpoint, Treatment Effect and Estimand Definition .................................. 17 
5.7.2.2 
Primary Analysis .......................................................................................... 18 
5.7.2.3 
Sensitivity Analysis ....................................................................................... 18 
5.7.2.4 
Supplementary Analysis ............................................................................... 19 
5.7.2.5 
Subgroup Analysis ....................................................................................... 20 
5.7.3 
Analysis of Secondary Efficacy Endpoints ................................................ 21 
5.7.3.1 
Foot pain NPRS score .................................................................................. 21 
5.7.3.2 
mFFI ............................................................................................................ 21 
5.7.3.3 
Patient Global Impression (PGI) ................................................................. 22 
5.7.3.4 
HV angle and intermetatarsal angle ............................................................ 24 
5.7.3.5 
Quality of life (SF-36) .................................................................................. 24 
5.7.3.6 
Time to retreatment ...................................................................................... 25 
5.7.4 
Analysis of Exploratory Efficacy Endpoints .............................................. 25 
5.7.5 
Analysis of Additional Endpoints ............................................................... 26 
5.8 
Safety .............................................................................................................................. 26 
5.8.1 
General Consideration ................................................................................ 26 
5.8.2 
Extent of exposure ...................................................................................... 26 
5.8.3 
Adverse Event .............................................................................................. 27 
5.8.4 
Laboratory Data .......................................................................................... 29 
5.8.5 
Vital Signs ................................................................................................... 29 
5.8.6 
Physical Examination ................................................................................. 30 
5.8.7 
Examination of Injected Foot ..................................................................... 30 
5.9 
Pharmacokinetics and Pharmacodynamics ................................................................ 30 
5.10  Anti-drug Antibodies .................................................................................................... 30 
6 
DATA HANDLING ...................................................................................................... 31 
6.1 
Visit Window ................................................................................................................. 31 
6.2 
Unscheduled Visits, Retest, Withdrawal Visit ............................................................ 31 
7 
DERIVED DATA .......................................................................................................... 31 
8 
REFERENCES .............................................................................................................. 31 
9 
APPENDICES ............................................................................................................... 33 
A1.  SAS code ........................................................................................................................ 33 
A2.  List of PCSA criteria .................................................................................................... 34 
A3.  Partial/Missing Date Convention ................................................................................ 36 
A4.  Programming Convention for Outputs ....................................................................... 37 
A5.  Listings conventions ...................................................................................................... 38 
 


SAP Final: Version 1.0 20 September 2019 
6/38 
 
CONFIDENTIAL  
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
BTX 
Botulinum Toxin 
BTX-A 
Botulinum Toxin Type A 
BTX-A-HAC 
Botulinum Toxin Type A Hemagglutinin Complex 
CMC 
Chemistry Manufacturing Control 
CRO 
Contract research organisation 
CSR 
Clinical Study Report 
DB 
Double-blind 
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration 
FFI 
Foot Function Index 
GCP 
Good Clinical Practice 
HV 
Hallux Valgus (angle) 
IA 
Interim Analysis 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IRB 
Institutional review board 
IRT 
Interactive response technology 
ITT 
Intent-to-treat 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
mFFI 
Modified Foot Function Index 
NPRS 
Numeric Pain Rating Scale 
OL 
Open-label 
PCSA 
Potentially Clinically Significant Abnormalities 
PGI-I 
Patient Global Impression of Improvement 
PGI-S 
Patient Global Impression of Severity 
PP 
Per protocol 
SAE 
Serious adverse event 


SAP Final: Version 1.0 20 September 2019 
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CONFIDENTIAL  
 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOP 
Standard Operating Procedure 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
Treatment emergent adverse event 
US(A) 
United States (of America) 
WHO 
World Health Organisation 
 
 
 


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CONFIDENTIAL  
 
mean daily NPRS score averaged for the 7 consecutive days prior the double-blind 
(DB) Week 8 visit. 
• 
H1: There is a difference between treatment with Dysport 300 U or Dysport  
500 U and treatment with Placebo with respect to the change from baseline in the 
mean daily NPRS score averaged for the 7 consecutive days prior the DB Week 8 
visit. 
2.2 
Overall Study Design and Investigational Plan 
This is a multiple-dose, randomized, parallel-group, DB, placebo-controlled study to 
evaluate the efficacy and safety of Dysport at doses of 300 U and 500 U compared 
with placebo in adult subjects suffering from clinically significant HV who have not 
undergone surgery for their condition. The study will consist of a screening period, 
followed by a DB period where subjects will receive a single treatment with either 
Dysport (300 U and 500 U dose groups) or placebo (Cycle 1) followed by an open-
label (OL) extension period where subjects may receive up to two additional cycles 
of Dysport (300-500U) in the affected foot. As such, the maximum duration of 
participation in the study for a given subject will be 36 weeks. The randomization will 
be stratified by patients having either unilateral or bilateral HV. 
2.3 
Sample Size Determination and Power 
Several lines of evidence have established that a reduction of approximately 2 points 
or 10% to 30% on the NPRS represents a clinically important difference for 
evaluations of pain intensity in numerous musculoskeletal disorders, as well as 
specifically in HV patients following treatment. Several interventional studies have 
demonstrated treatment-placebo differences in the NPRS ranging from 1.5 to 2.0 
points in HV patients. Based on these findings, a difference of 1.5 points between 
Dysport and Placebo is anticipated in the change from baseline in the mean daily 
NPRS score averaged for the 7 consecutive days prior to the Week 8 DB visit. 
A sample size of 165 subjects (55 subjects per treatment group) is required to 
demonstrate the superiority of each of the two Dysport doses (300 U and 500 U) over 
placebo. This calculation is based on the following assumptions: 
• 
a mean difference of 1.5 points observed between the Dysport and placebo 
groups in the mean daily NPRS score averaged for the 7 consecutive days prior 
to the Week 8 visit in the DB period, 
• 
a common standard deviation of 2.5, 
• 
a treatment group ratio of 1:1:1, 
• 
a Hochberg procedure is implemented to control the family-wise Type 1 error 
rate at one-sided 2.5% level for comparisons of two Dysport doses versus 
placebo, 
• 
a minimal power of 80%, corresponding for a comparison based on power using 
a Type I error rate from a one-sided test at 1.25% level. 
 
An interim analysis will be conducted after the first 110 randomised subjects have 
been followed up for at least 12 weeks. The interim analysis is described in section 
3.2.1. This interim analysis plan results in a minimal power of at least 80% to detect 
a treatment effect of 1.5 units in a Dysport arm. 
 
2.4 
Randomization and Blinding 
All Investigational Medicinal Product (IMP) will be similar in size, colour, smell, 
taste and appearance allowing the blinded conditions of the study to be maintained. 


