Conditions: Pediatrics Muscle Spasticity Cerebral Palsy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 384
Healthy volunteers: no

Brief summary:
This study will evaluate the safety and efficacy of BOTOX® (botulinum toxin Type A) in pediatric patients with lower limb spasticity.

Detailed description:

Arms:
arm 1: Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 U per kg of body weight (4 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly physical therapy (PT). arm 2: Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 8 U per kg of body weight (8 U/kg) into specified muscles of the lower limb on Day 1. Participants received weekly PT. arm 3: Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb on Day 1. Participants received weekly PT.

Interventions: intervention 1: botulinum toxin Type A intervention 2: Normal Saline (Placebo)
Intervention descriptions: intervention 1: Participants received intramuscular injections of botulinum toxin Type A into specified muscles of the lower limb on Day 1. intervention 2: Participants received intramuscular injections of normal saline (placebo) into specified muscles of the lower limb on Day 1.

Protocol document:
Prot_001.pdf: 
NCT01603628 
 
Study ID: 191622-111 
 
Title: BOTOX® Treatment in Pediatric Lower Limb Spasticity: Double-blind Study 
 
Protocol Amendment 3 Date: July 25, 2016 


 
 
Approval Date: 
 
25-Jul-2016
Allergan Confidential 
Protocol 191622-111, Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
1 
 
 
Title Page 
ALLERGAN – CONFIDENTIAL 
The following contains confidential, proprietary information  
which is the property of Allergan 
STUDY TITLE 
BOTOX® Treatment in Pediatric Lower Limb Spasticity:  Double-blind Study 
 
Protocol Number:   
191622-111 Amendment 3 
EudraCT Number: 
2012-000042-35 
Phase: 
3 
Name of Investigational 
Product: 
BOTOX® (botulinum toxin type A) purified neurotoxin 
complex (US Adopted Name is onabotulinumtoxinA) 
Sponsor: 
 
Allergan (North America) 
2525 Dupont Drive 
Irvine, California USA 
92612 
+1-714-246-4500 
+1-800-347-4500 
Allergan Ltd. 
1st Floor, Marlow 
International, 
The Parkway, Marlow 
Buckinghamshire 
SL7 1YL United Kingdom 
Tel: +44 (0) 1628 494444 
Fax: +44 (0) 1628 494449 
Emergency Telephone 
Number(s): 
Refer to the Study Contacts Page. 
 
 
 
   
 
 
  
 
 
 
 
 


 
 
Approval Date: 
 
25-Jul-2016
Allergan Confidential 
Protocol 191622-111, Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
2 
 
 
Allergan Signatory: 
  
 
  
Refer to the final page of this protocol for electronic 
signature and date of approval. 
 
The following information can be found on FDA Form 1572 and/or study contacts page:  
Name and contact information of Allergan study personnel and Emergency Telephone 
Numbers; name, address, and statement of qualifications of each investigator; name of each 
subinvestigator working under the supervision of the investigator; name and address of the 
research facilities to be used; name and address of each reviewing IRB; 21 CFR 312.23 
section 6(iii)b. 
 


 
 
Approval Date: 
 
25-Jul-2016
Allergan Confidential 
Protocol 191622-111, Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
3 
 
 
INVESTIGATOR SIGNATURE PAGE 
INVESTIGATOR: 
 
STUDY LOCATION: 
 
 
I agree to: 
• Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. 
• Maintain all information supplied by Allergan in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Independent Ethics Committee 
(IEC) or another group, it will be submitted with a designation that the material is 
confidential. 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 
 
 


 
 
Approval Date: 
 
25-Jul-2016
Allergan Confidential 
Protocol 191622-111, Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
4 
 
 
Table of Contents 
Table of Contents ...................................................................................................................... 4 
List of Tables ............................................................................................................................. 8 
List of Figures ........................................................................................................................... 8 
Protocol Summary .................................................................................................................... 9 
1. 
Background and Clinical Rationale ................................................................................. 17 
1.1 
Pediatric Spasticity ................................................................................................. 17 
1.2 
Management of Spasticity in Children ................................................................... 18 
1.3 
BOTOX for Management of Pediatric Spasticity .................................................. 19 
1.3.1 
Use of BOTOX in Pediatric Lower Limb Spasticity .......................... 19 
1.4 
Dose Justification ................................................................................................... 20 
2. 
Study Objectives and Clinical Hypotheses ...................................................................... 22 
2.1 
Study Objectives .................................................................................................... 22 
2.2 
Clinical Hypotheses ............................................................................................... 22 
3. 
Study Design .................................................................................................................... 22 
3.1 
Safety Data Review Committee ............................................................................. 23 
4. 
Study Population and Entry Criteria ................................................................................ 23 
4.1 
Number of Patients ................................................................................................. 23 
4.2 
Study Population Characteristics ........................................................................... 23 
4.3 
Inclusion Criteria .................................................................................................... 23 
4.4 
Exclusion Criteria .................................................................................................. 25 
4.5 
Permissible and Prohibited Medications/Treatments ............................................. 29 
4.5.1 
Permissible Medications/Treatments .................................................. 29 
4.5.1.1  Acceptable Contraceptive Methods and Definition of Females of 
Childbearing Potential ................................................................. 29 
4.5.2 
Prohibited Medications/Treatments .................................................... 30 
4.5.3 
Special Diet or Activities .................................................................... 31 
5. 
Study Treatments ............................................................................................................. 32 
5.1 
Study Treatments and Formulations ....................................................................... 32 
5.2 
Control Treatment .................................................................................................. 33 
5.3 
Methods for Masking/Blinding .............................................................................. 33 