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CONFIDENTIAL  
 
Subjects and investigators will remain blinded to treatment assignment during the 
Double Blind period. The sponsor’s randomization manager who is a statistician 
independent from the study will prepare: 
• 
A list of randomization numbers (List A). It will be produced in blocks, on a 
balanced ratio (1 placebo: 1 Dysport 300 U: 1 Dysport 500 U) and will be 
stratified by unilateral and bilateral HV. 
• 
A list of treatment numbers/treatment which will be dispatched to the sites (list 
B). It will be produced in blocks, on a balanced ratio (1 placebo: 1 Dysport 300 
U: 1 Dysport 500 U). 
2.5 
Schedule of Assessments 
Schedule of assessments is presented in section 5.1 from the protocol. 
 
3 
PLANNED ANALYSES 
3.1 
Safety Monitoring  
No independent DMC will be used in this study. 
3.2 
Interim Analysis / Primary Analysis 
3.2.1 
Interim Analysis 
An interim analysis will be conducted after the first 110 randomised subjects have 
been followed up for at least 12 weeks. The aim of this interim analysis is to both 
assess futility and the potential for early stopping due to efficacy of one of the Dysport 
group as compared to the Placebo group. A decision to continue with the study will 
be determined by an independent DMC based on the outcome of the interim analysis. 
No interruption to recruitment will occur whilst the decision-making process is 
ongoing. The decision rule is described in section 5.7.1.2. 
 
Details regarding operational aspects of the interim analysis are described in the 
Interim Analysis Charter. 
 
3.2.2 
Primary Analysis 
A primary analysis will be conducted once all subjects have completed the Week 12 
of the DB period. At this point, all subjects will have completed the Week 8 visit and 
had adequate safety follow-up. 
 
3.3 
Final Analysis 
A final analysis will be carried out once all subjects have completed end of study 
evaluation, after the database lock. 
 
4 
ANALYSIS POPULATIONS  
4.1 
Safety population 
All subjects who received at least one dose of IMP administration (including only 
partial administration). Subjects will be analyzed using subjects as treated for the 
safety analyses.  


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CONFIDENTIAL  
 
4.2 
Intention-To-Treat (ITT) population  
All randomized subjects (i.e. who were randomly allocated to a treatment group by 
IRT). Subjects will be analyzed using subjects as randomized for the efficacy 
analyses. 
 
4.3 
Per Protocol (PP) population 
All subjects in the ITT population for whom no major protocol deviations (which may 
interfere with efficacy evaluation) occurred until Week 8 of the DB period. 
Major protocol deviations are listed in the protocol deviation plan. 
Data will be excluded from the Per Protocol population on a subject basis and not on 
a visit basis. 
 
4.4 
Active Treatment population 
All randomized subjects who received at least one dose of Dysport (including only 
partial administration) during the DB or OL period. Subjects will be analyzed using 
subjects as randomized for the efficacy analyses and using subjects as treated for the 
safety analyses. 
 
4.5 
Mis-Stratification 
For statistical analysis, in the event a subject is stratified incorrectly, “randomized 
stratum” will be used rather than “actual stratum”. Preservation of the initial 
randomization in analysis is important in preventing bias and in providing a secure 
foundation for statistical tests (ICH E9). 
 
5 
STATISTICAL METHODS/ANALYSES 
The statistical analyses will be performed by Medpace in accordance with ICH E9 
guideline and guidelines presented in section 8. 
 
Overall, the analysis strategy is to evaluate efficacy and safety of two doses of 
Dysport compared to Placebo after single administration (DB period), and to evaluate 
efficacy and safety over repeated Dysport treatments, using analyses by Active 
Treatment Cycle. 
Listings will be presented by subject for DB and OL periods together while the tables 
associated with the DB period will be separated from the tables assessing repeat 
treatment with Dysport. 
Statistical inferences will only be performed on the DB period until Week 12. 
 
5.1 
General Considerations 
All statistical analyses will be performed using the SAS® software version 9.4. 
 
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 only. 


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CONFIDENTIAL  
 
5.1.1.2 
Presentation of Treatment Group 
Double-Blind Period Analyses 
For the analysis of the DB period, tables will be displayed using the following 
treatment group labels, in the following order: 
• 
Placebo 
• 
Dysport 300 U 
• 
Dysport 500 U 
• 
All Dysport 
Repeat treatment: Active Treatment Analyses 
To assess efficacy and safety data over repeat treatments, data will be analysed using 
the Active Treatment Cycle approach as described in Figure 1 below. These analyses 
will be performed on the Active Treatment population:  
 for subjects treated with Dysport in the DB period, the first cycle in the DB 
period will be the first Active Treatment Cycle.  
 for subjects treated with placebo in the DB period, the first cycle in the OL 
period will be the first Active Treatment Cycle.  
Figure 1 Active Treatment Cycle Analysis 
 
Three types of summary tables will be produced: 
 Summary by number of active treatment cycles: these tables will present the 
long-term efficacy and safety data with all doses combined, and will display 
subjects with at least 1 (2 and 3) active treatment cycles. In each treatment 
cycle, the summary will be by whether the first active treatment is in DB or 
OL (when applicable), and in total. 
 Summary by sequence of doses and active treatment cycle: these tables will 
present the efficacy of the first two doses for subjects having at least two 
doses, and the three doses for subjects having three doses. 
 Summary by dose received at each active treatment cycle: to evaluate the 
safety of each dose at a given cycle.  
 


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CONFIDENTIAL  
 
The type of summary table(s) used for each endpoint are described in sections 5.7 and 
5.8. 
 
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 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), 
median, minimum and maximum.  
 
5.1.3 
Baseline value 
Unless otherwise specified, baseline is defined as the last non-missing measurement 
taken prior to first IMP administration (including unscheduled assessments).  
 
5.1.4 
Reference Start Date and Study Day 
Reference start date is defined as the day of the first IMP administration. For subjects 
who are randomized but do not receive study drug, randomization date should be 
taken as reference start date for efficacy analysis (ITT). 
The day of the first 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 listings where an assessment date or event date appears. 
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 
Randomization, Disposition and Population 
A listing presenting randomization details will be provided. 
A listing of re-enrolled patients will be provided. 
Following disposition summaries and listings will be provided: 
- 
Summary table with the number and percentages of randomized subjects per site 
by DB treatment group on the ITT population, 
- 
Summary table with the number and percentage of subjects screened, screen 
failed, reason for screen failure, randomized, completed, withdrawn and reason 
for withdrawal by DB treatment group on all screened subjects, 
- 
Summary table with the number and percentage of subjects withdrawn and reason 
for withdrawal by Active Treatment Cycle on the Active Treatment population. 
- 
Summary table on duration of subject participation in the study on the ITT 
population. The definition of the duration of subject participation is date of 
consent – date of the last study visit + 1. 
- 
Listing of dates of visit on the ITT population, 
- 
Listing of screen failure subjects on all subjects, 


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CONFIDENTIAL  
 
- 
Listing of withdrawn subjects on the ITT population. 
 
Following analysis population summaries and listings will be provided for the ITT 
population: 
- 
Listing of subjects violated inclusion criteria,  
- 
Listing of subjects fulfilled exclusion criteria,  
- 
Summary of the number and percentage of subjects in each analysis population 
by DB treatment group and overall, based on all randomized subjects with reasons 
for exclusion from each analysis population, 
- 
Listing including flag for each analysis population and reason for exclusion from 
each population. 
 
5.3 
Protocol Deviations 
A list of major protocol deviations and any action taken have been defined in the 
Protocol Deviation Plan. Patients with major protocol deviations will be determined 
before unblinding of the study. A final review will be done during the blind data 
review and documented in a separate document and the impact on the per protocol 
population will be assessed. Confirmation of major deviations related to treatment 
and dose will be done after unblinding.   
Number and percentage of subjects with protocol deviations will be summarized by 
deviation category for all randomized subjects. A Listing of major protocol deviations 
will also be provided. 
 
5.4 
Demography and Other baseline characteristics 
All demographic and baseline characteristics summaries will be provided for the ITT 
and safety population (if different from ITT population). Disease characteristics (HV 
bilaterality, baseline severity [average NPRS score], screening and baseline Hallux 
Valgus (HV) angle, screening and baseline intermetatarsal angle, use of insoles, time 
since using insoles, type of insole, whether a device for ePRO is provided) will be 
included. No statistical comparison between treatment groups will be performed. 
Listings will also be provided for all the summaries listed above.  
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 first IMP administration to allow classification as either 
Prior only, Prior and Concomitant, or Concomitant only: 
 
Prior (P) 
Start and stop dates prior to the date of the first IMP 
administration.
Prior and 
Concomitant (PC) 
Start date before the date of the first IMP administration 
and stop date on or after the date of the first IMP 
administration.
Concomitant (C) 
Start date on or after the date of first IMP administration.


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CONFIDENTIAL  
 
Summary tables on prior medications, non-drug therapies, and surgical procedures 
will include “P” only, summary tables on concomitant medications, non-drug 
therapies, and 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. 
 
The following summaries, presenting count and percentages of subjects will be 
provided for the ITT population: 
- 
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), 
- 
Prior non-drug therapies (P) by primary SOC and PT, 
- 
Concomitant non-drug therapies (PC, C) by primary SOC and PT, and 
- 
Concomitant surgical procedures (C) by primary SOC and PT. 
 
Listings will be provided for all the summaries listed above. These listings should 
include a flag indicating the category (P, PC, C) as described in the table above.  
 
5.6 
Compliance 
A listing will be presented for drug administration (volume administered, specified 
difficulties during drug administration, injection sites, date) at all treatment cycles by 
DB treatment group and subject. 
 
5.7 
Efficacy  
5.7.1 
General Considerations 
5.7.1.1 
Significance Testing and Estimations 
For the primary efficacy analysis, a Hochberg procedure will be applied to control the 
global type I error at one-sided 2.5% significance level. 
For other efficacy analyses, all statistical tests will be performed one-sided with a 
type I error rate set at 2.5%. 
For safety analyses, no formal statistical analyses will be carried out; only descriptive 
statistics will be provided. 
 
Descriptive statistics will be provided for: 
 the DB period, by DB treatment group for the ITT population.  
 the Active Treatment Cycle, on the Active Treatment population either by 
number of active treatment cycles (all doses combined) or by sequence of 
dose in active treatment cycles (see section 5.1). The type of analysis will be 
specified for each endpoint.  
 


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CONFIDENTIAL  
 
5.7.1.2 
Statistical/analytical issues  
Adjustments for Covariates  
The randomization is stratified by unilateral and bilateral HV. Therefore, the planned 
statistical analysis for the demonstration of the superiority of Dysport compared to 
Placebo will include the stratification parameter (unilateral or bilateral HV) in the 
model as a factor. An analysis without the stratification parameter will also be 
performed to evaluate the effect of the stratification parameter on the results. 
 
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 
This is a multicentre study conducted in US. The centre effect will be explored using 
analysis centre. Analysis centre will be generated using the following procedure: 
• 
Centres are sorted by the total number of ITT subjects and centre ID in ascending 
order. 
• 
If the first (smallest) centre has less than 6 ITT subjects, it will be pooled with 
the next centre on the sorted list (i.e., the smallest of other sites) until the pooled 
(analysis) centre has at least 6 ITT subjects. 
• 
The previous step is repeated for the rest of the centres until all analysis centres 
have at least 6 ITT subjects. If the total number of ITT subjects in the rest of the 
centre(s) is less than 6, they will then be included in the previous analysis centre. 
 
The primary analysis will be repeated with the analysis centre as an additional factor 
in the model. If the hypothesis that the centre effect does not exist is rejected, the 
analysis centre will be included in all the analyses. 
 
Multiple Comparisons/Multiplicity  
 
Due to the multiple comparisons, significance levels will be adjusted using the 
Hochberg adjustment to reduce the risk of false positive results. The raw p-values will 
be included in the summary tables.  
 
To account for the interim analysis, the overall type I error for each comparison is 
controlled at the one-sided 0.025 level using O’Brien Fleming spending per Lan-
DeMets spending function specification. Treatment comparison with an O’Brien 
Fleming spending corresponds to a nominal one-sided alpha of 0.0062 at the interim 
and 0.0231 at the final analysis. 
 
To implement the Hochberg procedure, decision rules are the following: 
• 
At interim look: 
Compare larger p-value to 0.0062 
o If <larger of 2 p-values> <0.0062 then stop and declare evidence of effect 
for each arm, 
o If not, compare <smaller of 2 p-values> to 0.0062/2. If <smaller of 2  
p-values> <0.0062/2, then conclude evidence of effect for arm with the 
smallest p-value 


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CONFIDENTIAL  
 
• 
At final look (if outcome of IA is to continue): 
Compare larger p-value to 0.0231 
o If <larger of 2 p-values> <0.0231 then stop and declare evidence of effect 
for each arm 
o If not, compare <smaller of 2 p-values> to 0.0231/2. If <smaller of 2  
p-values> <0.0231/2, then conclude evidence of effect for arm with the 
smallest p-value 
 
The non-binding futility boundary is set to declare futility if the one-sided p-value for 
a comparison is above 0.30.   
 