 
 
Approval Date: 
 
25-Jul-2016
Allergan Confidential 
Protocol 191622-111, Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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5.4 
Treatment Allocation Ratio and Stratification ....................................................... 34 
5.5 
Method for Assignment to Treatment Groups/Randomization .............................. 34 
5.6 
Treatment Regimen and Dosing ............................................................................. 35 
5.6.1 
Treatment Regimen/Dosage Adjustments ........................................... 35 
5.6.1.1  Dosing Paradigm ......................................................................... 35 
5.7 
Storage of Study Medications/Treatments ............................................................. 37 
5.8 
Preparation of Study Medications/Treatments ....................................................... 37 
5.9 
Treatment Administration ...................................................................................... 37 
6. 
Response Measures and Summary of Data Collection Methods ..................................... 38 
6.1 
Efficacy Measures .................................................................................................. 38 
6.1.1 
Primary Efficacy Measures ................................................................. 38 
6.1.2 
Secondary Efficacy Measures ............................................................. 38 
6.1.3 
Other Efficacy Measures ..................................................................... 38 
6.1.4 
Safety Measures .................................................................................. 38 
6.2 
Examination Procedures, Tests, Equipment, and Techniques ................................ 39 
6.3 
Other Study Supplies .............................................................................................. 39 
6.4 
Summary of Methods of Data Collection .............................................................. 40 
7. 
Statistical Procedures ....................................................................................................... 40 
7.1 
Analysis Populations .............................................................................................. 41 
7.2 
Collection and Derivation of Primary and Secondary Efficacy Assessments ........ 41 
7.2.1 
Primary Efficacy Variables ................................................................. 42 
7.2.2 
Secondary Efficacy Variables ............................................................. 42 
7.2.3 
Other Efficacy Variables ..................................................................... 42 
7.3 
Hypothesis and Methods of Analysis ..................................................................... 42 
7.3.1 
Primary Efficacy Analyses .................................................................. 42 
7.3.2 
Secondary Efficacy Analyses .............................................................. 44 
7.3.3 
Other Efficacy Analyses ..................................................................... 44 
7.3.4 
Safety Analyses ................................................................................... 45 
7.4 
Subgroup Analyses ................................................................................................. 45 
7.5 
Sample Size Calculation ........................................................................................ 45 
7.6 
Interim Analyses .................................................................................................... 46 
7.7 
Additional Analysis/Inference for US FDA ........................................................... 46 
7.7.1 
Primary Efficacy Analyses .................................................................. 46 
8. 
Study Visit Schedule and Procedures .............................................................................. 47 


 
 
Approval Date: 
 
25-Jul-2016
Allergan Confidential 
Protocol 191622-111, Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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8.1 
Patient Entry Procedures ........................................................................................ 48 
8.1.1 
Overview of Entry Procedures ............................................................ 48 
8.1.2 
Informed Consent and Patient Privacy ............................................... 48 
8.2 
Procedures for Final Study Entry ........................................................................... 48 
8.3 
Visits and Associated Procedures ........................................................................... 48 
8.3.1 
Visit 1:  2 to 4 Weeks Before Day 1 (Screening) ................................ 49 
8.3.2 
Visit 2:  Week -2 (PT Start) – Visit with the Physical Therapist ......... 51 
8.3.3 
Visit 3:  Day 1 (Randomization/Treatment) ........................................ 51 
8.3.4 
Visits 4, 5, 6, and 7:  Weeks 2, 4, 6, and 8 (Follow-up Visits) ............ 53 
8.3.5 
Visit 8:  Week 12 or Early Termination (Exit Visit) ............................ 54 
8.4 
Instructions for the Patients .................................................................................... 55 
8.5 
Unscheduled Visits ................................................................................................. 55 
8.6 
Compliance With Protocol ..................................................................................... 55 
8.7 
Early Discontinuation of Patients .......................................................................... 55 
8.8 
Withdrawal Criteria ................................................................................................ 56 
8.9 
Study Termination .................................................................................................. 56 
9. 
Adverse Events ................................................................................................................ 56 
9.1 
Definitions .............................................................................................................. 56 
9.1.1 
Adverse Event ..................................................................................... 56 
9.1.2 
Serious Adverse Event ........................................................................ 57 
9.1.3 
Severity ............................................................................................... 57 
9.1.4 
Relationship to Study Drug or Study Procedure ................................. 57 
9.2 
Procedures for Reporting Adverse Events ............................................................. 57 
9.3 
Procedures for Reporting a Serious Adverse Event ............................................... 58 
9.4 
Procedures for Unmasking of Study Medication ................................................... 58 
10.  Administrative Items ....................................................................................................... 59 
10.1  Protection of Human Subjects ................................................................................ 59 
10.1.1 
Compliance with Informed Consent Regulations (US 21 CFR Part 50) 
and Relevant Country Regulations ..................................................... 59 
10.1.2 
Compliance With IRB or IEC Regulations ......................................... 59 
10.1.3 
Compliance With Good Clinical Practice ........................................... 60 
10.1.4 
Compliance With Electronic Records; Electronic Signatures 
Regulations (21 CFR Part 11) ............................................................. 60 
10.2  Changes to the Protocol ......................................................................................... 60 