During the interim analysis, if futility is concluded for the primary endpoint, the 
secondary endpoint mFFI pain subscale score (change from baseline in the daily mFFI 
pain subscale score averaged over the 7 consecutive days prior to the Week 8 DB 
visit) will be analysed using MMRM as described in Table 3. If a one-sided p-value 
is ≤ 0.05, then declare evidence of trend for the corresponding arm; Otherwise we 
conclude not having evidence of trend for the corresponding arm.   
 
Examination of Subgroups 
Subgroup analyses will be detailed in the concerned sections. 
 
5.7.2 
Analysis of Primary Efficacy Endpoint 
5.7.2.1 
Endpoint, Treatment Effect and Estimand Definition 
The primary efficacy endpoint is the change from baseline in foot pain, as measured 
by the daily NPRS score averaged over the 7 consecutive days prior to the Week 8 
DB visit. Baseline is defined as the daily NPRS score averaged over the 7 consecutive 
days prior to the baseline visit.  
To assess the primary objective, the hypothetical estimand is defined by the following 
key attributes: 
- 
Population: Subjects in the ITT. 
- 
Variable: Change from baseline in foot pain regardless of whether the subject has 
an intercurrent event during the study. 
- 
The potential intercurrent events are: 
(1) 
Use of prohibited pain medication, 
(2) 
Surgery for HV. 
- 
Population-level summary: Change from baseline in foot pain (estimate of the 
treatment effect). 
No treatment switch or interruption is possible as the primary efficacy endpoint is 
evaluated following a single injection of study treatment. Intercurrent event (1) is 
unlikely to occur, as the evaluation period for the primary efficacy endpoint is up to 
Week 8 (short period). Intercurrent event (2) is also unlikely to occur. All subjects 
with this level of pain severity and angular displacement are considered surgical 
candidates theoretically. However, the upper limit on HV angle (30 degrees) will 
likely limit the need of a “rescue” surgery. 
Subjects are expected to continue follow-up assessments regardless of these two 
intercurrent events. NPRS scores will be used as observed. 
 


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5.7.2.2 
Primary Analysis 
Descriptive statistics (including the summary of raw and change from baseline by 
treatment group and timepoint) will be provided for the DB period, by DB treatment 
group for the ITT population. Average score will be calculated if there are at least 4-
days of e-diary completed, otherwise, the average score will be considered missing. 
A mixed model for repeated measures (MMRM) on change from baseline in foot pain 
as measured by the daily NPRS score averaged over the 7 consecutive days prior to 
each scheduled assessment timepoint of the DB period (up to Week 12) will be used 
to evaluate the estimand and compare treatment groups. Missing data will be 
considered missing at random (MAR). For subjects without any available post-
baseline average scores, the Week 8 average pain score will be imputed as follows: 
 
• 
If a subject discontinues because of lack of efficacy, the Week 8 average pain 
score will be imputed by the mean of placebo group at Week 8, 
• 
If a subject discontinues for other reason that lack of efficacy, the Week 8 
average pain score will be imputed by the mean of the subject's treatment group 
at Week 8, 
• 
If a subject completes the study, but has no valid diary (less than 4 diary days 
completed) post-baseline, the Week 8 average pain score will be imputed by the 
mean of the subject's treatment group at Week 8. 
 
This model will include the fixed categorical effects of treatment group, visit, 
treatment group-by-visit interaction, and the stratification parameter as fixed 
categorical covariates and the baseline value as fixed continuous covariate. The 
treatment group factor will have three levels (Dysport 300 U, Dysport 500 U and 
placebo), the factor visit three levels (Week 4, Week 8 and Week 12) and the 
stratification parameter two levels (unilateral and bilateral HV). 
 
The following estimates will be provided:  
For each of the 3 treatment groups, the least squares mean of the change from Baseline 
to Week 8 in foot pain and associated 2-sided 95% confidence.  
For each of the 2 Dysport groups, the least squares mean of the difference against 
placebo with a 2-sided 95% confidence interval and p-value. 
See Appendix A1 for the SAS code. 
 
The study will be considered successful if the superiority of at least 1 Dysport group 
relative to placebo is demonstrated. 
Non-parametric tests may also be carried out to evaluate robustness of the results if 
the linearity, normality, homoscedasticity assumptions are violated. 
    
The daily pain scores will be listed along with the 7-day average prior to the scheduled 
visits. For any subjects and visits where the 7-day average was not able to be 
calculated, the imputed value will be provided and flagged in the listing. 
 
5.7.2.3 
Sensitivity Analysis 
Three sensitivity analyses will be performed to investigate the robustness of the 
primary efficacy analysis. All of them will only impute the missed Week 8 data if 
neither Week 4 or Week 12 value is available. For multiple imputation, missing data 
will be imputed 100 times to generate 100 complete data sets using the regression 


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CONFIDENTIAL  
 
method. For each of the 100 imputed datasets, the corresponding endpoint will be 
constructed, and the estimates from the 100 fitted models will be combined. Random 
seed = 3575 will be specified for the multiple imputation. 
(1) The primary efficacy analysis will be re-run imputing missing data as described 
in Table 1Table 1. 
Table 1      Rules for Missing Data Associated with the NPRS 
Reason for missing data 
Imputation of the missing NPRS score 
Subject completed partially (≤3 days) the 7-day NPRS 
e-diary 
Multiple imputation based on subject with similar 
characteristics on the same treatment group. Linear 
regression will be used with gender, stratification 
parameter as factors, baseline average NPRS score 
and age as covariate.
Subject withdrawal before Week 8 of the DB period 
due to lack of efficacy 
NPRS score imputed as the mean of placebo value 
at Week 8
Subject withdrawal before Week 8 of the DB period 
due to other reason 
Multiple imputation based on subject with similar 
characteristics in the same treatment group 
Subjects not withdrawn before Week 8 of the DB 
period with a missing NPRS at Week 8
Multiple imputation based on subject with similar 
characteristics within the same treatment group
DB=double blind; e-diary=electronic diary; NPRS=numeric pain rating scale 
 
(2)  If there are more than 5% subjects without any post Baseline data, a tipping point 
analysis will be performed as described below.  
 
Tipping Point Analysis 
Multiple imputation method based on the missing at random assumption will be used 
for each treatment group separately. Random seed = 3565 will be specified. Variables 
included in the imputation model are age, gender, stratification parameter (unilateral 
and bilateral HV), and baseline average NPRS score. In each treatment group, a 
penalty δ will be added to the imputed values (δ = 0 corresponds to the missing at 
random assumption). The smallest value of δ that reverses the conclusion for primary 
analysis will be provided.  
 
(3) Because it was noticed that several subjects had a pain score of 0 in between days 
of very high pain, the primary analysis will be repeated using the median NPRS 
pain score in the 7 consecutive days prior to each visit. It is possible that 0 was a 
default if the ePRO NPRS entry was started but not saved.  
If there are at least 4 values available for Week 4, Week 8 or Week 12 (within 7 
days prior to each visit), the data available will be used to determine the median 
NPRS pain score at that visit and no imputation will be needed. Otherwise, the 
Week 8 median score will be imputed using the same imputation method for 
primary analysis. 
 
5.7.2.4 
Supplementary Analysis 
Supplementary analyses will be performed in order to complement the primary 
estimand. The primary efficacy analysis will be first re-run on the PP population. In 
addition, three other estimands will be considered: 
(1) 
Proportion of responders in the NPRS pain score at Week 8 DB. A responder 
is defined as a subject with 20% decrease from baseline (30%, 40% and 50% 
cut-off will also be considered). 


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CONFIDENTIAL  
 
The NPRS pain score is the daily score averaged over the 7 consecutive days prior to 
the visit as described in the primary analysis. If the Week 8 average score is not 
available and average score for the next scheduled visit (Week 12) is available, the 
Week 8 average score will be imputed with the average score for the next scheduled 
visit (Week 12). If no available average score at Week 8 nor the scheduled visit after 
that (Week 12), the subject will be considered as a non-responder.  
A logistic regression model will be used to estimate the proportion of responders 
within each treatment group. The model will include the treatment group and the 
stratification parameter as fixed categorical covariates and the baseline value as a 
continuous covariate. 
See Appendix A1 for the SAS code. 
 
(2) 
The mean change in the area under the curve (AUC) of the daily NPRS score 
averaged over the 7 consecutive days prior to each visit up to Week 8 of the 
DB period. 
 
The AUC is calculated as ሺ𝑎ଵ൅2𝑎ଶ൅2𝑎ଷ൅2𝑎ସ൅2𝑎ହ൅2𝑎଺൅𝑎଻ሻ/2, where 
𝑎ଵ, 𝑎ଶ, … , 𝑎଻  are the daily scores of the 7 consecutive days prior to each visit. Missing 
values will be imputed as follows: 
• 
If missing input(s) at the beginning (e.g. first several days) of the 7 consecutive 
days, it (they) will be imputed with the first available input within these 7 days. 
(e.g., if 1st and 2nd days missing, 3rd day’s input available, then 1st and 2nd days’ 
inputs will be imputed with the 3rd day’s value.) 
• 
If missing input(s) at the end of the 7 consecutive days, it (they) will be imputed 
with the last available input within these 7 days. 
• 
If missing in the middle, it will be imputed with the average of the first available 
inputs before and after the missed day. (e.g., if 1st, 4th days values available and 
2nd , 3rd days missing, then 2nd, 3rd days’ values will be imputed with the average 
of 1st and 4th days’ values.) 
• 
If there is no input within the 7 consecutive days, the imputation method for the 
primary analysis will be used. 
 
Analysis of Covariance (ANCOVA) model on the change from baseline in AUC prior 
to each scheduled assessment timepoint of the DB period (up to Week 8) will be used 
to evaluate the estimand and compare treatment groups. 
This model will include treatment group and the stratification parameter as fixed 
categorical covariates and the baseline value as a continuous covariate.  
 
(3) 
Repeat the primary analysis using worst NPRS pain score in the 7 consecutive 
days prior to each visit instead of the average. 
If there are at least 4 values available for Week 4, Week 8 or Week 12 (within 7 days 
prior to each visit), the data available will be used to determine the worst NPRS pain 
score at that visit and no imputation will be needed. Otherwise, the Week 8 worst 
score will be imputed using the same imputation method for primary analysis. 
 
5.7.2.5 
Subgroup Analysis 
Descriptive statistics for the primary efficacy endpoint will be provided on the 
stratification parameter (unilateral or bilateral HV) on the ITT population by DB 
treatment group. 


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5.7.3 
Analysis of Secondary Efficacy Endpoints 
Subjects are expected to continue follow-up assessments regardless of the intercurrent 
events define above. Scores will be used as observed. No imputation of missing data 
will be done. 
According to the scale and as detailed in the following section, an MMRM model or 
a mixed-linear-generalized model on change from baseline including each scheduled 
timepoint up to Week 12 DB will be used to evaluate the estimands and compare 
treatment groups. Missing data will be considered as MAR. 
Only descriptive statistics will be used to present the estimands after Week 12 DB 
visit, including the active treatment cycles. 
 
5.7.3.1 
Foot pain NPRS score 
The following summaries and analysis output will also be provided for the foot pain 
NPRS score. 
Table 2 
Foot Pain NPRS Score - Endpoints and Corresponding Analyses 
Endpoint 
Analyses 
The change from baseline 
in the daily NPRS score 
averaged over the 7 
consecutive days prior to 
scheduled visits. 
- descriptive statistics: actual values and change from baseline 
values will be presented at all timepoints including Week 8.  
- Frequency table will be presented for number of days completed 
by treatment group. 
 
DB:  
 - MMRM as described in the primary efficacy analysis. The same 
outputs will be provided for Week 4 and Week 12. 
 
Active Treatment Cycle:  
- A summary by number of active treatment cycles  
- A summary by sequence of active doses of each treatment cycle. 
 
5.7.3.2 
mFFI 
The mFFI (provided in protocol Appendix 1) consists of a total of 21 items grouped 
into three subscales: pain (seven questions), disability (nine questions), and activity 
limitation (five questions). The mFFI items are rated using numeric rating scales 
ranging from 0 to 10 and cover a period of the ‘past’ 24 hours. The poles are labelled 
“no pain” and “worst pain imaginable” (pain), “no difficulty” and “so difficult unable 
to do” (disability), and “none of the time” and “all of the time” (limitations). For each 
item, the subject is asked to record the number value which best corresponds to the 
effect of the foot complaints.  
To obtain a subscale score, the item scores for a given subscale (i.e. pain, disability 
or activity limitation subscales) are totalled and divided by the maximum total 
possible and then multiplied by 100. Each subscale score, as well as the total score, 
will range from 0 to 100. If a patient did not perform the task listed in the question, 
they will be instructed to mark the item as not applicable (N/A). 
 
Subscale and total scores will be calculated when at least 50% of the items for that 
subscale/total score are present (not including the N/A answers). The average will be 
calculated only if there is at least 4 out of 7 days completed. 
 


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CONFIDENTIAL  
 
Table 3 
mFFI - Endpoints and Corresponding Analyses 
Endpoint 
Analyses 
The change from baseline in the 
daily mFFI disability subscale 
score averaged over the 7 
consecutive days prior to each 
post-treatment visit. 
- Descriptive statistics: actual values and change from 
baseline values will be presented at all timepoints.  
 
DB:  
- MMRM at Week 4, Week 8 and Week 12.  
 MMRM setup is similar to the primary analysis. 
- The MMRM above will be repeated using the median 
instead of mean 
- Frequency table will be presented for number of days total 
score calculated by treatment group. 
- Descriptive statistics: score for each item by treatment 
group. 
 