 
 
Approval Date: 
 
25-Jul-2016
Allergan Confidential 
Protocol 191622-111, Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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10.3  Patient Confidentiality ........................................................................................... 60 
10.3.1 
Patient Privacy .................................................................................... 60 
10.4  Documentation ....................................................................................................... 61 
10.4.1 
Source Documents .............................................................................. 61 
10.4.2 
Case Report Form Completion ........................................................... 62 
10.4.3 
Study Summary ................................................................................... 62 
10.4.4 
Retention of Documentation ............................................................... 62 
10.5  Labeling, Packaging, and Return or Disposal of Study Medications/Treatments.. 63 
10.5.1 
Labeling/Packaging............................................................................. 63 
10.5.2 
Clinical Supply Inventory ................................................................... 63 
10.5.3 
Return or Disposal of Study Medications/Treatments and/or Supplies
............................................................................................................. 63 
10.6  Monitoring by the Sponsor .................................................................................... 64 
10.7  Handling of Biological Specimens ........................................................................ 64 
10.8  Publications ............................................................................................................ 64 
10.9  Coordinating Investigator ...................................................................................... 64 
11.  References ........................................................................................................................ 65 
12.  Attachments ..................................................................................................................... 69 
12.1  Examination Procedures, Tests, Equipment, and Techniques ................................ 69 
12.1.1 
Physical Examination.......................................................................... 69 
12.1.2 
Vital Signs ........................................................................................... 69 
12.1.3 
Electrocardiogram ............................................................................... 69 
12.1.4 
Hematology and Serum Chemistry ..................................................... 69 
12.1.5 
Immunogenicity Testing ..................................................................... 72 
12.1.6 
Pregnancy Test .................................................................................... 72 
12.1.7 
Barry-Albright Dystonia (BAD) Scale ............................................... 72 
12.1.8 
Hypertonia Assessment Tool (HAT) ................................................... 73 
12.1.9 
Gross Motor Function Classification System – Expanded and Revised 
(GMFCS–E&R) .................................................................................. 75 
12.1.10 
Modified Ashworth Scale-Bohannon (MAS-B) ................................. 75 
12.1.11 
Modified Tardieu Scale (MTS) ........................................................... 76 
12.1.12 
 ..................... 76 
12.1.13 
 
 ....................................................................................... 77 
12.1.14 
Goal Attainment Scale (GAS) by Physician ....................................... 77 
12.1.15 
Clinical Global Impression of Overall Change (CGI) by Physician ... 78 


 
 
Approval Date: 
 
25-Jul-2016
Allergan Confidential 
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BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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12.1.16 
 ........................ 78 
12.1.17 
 .................................................. 79 
12.1.18 
Columbia-Suicide Severity Rating Scale (C-SSRS) ........................... 79 
12.2  Package Insert/Summary of Product Characteristics ............................................. 81 
12.3  Glossary of Abbreviations ...................................................................................... 82 
12.4  Protocol Amendment 1 Summary .......................................................................... 84 
12.5  Protocol Amendment 2 Summary .......................................................................... 86 
12.6  Protocol Amendment 3 Summary .......................................................................... 90 
 
List of Tables 
Table 1 
Schedule of Visits and Procedures .................................................................. 14 
Table 2 
Dilution of Study Drug ................................................................................... 33 
Table 3 
Dosing Paradigm ............................................................................................. 36 
Table 4 
Sample Size Assumptions and Power Calculations ........................................ 46 
Table 5 
Reference Ranges for Alkaline Phosphatase and Glucose .............................. 71 
 
List of Figures 
Figure 1 
Common Gait Patterns:  Spastic Hemiplegia.................................................. 26 
 
 


 
 
Approval Date: 
 
25-Jul-2016
Allergan Confidential 
Protocol 191622-111, Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
9 
 
 
Protocol Summary 
 
Study Compound:  BOTOX® (botulinum toxin type A) purified neurotoxin complex (US Adopted Name, 
onabotulinumtoxinA)   
Phase:  3 
Study Objectives:  To evaluate the safety and efficacy of a single treatment of 2 doses (4 U/kg and 8 U/kg) of 
BOTOX with standardized physical therapy (PT) in pediatric patients with lower limb spasticity 
Clinical Hypotheses:  
1) 
A single treatment of BOTOX at doses of 4 U/kg and 8 U/kg in the lower limb has an 
acceptable safety profile. 
2) 
BOTOX with standardized PT is more effective than placebo with standardized PT as 
measured by a reduction in muscle tone on the Modified Ashworth Scale-Bohannon (MAS-B). 
For United States [US] Food and Drug Administration [FDA] only, the hypothesis is that 
BOTOX with standardized PT is more effective than placebo with standardized PT as 
measured by a reduction in muscle tone on the MAS-B and improvement on the Clinical 
Global Impression of Overall Change (CGI) by Physician. 
 