Active Treatment Cycle:  
- A summary by number of active treatment cycles  
 
 
 
The change from baseline in the 
daily mFFI pain subscale score 
averaged over the 7 consecutive 
days prior to each post-treatment 
visit. 
The change from baseline in the 
daily mFFI total score averaged 
over the 7 consecutive days prior 
to each post-treatment visit.
The change from baseline in the 
daily mFFI activity limitation 
subscale score averaged over the 7 
consecutive days prior to each 
post-treatment visit. 
 
5.7.3.3 
Patient Global Impression (PGI) 
Patient Global Impression of Improvement of Foot Pain 
An assessment of PGI-I of foot pain will be conducted by the subject using a 7-point 
Likert scale (from -3: very much worse to +3: very much improved). The PGI-I will 
be assessed by the subject answering the following question: “Compared to your foot 
pain prior to the study treatment initiation, your foot pain while performing physical 
activities (e.g. standing, walking or running) now is: +3=very much improved; 
+2=much improved; +1=minimally improved; 0=no change; -1=minimally worse; -
2=much worse; -3=very much worse”). Also, an additional question will be included 
in the PGI-I assessment which will ask patients the following: "If you experienced a 
change, was this change meaningful to you? (Yes/No)"  
 
Patient Global Impression of Severity of Foot Pain 
An assessment of PGI-S of foot pain will be conducted by the subject using a 4-point 
Likert scale (from 0: no pain to 3: severe pain). The PGI-S will be assessed by the 
subject by answering the following question: “How severe was your foot pain while 
performing physical activities (e.g. standing, walking or running) over the past 
week?” (0=no pain; 1=mild pain; 2=moderate pain; 3=severe pain). 
 
Patient Global Impression of Improvement of Disability 
An assessment of PGI-I of the subject's disability will be conducted by the subject 
using a 7-point Likert scale (from -3: very much worse to +3: very much improved). 
The PGI-I will be assessed by the subject answering the following question: 
“Compared to your disability prior to the study treatment initiation, your disability 
while performing physical activities (e.g. standing, walking or running) now is: 
+3=very much improved; +2=much improved; +1=minimally improved; 0=no 
change from baseline; -1=minimally worse; -2=much worse; -3=very much worse”). 
In addition, an additional question will be included in the PGI-I assessment which 
will ask patients the following: "If you experienced a change, was this change 
meaningful to you? (Yes/No)".  


SAP Final: Version 1.0 20 September 2019 
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CONFIDENTIAL  
 
Patient Global Impression of Severity of Disability 
An assessment of PGI-S of disability will be conducted by the subject using a 4-point 
Likert scale (from 0: no disability to 3: severe disability). The PGI-S will be assessed 
by the subject by answering the following question: “How severe was your disability 
while performing physical activities (e.g. standing, walking or running) over the past 
week?” (0=no disability; 1=mild disability; 2=moderate disability; 3=severe 
disability). 
 
After protocol amendment 3 (September 07, 2018), the collection period for PGI went 
from daily 7 days prior to the visit to only being collected at the visit. For subjects 
who have the diary data collected daily 7 days prior to the visit, the last value on or 
before (within 7 days prior to the visit) will be used for the result at the visit for 
summary and analysis. All the diary data will be provided in the listing. 
 
Endpoints and corresponding analyses are described in Table 4. 
 
Table 4 
PGI -  Endpoints and Corresponding Analyses 
Endpoint 
Analyses 
Mean change from 
baseline to each post-
treatment visit in the 
PGI-S pain and 
disability scores at 
each post-treatment 
visit 
 
- Frequency table will be presented at all timepoints.  
 
DB:  
 - ANCOVA at Week 4, Week 8 and Week 12 (separately). This model 
will include treatment group, and the stratification parameter as fixed 
categorical covariates and the baseline value as a continuous covariate.  
 
Active Treatment Cycle:  
- A summary by number of active treatment cycles  
 
Mean PGI-I pain and 
disability scores at 
each post-treatment 
visit  
- Frequency table will be presented at all timepoints.  
 
DB:  
 - ANCOVA at Week 4, Week 8 and Week 12 (separately). This model 
will include treatment group, and the stratification parameter as fixed 
categorical covariates.  
The additional question will be summarized and listed but will not be 
used for statistical analysis. 
 
Active Treatment Cycle:  
- A summary by number of active treatment cycles  
 


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CONFIDENTIAL  
 
5.7.3.4 
HV angle and intermetatarsal angle 
Endpoints and corresponding analyses are described in Table 5. 
 
Table 5 
HV Angle and Intermetatarsal Angle -  Endpoints and Corresponding Analyses 
Endpoint 
Analyses 
Mean change from 
baseline to each post-
treatment visit in the HV 
angle as measured 
directly by weight-
bearing anterior-posterior 
radiographs 
 
- descriptive statistics: actual values and change from baseline values 
will be presented at all timepoints.  
 
DB:  
 - MMRM at Week 4, Week 8 and Week 12.  
 MMRM setup is similar to the primary analysis. 
 
Active Treatment Cycle:  
- A summary by number of active treatment cycles  
 
Mean change from 
baseline to each post-
treatment visit in 
intermetatarsal angle as 
measured directly by 
weight-bearing anterior-
posterior radiographs 
 
5.7.3.5 
Quality of life (SF-36) 
The SF-36 is a 36-item questionnaire which measures the extent to which physical 
health impacts an individual's functional ability and perceived well-being in mental, 
social and physical aspects of life. The SF-36 has eight individual subscales divided 
across physical and psychological domains: physical function, role physical, bodily 
pain, global health, vitality, social function, role emotional and mental health. Scores 
on these subscales can be combined to form two higher-order summary scores, the 
Physical Component Summary and Mental Component Summary. The Physical 
Component Summary is calculated by positively weighting the four subscales in the 
physical domain (physical function, role physical, bodily pain and global health) and 
the remaining psychological domain subscales negatively. In contrast, the Mental 
Component Summary is calculated by positively weighting the four mental domain 
subscales (mental health, vitality, social function and role emotional), and negatively 
weighting the four physical domain subscales. 
 
Endpoints and corresponding analyses are described in Table 6 
 


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CONFIDENTIAL  
 
• 
A summary table with the total number of subjects in the Safety population 
by sequence of dose will be provided. 
 
To describe the doses received, the following summary tables will be provided: 
• 
Description of the actual dose in DB period by DB treatment group from 
the safety population.  
• 
Actual dose will be described for each dose levels. 
• 
Description of the actual dose at each treatment cycle, by treatment group  
from the safety population. 
• 
Actual dose will be described for each dose levels. 
• 
A listing of exposure data will also be provided. 
 
5.8.3 
Adverse Event 
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 on or after the date of first IMP administration.  
• 
Events whose severity worsens on or after the date of first IMP administration,  
• 
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 AE summaries will be provided: 
 
• 
An overview table summarizing the number and percentage of subjects with at 
least one of the following AEs: any AE; any TEAE; treatment-related TEAE; 
TEAE leading to discontinuation from the study, SAE, treatment-related SAE, 
SAE leading to death, AESI, (this summary table will also be provided by dose 
received at each active treatment cycle), 
• 
A summary of the number and percentage of subjects reporting a TEAE by 
treatment group, SOC and PT, (this summary table will be also be provided by 
dose received at each active treatment cycle), 
• 
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 
severity, SOC and PT, 
• 
A summary of the number and percentage of subjects reporting a TEAE by 
treatment group, causality, SOC and PT, and 
• 
A summary of non-serious TEAE by treatment group, SOC and PT. 
 
For DB period, AEs summaries will be ordered in term of decreasing frequency for 
SOC and PT within SOC in the Dysport 500 U group and then similarly by decreasing 
frequency in the Dysport 300 U 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 within a particular PT are 
counted only once for that PT; 


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- 
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; 
- 
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; 
- 
Summary by intensity will be presented on that order: severe > missing > moderate 
> mild; 
- 
If the causality is missing for a TEAE, it will be considered related in the summary 
tables. 
 
A listing with all AE data will be listed by treatment group including non-TEAEs. 
Treatment-emergence status will be flagged. 
 
Deaths, Serious Adverse Events, and Other Significant Adverse Events 
The following summary tables will be provided if more than 5 subjects satisfy the 
corresponding criteria: 
• 
A summary of the number and percentage of deaths during the study, by 
treatment group, SOC and PT, 
• 
A summary of the number and percentage of subjects reporting a serious 
TEAE, by treatment group, SOC and PT, 
• 
A summary of the number and percentage of subjects with AEs leading to 
discontinuation of study treatment, by treatment group, SOC and PT. 
 
Adverse events of special interest (AESIs) for 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 Dysport will be 
identified using the list of MedDRA PTs compatible with the mechanism of action of 
BTX-A-HAC 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.xlsx. 
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 AESI summary will be provided. 


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• 
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 also 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 study discontinuation, 
• 
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 summaries will be provided: 
• 
A summary of the actual and change from baseline in each laboratory 
parameter by treatment group and timepoint,   
• 
A summary of the number and percentage of subjects experiencing Potentially 
Clinically Significant Abnormalities (PCSA). PCSA criteria for laboratory 
parameters are defined in appendix A2, 
 
For PCSA table, the denominator should be the number of subjects with both a 
baseline and a post-baseline assessment at a given timepoint. 
 
In addition, the following listings will be provided: 
• 
A listing of all laboratory data. Out-of-reference-range values will be flagged 
as high (H), low (L), clinically significant [C]. Any unscheduled laboratory 
assessments will be flagged as such in the listings. 
• 
Laboratory reference ranges, 
• 
A listing will present all values of the parameter for a subject with at least a 
clinically significant abnormal value for hematology and biochemistry. 
• 
A listing of PCSA. All data for a laboratory parameter will be displayed for a 
subject having at least one post-baseline PCSA (with flag indicating PCSA). 
• 
A listing will present the urine drug screening and urine pregnancy test. 
• 
A listing will be provided for patients with abnormal result of drug abuse test. 
 
5.8.5 
Vital Signs 
The following summaries will be provided. 
• 
A summary of the actual and change from baseline in each vital sign parameter 
by treatment group, 
• 
A summary of the number and percentage of subjects experiencing PCSA. 
PCSA criteria are defined in appendix A2. 
 
The following listing are to be provided: 
• 
A listing of vital sign data by treatment group, with abnormal value highlighted 
and unscheduled vital signs flagged,  
• 
Listing of PCSA. All data for a vital sign parameter will be displayed for a 
subject having at least one post-baseline PCSA (with flag indicating PCSA). 
 
Any clinically significant vital sign abnormalities observed during the study will be 
reported as AEs.  


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5.8.6 
Physical Examination 
The following summary and listings will be provided: 
• 
A shift from baseline (normal vs abnormal) to each post-baseline visit  
• 
A listing of physical examination data, with unscheduled visit flagged 
• 
A listing with any subjects with at least one physical examination abnormality. 
  
5.8.7 
Examination of Injected Foot 
The following summary and listings will be provided: 
• 
A summary of each parameter for the dermatologic exam, neurological exam, 
and musculoskeletal exam at each visit by treatment group,  
• 
A separate listing will be provided for all subjects and results, with unscheduled 
visit flagged [U].  
• 
A listing of examination data, with unscheduled visit flagged [U], for subjects 
with at least one abnormal result. All results will be displayed for the subject if 
one result is abnormal.  
 
5.9 
Pharmacokinetics and Pharmacodynamics 
Pharmacokinetics and pharmacodynamics are not assessed in this study. 
 
5.10 
Anti-drug Antibodies 
 
The following definitions will be considered: 
• 
Seroconverters are subjects with ADA titer ≤1 for antibody at baseline and 
ADA titer > 1 post-treatment.  
• 
Seroreverters are subjects which ADA titer > 1 at baseline and ADA titer <= 
1 post-treatment.  
• 
Treatment boosted ADA are subjects with ADA titer > 1 at baseline that were 
boosted to a higher-level following IMP administration (the ADA titer is 
greater than 100 times the baseline titer). 
• 
Incidence is defined as the proportion of seroconverters or treatment-boosted 
subjects.  
 
The following conventions will be considered: 
- Percentage of seroconverters and incidence should be calculated using the number 
of subjects with a baseline and at least one ADA assessment post-treatment. 
- Percentages of seroreverters and Treatment boosted ADA should be calculated using 
the number of subjects with ADA titer > 1 at baseline and at least one ADA 
assessment post-treatment. 
 
The following summaries of ADA data will be provided:  
• 
An overall summary of ADA status for binding and neutralizing with: 
- 
number and percentage of positive baseline results, 
- 
quartiles of the titer range, 
- 
number of seroreverters, 
- 
number of treatment-boosted, 
- 
number and percentage of seroconverters, 
- 
incidence. 