Study Design 
Structure:  Multicenter, randomized, double-blind, placebo-controlled, parallel-group  
Duration:  16 weeks (up to 4 weeks of screening and 12 weeks of posttreatment follow-up) 
Study Treatment Groups (BOTOX doses are expressed as units per total body weight): 
4 U/kg BOTOX + PT 
8 U/kg BOTOX + PT 
Placebo + PT 
Control:  Placebo 
Dosage/Dose Regimen: 
There will be 1 treatment in the study.  Eligible patients will be injected in the affected leg (referred to 
as the study limb) with the dose specified in Table 3 according to the randomization assignment.  
Patients will receive 1 of the 2 doses of BOTOX (4 U/kg not to exceed 150 U or 8 U/kg not to exceed 
300 U) or placebo injected to the study limb in the gastrocnemius (both medial and lateral heads), 
soleus, and tibialis posterior muscles. 
Randomization/Stratification:   
Patients will be randomized to 1 of 3 treatment groups in a 1:1:1 ratio within each combination of 
strata.  The stratification categories are as follows: 
• 
Age (≤ 6 years and > 6 years)  
• 
Baseline (day 1) MAS-B score of the ankle with knee extended (MAS-B = 2 and MAS-B > 2)  
Visit Schedule:   
There will be 8 visits and approximately 13 PT sessions during the study: 
Visit 1: Week -4 to week -2 (screening) 


 
 
Approval Date: 
 
25-Jul-2016
Allergan Confidential 
Protocol 191622-111, Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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Visit 2: Week -2 (initiation of standardized weekly PT) 
Visit 3: Day 1 (randomization and treatment) 
Visit 4: Week 2 (follow-up visit) 
Visit 5: Week 4 (follow-up visit) 
Visit 6: Week 6 (follow-up visit) 
Visit 7: Week 8 (follow-up visit) 
Visit 8: Week 12 (exit visit) 
 
Study Population Characteristics 
Number of Patients:  
Approximately 412 patients will be enrolled to ensure that at least 351 patients (117 per treatment 
group) will complete the study.  
Condition/Disease:   
Medically stable monoplegic or hemiplegic pediatric patients with cerebral palsy who have dynamic 
muscle contracture of the ankle plantar flexors associated with equinus foot position   
Key Inclusion Criteria:   
• 
Male or female, 2 to 16 years and 11 months of age (prior to 17th birthday) at the day 1 visit 
• 
Minimum weight of 10 kg at the screening and day 1 visits 
• 
Monoplegic or hemiplegic patients with cerebral palsy who have dynamic muscle contracture 
(spasticity confirmed by Hypertonia Assessment Tool [HAT]) of the ankle plantar flexors.  
Equinovarus or equinovalgus deformities are acceptable. 
• 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 


 
 
Approval Date: 
 
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BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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Key Exclusion Criteria:  
• 
 
• 
Any medical condition that may put the patient at increased risk with exposure to Botulinum Toxin 
Type A Purified Neurotoxin Complex, including diagnosed muscular dystrophy (eg, Duchenne’s 
muscular dystrophy), myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, 
mitochondrial disease, or any other significant disease that might interfere with neuromuscular 
function 
• 
 
• 
 
 
 
 
• 
Uncontrolled epilepsy defined as more than 1 generalized seizure in any month within the 3 months 
prior to the day 1 visit or history of any of the following within 9 months prior to the day 1 visit:  
prolonged seizures or repetitive seizure activity requiring administration of a rescue benzodiazepine 
(oral, rectal, etc) more than once a month, seizures lasting more than 10 minutes, status epilepticus, or 
epilepsy with autonomic involvement  
• 
 
 
 
  
 
 
 
 
 
 
 
• 
Botulinum toxin therapy of any serotype for any condition within 6 months prior to the day 1 visit 
• 
 
 
 
 
 
 
 
 
• 
History of surgical intervention of the lower leg (the knee and below of the study limb; except for 
tendon lengthening more than 12 months prior to the day 1 visit) or planned surgical intervention of 
any limb(s) during the study 
• 
Previous casting within 6 months prior to the day 1 visit or splinting with a dynamic splint (eg, 
Dynasplint® or UltraFlex®) within 3 months prior to the day 1 visit for spasticity of the study limb or 
the affected upper limb, or planned casting or splinting with a dynamic splint (eg, Dynasplint or 
UltraFlex) for spasticity of the study limb or affected upper limb during the study 
• 
  
 
 


 
 
Approval Date: 
 
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Protocol 191622-111, Amendment 3 
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• 
 
 
Response Measures 
Efficacy: 
Primary efficacy measures:   
• 
MAS-B ankle score with knee extended 
• 
CGI by Physician (co-primary efficacy measure is for US FDA only) 
Secondary efficacy measures:  
• 
CGI by Physician (for non-US FDA analyses) 
• 
Goal Attainment Scale (GAS) by Physician 
• 
Modified Tardieu Scale (MTS) of the ankle with knee extended and knee flexed 
Other efficacy measures: 
• 
 
 
 
 
 
 
 
 
 
 
Safety:   
• 
Adverse events 
• 
Physical examination 
• 
Urine pregnancy tests (for all females of childbearing potential) 
• 
Hematology and serum chemistry 
• 
Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) 
• 
Body weight  
• 
Immunogenicity testing (for patients who weigh at least 15 kg at the screening visit) 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS, for patients ≥ 6 years of age at day 1) 
General Statistical Methods and Types of Analyses:  
Safety data will be analyzed on the basis of all treated patients based on treatment received, defined as the 
safety population.  Efficacy data will be analyzed on the basis of the modified intent-to-treat (mITT) population, 
defined as all randomized patients with a valid baseline MAS-B ankle score with knee extended and at least one 
post-baseline measurement at weeks 2, 4, or 6 for the MAS-B ankle score with knee extended and the CGI by 
Physician.  The primary efficacy endpoint will be the average grade change from baseline in the MAS-B ankle 
score at weeks 4 and 6.  For US FDA only, the average grade change from baseline in MAS-B ankle score at 
weeks 4 and 6 and the average CGI by Physician at weeks 4 and 6 will be analyzed as co-primary endpoints.  
Mixed Model Repeated Measures (MMRM) with unstructured covariance structure will be performed with 
baseline MAS-B as a covariate and factors of age group, treatment group, visit, treatment-by-visit interaction, 
study center, and previous botulinum toxin exposure.  Continuous secondary and other efficacy variables will 
be summarized by treatment group and analyzed by Analysis of Covariance (ANCOVA).  Categorical efficacy 


 
 
Approval Date: 
 
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Protocol 191622-111, Amendment 3 
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variables, such as the responder status for MAS-B, will be analyzed by logistic regression.  All statistical tests 
will be 2-sided with a significance level of 0.05.  Safety variables, such as the adverse event incidence rate, vital 
signs and changes from baseline in vital signs, the incidence of suicide-related events, and laboratory test values 
and their changes from baseline, will be summarized by treatment group. 
 
Sample Size Calculation: 
Approximately 412 patients will be enrolled to ensure that at least 351 patients (117 per treatment group) will 
complete the study.  Using a 2-sample t-test, a significance level of 0.05, and the assumptions in the table below, 
the power for MAS-B change from baseline is 94% (PASS, Hintze, 2008). The calculation is based on 
assumptions for 8 U/kg group and placebo group.  Since there are 2 co-primary endpoints for the US FDA 
analysis, for 8 U/kg group the power for CGI by Physician is calculated to be 97%, and the overall power for 
the US FDA co-primary endpoints will be at least 91%.  The assumption for MAS-B were based on results of 
completed Studies BTX108509 and BTX108512; the estimates for CGI were based on results of completed 
Study 191622-021.   
Endpoint 
Average of 
Week 4 and 6 
for 8 U/kg group
Average of 
Week 4 and 6 
for Placebo group
Standard 
Deviation 
Power
MAS-B Change from Baseline 
-0.8
-0.45
0.75 
94%
CGI by Physician (Co-primary for US 
FDA Analysis) 
1.2 
0.6 
1.2 
97% 
Overall Endpoints 
91%
 
 
 


 
 
 
 
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1. 
Background and Clinical Rationale  
1.1 
Pediatric Spasticity 
Spasticity is classically defined as a disorder of the sensorimotor system characterized by a 
velocity-dependent increase in muscle tone with exaggerated tendon jerks, resulting from 
hyperexcitability of the stretch reflex (Lance, 1980).  The most common cause of focal 
spasticity in children is cerebral palsy.  Cerebral palsy is a disorder caused by a 
non-progressive insult of the central nervous system (CNS) that occurs prenatally, perinatally, 
or during the first 2 years of life and can result in functional motor impairment, irregular 
movement, and abnormal posture.  The increase in the muscle-stretch reflex causes muscle 
contraction of abnormal strength and duration.  Spastic muscles show “velocity-dependent” 
resistance to passive movement and exaggerated tendon jerks (Lance, 1980). 
The patterns of spasticity depend on the areas of the developing brain that are damaged.  In 
patients with hemiplegic spasticity, one half of the body (1 arm and 1 leg) is affected with 
spasticity.  Approximately 25% of children with cerebral palsy present with hemiplegic 
spasticity in which the upper limb is usually more affected than the lower limb 
(Stanley et al, 2000).  Spastic diplegia, presented in about 13% to 30% of patients with 
cerebral palsy, is characterized by spasticity of both legs with relative sparing of the arms 
(Odding et al, 2006; Stanley et al, 2000).  Although the arms are less affected, they may still 
show abnormal reflexes and reduced dexterity.  Spastic triplegia is characterized by spasticity 
affecting both lower extremities and 1 arm is usually affected more severely than the other.  
Spastic quadriplegia affects all 4 limbs and is the most severe but least common form of 
spastic cerebral palsy, affecting approximately 20% of patients.  Since both cerebral 
hemispheres are affected, intellectual impairment is common.  Patients with quadriplegia 
may also have severe dysarthria, dysphagia, and other comorbidities such as epilepsy and 
blindness.  Spasticity and abnormal muscle tone contribute both to impairment of function 
and reduced longitudinal muscle growth in children with cerebral palsy (Dunne et al, 1995).   
Cerebral palsy is the most common etiology associated with pediatric spasticity with a 
prevalence rate of approximately 2.5 in 1000 live births, a number that has increased from 
1.5 in 1000 live births 40 years ago (Odding et al, 2006), and is considered to be the most 
severe childhood physical disability (Beckung and Hagberg, 2002).  Essentially all patients 
with cerebral palsy have impaired motor function with spasticity affecting as many as 90%.  
Other less prevalent types of disorders associated with pediatric spasticity include 
posttraumatic brain or spinal cord injury, multiple sclerosis, and other neurodegenerative 


 
 