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The following listings should be provided: 
• 
A listing of any ADA data, including baseline BTX status (if the subject has 
previously received any treatment with BTX), and the status and titer for 
binding ADA and titer for neutralizing ADA,  
• 
An overall ADA status of each subject, 
• 
A listing for all subjects with binding titer > 1 post baseline. This listing will 
include the combined information about baseline BTX status, primary efficacy 
results and TEAEs, 
• 
A listing for all subjects with neutralizing titer > 1 post baseline. This listing 
will include the combined information about baseline BTX status, primary 
efficacy results and TEAEs, 
 
6 
DATA HANDLING 
 
6.1 
Visit Window 
No time window for visit/timepoints will be defined. 
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.  
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 
or vital signs values. 
If a value requires a retest (for laboratory values or vital signs) the closest 
non-missing reliable value to the scheduled visit will be used in the summary tables. 
Subjects who have withdrawn early from the study have their last assessment entered 
in the Case Report Form (CRF). By convention, for these subjects, the visit number 
will be reassigned to the next empty visit number. 
 
7 
DERIVED DATA 
All the derived data are defined in the corresponding sections.  
 
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 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 


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- 
Missing data in confirmatory clinical trials 
- 
Application with Meta Analyses, One pivotal study 
- 
Multiplicity issues in clinical trials 
- 
Switching between superiority and non-inferiority 
 
Reference to FDA guidelines: 
- 
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
 
Standard SDTM+ user guide 
 
References for ADA: 
- 
 ABIRISK Terms and Definitions for Reporting Immunogenicity Results 
 


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9 
APPENDICES 
 
A1. SAS code 
 
SAS code for primary efficacy analysis: 
 
******************************************************************* 
 
** CHG  = Change from Baseline to the specific visit in foot pain**  
 
** Trt  = Treatment group, Placebo, Dysport 300U and 500U        ** 
 
** Visit= Week 4, Week 8 and Week 12                      
    ** 
 
** Base = Baseline pain                                          ** 
 
** Type = Stratification parameter, unilateral and bilateral HV  ** 
 
** Usubjid = Subject id                                          ** 
 
******************************************************************* 
 
PROC MIXED; 
 
   CLASS Trt(ref="Placebo") Type Visit(ref="Week8") Usubjid; 
 
   MODEL CHG = Base Trt Type Visit Trt*Visit / CL ALPHA=0.05;  
 
   LSMEANS Trt / PDIFF CL;  
 
   REPEATED Visit / TYPE=UN SUB=Usubjid; 
 
RUN; 
 
SAS code for Supplementary analysis (1): 
******************************************************************* 
 
** Responder = 1 if is Responder, otherwise zero                 ** 
 
** Trt  = Treatment group: Placebo, Dysport 300U and 500U        ** 
 
** Base = Baseline pain                                          ** 
 
** Type = Stratification parameter, unilateral and bilateral HV  ** 
******************************************************************* 
PROC LOGISTIC; 
   CLASS Trt Type; 
   MODEL Responder = Base Type Trt / EXPB;  
   ODDSRATIO Trt; 
   LSMEANS Trt / e diff oddsratio cl; 
RUN; 
 


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A2. List of PCSA criteria 
 
PCSA for Vital Signs parameters: 
Parameter 
PCSA 
Systolic Blood Pressure 
≤ 90 mmHg and change from baseline ≤ -20 mmHg 
≥ 180 mmHg and change from baseline ≥ 20 mmHg 
Diastolic Blood Pressure 
≤ 50 mmHg and change from baseline ≤ -15 mmHg 
≥ 105 mmHg and change from baseline ≥ 15 mmHg 
Heart Rate 
≤ 50 bpm and change from baseline ≤ -15 bpm 
≥ 120 bpm and change from baseline ≥ 15 bpm 
Weight 
≤ -5% change from baseline 
≥ 5 % change from baseline
 
PCSA for blood chemistry parameters: 
Parameter 
PCSA
ALT/SGPT 
≥ 3 x ULN IU/L
AST/SGOT 
≥ 3 x ULN IU/L
GGT 
≥ 3 x ULN IU/L
ALP (Alkaline Phosphatase) 
≥ 1.5 x ULN IU/L or ≥ 3 x ULN IU/L
Creatinine 
≥ 150 μmol/L (Adults)
Blood Urea Nitrogen 
> 10 mmol
Chloride 
≤ 90 mmol/L 
≥ 115 mmol/L
Calcium 
<1.75 mmol/L 
>3 mmol/L
Sodium 
<130 mmol/L 
> 150 mmol/L
Potassium 
<2.5 mmol/L 
>6 mmol/L
Total cholesterol 
> 6.22 mmol/L
Triglycerides 
> 2.26 mmol/L
Lipase 
≥ 3 x ULN U/L
Amylase 
≥ 3 x ULN U/L
Glucose 
<2.7 mmol/L 
> 11 mmol/L (unfasted)
HbA1c 
> 8%
Albumin 
≤ 25 g/L
Direct bilirubin 
> 2 ULN μmol/L
Total bilirubin 
> 2 ULN mmol/L
Phosphorous 
< 0.75 mmol/L 
> 1.8 mmol/L
Total protein 
< 40 g/L
 


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PCSA for haematology parameters (proposal - PCSA criteria need medical input): 
Parameter 
PCSA
White blood cell 
≤ 2.8 10^9/L 
≥ 16 10^9/L
Red blood cell 
< 3 10^12/L 
> 6 10^12/L
Hematocrit 
≤ 0.32 and 0.03 decrease from baseline L/L (female) 
≤ 0.37 and 0.03 decrease from baseline L/L (male) 
Lymphocytes 
< 0.3 10^9/L 
> 11.0 10^9/L
Neutrophilis 
< 1 10^9/L 
> 13 10^9/L
Monocytes 
> 2.3 10^9/L
Basophilis 
10^9/L
Eosinophilis 
10^9/L
Hemoglobin 
≤ 95 g/l (female) 
≤ 115 l/l (male)
Platelet count 
<75.1 10^9/L 
≥ 700 10^9/L
 
PCSA for coagulation parameters: 
Parameter 
PCSA
INR 
>3
Prothrombin Time (PT) 
> 17.1 seconds
Partial Thromboplastin Time 
(PTT) 
 
 
> 59 seconds 


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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 missed day and 
January for missing month, 
- 
If a partial stop date, the last day of the month will be imputed for missed days and 
December will be imputed for missing month. 
In case incomplete start or stop date does not allow the classification, the medication, non-drug 
therapy, or surgical procedure will be classified as concomitant. 
 
If the start date of a medication is partial or missing, the medication will be assigned to the most 
recent treatment received on or before the medication start date (taking into account date 
stopped). 
 
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 A1. 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 A1: 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. 
 
If an AE onset date is partial or missing, the event will be allocated to the first IMP 
administration where onset could have occurred (taking into account date and time stopped). 
 
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. 
 
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 


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in a footnote for clarification if necessary. If sample sizes are small (less than 15), 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. In 
summary tables or analysis, data like “<a” will be replaced with “0.5*a”, data like “>b” will be 
replaced with “b”.  
 
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. Listings should be broken down by centre and treatment 
group.