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conditions (Hawamdeh et al, 2007).  All of these conditions are associated with significant 
morbidity and mortality and present an unmet medical need with limited treatment options.  
Equinus foot deformity is the most common (75%) form of spasticity in patients with 
cerebral palsy (Cobeljic et al, 2009).  The increased muscle tone first presents as dynamic 
deformity and, if left untreated, transforms to fixed deformity as the child grows 
(Detrembleur et al, 2002).  Early treatment to prevent the development of fixed contracture is 
therefore important in the management of spasticity in this population. 
1.2 
Management of Spasticity in Children 
Management of spasticity associated with cerebral palsy is focused on helping the child 
achieve maximal potential in growth and development.  Most patients are managed with a 
combination of treatment modalities, including non-pharmacologic, systemic pharmacologic, 
local pharmacologic, and surgical treatments. 
Non-pharmacologic and non-surgical treatments for spasticity aim to strengthen weakened 
muscles, weaken spastic muscles, and improve joint range of motion as well as motor 
development (Koman et al, 2004).  These interventions include occupational therapy (OT), 
physical therapy (PT), orthotics, splints, casting and other devices, or any combination of 
these methods.  PT and OT are regarded as essential for successful medical and surgical 
interventions (Butler and Darrah, 2001; Dumas et al, 2001) but the overall evidence 
supporting this is weak (Lannin et al, 2006).  A recent study has demonstrated the enhanced 
effectiveness of OT used in combination with BOTOX® (botulinum toxin type A) purified 
neurotoxin complex (US Adopted Name is onabotulinumtoxinA), hereafter referred to as 
BOTOX (Wallen et al, 2007). 
Systemic pharmacologic treatments include anti-spastic drugs such as baclofen, dantrolene, 
diazepam, scopolamine, and tizanidine (Gracies et al, 1997; O’Flaherty and Waugh, 2003; 
Scheinberg et al, 2006; Steinbok, 2006).  The aim of systemic pharmacologic management is 
to reduce the muscle overactivity associated with spasticity.  Mechanisms of action vary but 
the result is either a suppression of muscle excitation or an enhancement of neural inhibition.  
Response to these medications is variable and unpredictable (O’Flaherty and Waugh, 2003).  
Major drawbacks of systemic anti-spastic therapy include the lack of specificity of targeting 
muscle groups and CNS side effects such as drowsiness, constipation, and cognitive 
impairment.  Local pharmacologic treatments include phenol or alcohol injections for 
specific chemolysis of targeted nerves.  The main risks of phenol are its potential to cause 
irreversible damage to the nerve and nearby structures, as well as reduce sensation and cause 


 
 
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dysesthesias and neuropathic pain (Gracies et al, 1997).  Intrathecal baclofen is reserved for 
patients with disabling general spasticity that is unresponsive to conservative 
pharmacotherapy (Koman et al, 2004). 
Orthopedic procedures such as contracture release, tendon lengthening, and tendon transfer 
can reduce spasticity symptoms that may result in improved access for hygiene and brace 
(orthotic) tolerability.  These surgical procedures may also result in pain reduction, as well as 
reduction in bone deformity (osteotomy).  However, many forms of surgery are best delayed 
until tendons and joints have grown to a reasonable proportion of their adult size since it is 
more difficult to predict the outcome of surgery in younger children.  Surgical procedures 
have been reported as delayed due to the ability of botulinum toxin (type A) therapy to 
minimize fixed muscle shortening and soft tissue and skeletal deformation associated with 
spasticity (Molenaers et al, 2006). 
Neurosurgical procedures include selective dorsal rhizotomy and selective peripheral 
neurotomy (Chambers, 1997; Steinbok, 2006).  Selective dorsal rhizotomy is used to treat 
severe spasticity of the lower extremities that interferes with mobility or positioning.  It is 
usually most effective in a small number of select diplegic or quadriplegic children with 
cerebral palsy who are expected to be independent ambulators.  In children with underlying 
muscle weakness, rhizotomy can worsen rather than improve function. 
1.3 
BOTOX for Management of Pediatric Spasticity 
Botulinum neurotoxin type A (BoNT-A) blocks neuromuscular conduction by binding to 
receptor sites on motor nerve terminals, entering the nerve terminals, and inhibiting the 
release of acetylcholine.  When injected intramuscularly at therapeutic doses, BoNT-A 
produces localized chemical denervation of the muscle, resulting in focal muscle weakness.  
This muscle weakness is reversible through nerve ending recovery over a period of 3 or more 
months.  Relaxation of rigid muscles by BoNT-A allows a child to participate in PT or OT, 
which encourages the use of both targeted and antagonistic muscles with goals of muscle 
stretching, strengthening, improved motor control, and acquisition of new skills.  There has 
been considerable experience worldwide since the early 1990s with the use of BOTOX in the 
treatment of spasticity associated with cerebral palsy. 
1.3.1 
Use of BOTOX in Pediatric Lower Limb Spasticity 
Allergan has completed 5 trials with BOTOX for the treatment of lower limb spasticity in 
children with cerebral palsy.  These studies have demonstrated an acceptable safety profile of 


 
 
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BOTOX at the dose ranges evaluated for this patient population.  Study OCUL-118-8051, a 
placebo-controlled study, included 145 patients (72 BOTOX; 73 placebo) with equinus foot 
deformity who were 2 to 14 years old.  Patients received injections of BOTOX (4 to 8 U/kg; 
note that BOTOX doses throughout this protocol are expressed per body weight) or placebo.  
The proportion of responders based on gait pattern score was significantly greater (p ≤ 0.05) 
in the BOTOX group compared to the placebo group at weeks 2, 8, and 12.   
Study OCUL-119-8051, an open-label multiple-treatment extension of study 
OCUL-118-8051, included 207 patients who received injections of BOTOX at 4 U/kg.  For 
the first 2 years of the study the proportion of responders ranged from 39% to 64%.   
Study OCUL-120-8051, a placebo-controlled study, included 35 ambulatory patients with 
equinus foot deformity (17 BOTOX; 18 placebo) who were 2 to 14 years old.  Patients 
randomized to BOTOX received 4 U/kg in the affected limb.  The proportion of responders 
based on gait pattern score was significantly greater (p ≤ 0.05) in the BOTOX group 
compared to the placebo group at weeks 8 and 12.  Twenty-five of the 35 patients entered a 
2-year, multiple-treatment open-label follow-up study (BTOX-121-8051).   
The fifth study (191622-021), a placebo-controlled study, included 149 patients with equinus 
foot deformity (73 BOTOX; 76 placebo) who were 2 to 8 years old.  Patients randomized to 
BOTOX received 4 U/kg in each affected limb (up to a maximum of 8 U/kg).  No significant 
differences in the proportion of responders based on the gait pattern score were observed 
between the 2 treatment groups. 
1.4 
Dose Justification 
The purpose of this study is to further investigate the safety and efficacy of BOTOX 
treatment in pediatric patients with cerebral palsy who have dynamic muscle contracture of 
the ankle plantar flexors associated with equinus foot position. 
Three treatment groups were selected for the study:  4 U/kg (not to exceed 150 U) + PT, 
8 U/kg (not to exceed 300 U) + PT, and placebo + PT.  The BOTOX doses were selected 
based on Allergan clinical trial experience in pediatric lower limb spasticity, clinical expert 
advice, published literature including consensus guidelines for botulinum toxin type A 
treatment of pediatric spasticity, and nonclinical toxicology data. 
The 5 completed Allergan-sponsored clinical trials in pediatric lower limb spasticity used 
doses ranging from 4 to 8 U/kg (Studies OCUL-118-8051, OCUL-119-8051, 


 
 
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OCUL-120-8051, BTOX-121-8051, 191622-021).  In Studies OCUL-118-8051 and OCUL-
120-8051, patients received 2 doses of 4 U/kg within a month, for a total of 8U/kg.  All of 
these studies demonstrated an acceptable safety profile and all but Study 191622-021 
documented statistically significant improvement in a variety of efficacy outcomes.  In Study 
191622-021, patients with a minimum severity of baseline spasticity of at least a Modified 
Ashworth Scale-Bohannon (MAS-B) score of 1+ received 4 to 8 U/kg in the affected limb(s).  
A post hoc analysis of a subgroup of patients with more severe baseline spasticity with a 
MAS-B score of at least 2 demonstrated a significant trend (p = 0.085) based on the MAS-B 
change over the 12-week posttreatment period in the BOTOX group compared to the placebo 
group.  
The doses in the present study are further supported by the dose ranges described in the 
consensus guidelines and published literature.  The European consensus paper 
(Heinen et al, 2010) recommended a dose range of 1 to 20 U/kg with a maximum total dose 
of 400 U, regardless of location of injection.  The American Academy of Neurology also 
concluded that botulinum toxin doses ranging from 2 to 30 U/kg for treatment of the upper 
and lower limbs are effective and generally safe (Delgado et al, 2010).  The 2010 
International Consensus Paper for botulinum toxin treatment in lower limb spasticity for 
children with cerebral palsy recommends a dose range of 16 to 20 U/kg for patients with 
Gross Motor Function Classification System – Expanded and Revised (GMFCS-E&R) 
level I to IV without risk factors (Love et al, 2010).  The higher dose ranges were based on 
studies allowing injections to multiple muscles (multi-level injections) across upper and 
lower extremities (Heinen et al, 2006; Molenaers et al, 2009).   
Doses recommended for individual muscles are 3 to 6 U/kg for gastrocnemius, 2 to 3 U/kg 
for soleus, and 1 to 2 U/kg for tibialis posterior (Russman et al, 2008).  In published double-
blind studies in pediatric patients with lower limb spasticity, a dose of 2 to 8 U/kg was most 
commonly used for the gastrocnemius muscles.  The maximum dose ranged from 200 to 
600 U for both legs.  Doses used in the present study are consistent with the range of doses 
recommended by the consensus documents and reflect current clinical practice. 
In addition, the safety of 8 U/kg in this study is also supported by the no-observable-adverse-
effect levels (NOAELs) established in BOTOX toxicology studies.  In single and repeated-
dose studies in rats, 10 and 16 U/kg were defined as NOAELs, respectively.  In monkeys, the 
single-dose intramuscular NOAEL was determined to be 16 U/kg when administered into the 
gastrocnemius muscle.  In repeated-dose toxicity studies in monkeys involving multiple 


 
 
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injection sites that more closely mimic clinical use, the NOAEL was 8, 12, or 16 U/kg for 2, 
4, or 6 injection sites, respectively. 
2. 
Study Objectives and Clinical Hypotheses  
2.1 
Study Objectives 
To evaluate the safety and efficacy of a single treatment of 2 doses (4 U/kg and 8 U/kg) of 
BOTOX with standardized PT in pediatric patients with lower limb spasticity. 
2.2 
Clinical Hypotheses 
1) A single treatment of BOTOX at doses of 4 U/kg and 8 U/kg in the lower limb has an 
acceptable safety profile. 
2) BOTOX with standardized PT is more effective than placebo with standardized PT as 
measured by a reduction in muscle tone on the MAS-B.  For United States (US) Food 
and Drug Administration (FDA) only, the hypothesis is that BOTOX with 
standardized PT is more effective than placebo with standardized PT as measured by 
a reduction in muscle tone on the MAS-B and improvement on the Clinical Global 
Impression of Overall Change (CGI) by Physician. 
3. 
Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 12-week 
study evaluating 2 doses of BOTOX, 4 and 8 U/kg, and placebo with standardized PT for the 
treatment of spasticity involving the ankle plantar flexors in monoplegic and hemiplegic 
children.  Patients who successfully complete this study without major protocol deviations 
(eg, noncompliance to protocol-required procedures) will be given the option of enrolling in 
the open-label extension Study 191622-112 if they meet eligibility criteria. 
The maximum study duration per patient will be approximately 16 weeks (including up to 
4 weeks in the screening period).  Patients will complete 8 study visits as follows:  screening 
(week -4 to week -2), initiation of standardized PT (week -2), randomization and treatment 
visit (day 1), and post-injection follow-up visits at weeks 2, 4, 6, 8, and 12.  
There will be 1 treatment cycle in the study.  Only 1 affected lower limb (referred to as the 
study limb) will be treated.  Patients will be randomized in a 1:1:1 ratio to one of the 


 
 
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following treatment groups:  4 U/kg (not to exceed 150 U) + PT, 8 U/kg (not to exceed 
300 U) + PT, or placebo + PT. 
3.1 
Safety Data Review Committee  
The safety of the study participants will be monitored by a Safety Data Review Committee 
(SDRC) composed of at least 2 non-Allergan physicians and a study-independent statistician.  
Additional ad hoc participants (eg, physician specialists) may be invited to participate in 
review meetings depending on the safety findings and required scope of expertise.   
The SDRC will conduct periodic review and assessments of the blinded adverse events data 
throughout the study to ensure the safety of study participants.  The SDRC may elect to 
review additional safety parameters (eg, laboratory data), unblind the data, or change the 
frequency of their review meetings depending upon emerging safety findings or changes in 
patient enrollment rates.   
For additional details regarding SDRC membership, standard operational procedures, 
frequency of review meetings, and other details, please refer to the SDRC charter.  
4. 
Study Population and Entry Criteria 
4.1 
Number of Patients  
Approximately 412 patients will be enrolled to ensure that at least 351 patients (117 per 
treatment group) will complete the study.   
4.2 
Study Population Characteristics 
The study population is medically stable monoplegic or hemiplegic pediatric patients with 
cerebral palsy who have dynamic muscle contracture of the ankle plantar flexors associated 
with equinus foot position. 
4.3 
Inclusion Criteria 
The following are requirements for entry into the study: 
1. Male or female, 2 to 16 years and 11 months of age (prior to 17th birthday) at the 
day 1 visit 


 
 
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2. Minimum weight of 10 kg at the screening and day 1 visits 
3. Monoplegic or hemiplegic patients with cerebral palsy who have dynamic muscle 
contracture (spasticity confirmed by Hypertonia Assessment Tool [HAT]) of the ankle 
plantar flexors.  Equinovarus or equinovalgus deformities are acceptable. 
4. 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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14. 
 
 
 
  
 
 
4.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
1. 
 
 
2. Any medical condition that may put the patient at increased risk with exposure to 
Botulinum Toxin Type A Purified Neurotoxin Complex, including diagnosed 
muscular dystrophy (eg, Duchenne’s muscular dystrophy), myasthenia gravis, Eaton-
Lambert syndrome, amyotrophic lateral sclerosis, mitochondrial disease, or any other 
significant disease that might interfere with neuromuscular function 
3. 
 
 
 
 
 
 
 


 
 
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13. Uncontrolled epilepsy defined as: 
a. more than 1 generalized seizure in any month within the 3 months prior to the 
day 1 visit, or 
b. history of any of the following within 9 months prior to the day 1 visit:  
prolonged seizures or repetitive seizure activity requiring administration of a 
rescue benzodiazepine (oral, rectal, etc) more than once a month, seizures 
lasting more than 10 minutes, status epilepticus, or epilepsy with autonomic 
involvement  
 
 
 
    
 
 
 
 
  
 
 
 
 
 
 
 
 
   
19. Botulinum toxin therapy of any serotype for any condition within 6 months prior to 
the day 1 visit 
 
 


 
 
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23. History of surgical intervention of the lower leg (the knee and below of the study 
limb; except for tendon lengthening more than 12 months prior to the day 1 visit) or 
planned surgical intervention of any limb(s) during the study 
 
25. Previous casting within 6 months prior to the day 1 visit or splinting with a dynamic 
splint (eg, Dynasplint® or UltraFlex®) within 3 months prior to the day 1 visit for 
spasticity of the study limb or the affected upper limb, or planned casting or splinting 
with a dynamic splint (eg, Dynasplint or UltraFlex) for spasticity of the study limb or 
affected upper limb during the study 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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4.5 
Permissible and Prohibited Medications/Treatments 
4.5.1 
Permissible Medications/Treatments 
Patients who are already on stable concomitant anti-spastic medications or muscle relaxants 
(eg, benzodiazepines, baclofen [oral], scopolamine [oral or patch], tizanidine, vigabatrin, or 
dantrolene) prior to the day 1 visit and otherwise eligible for the study will be permitted to 
continue taking their medications at the same dose and regimen during the study.  Patients 
who are on oral concomitant anti-spastic medications, anti-epileptics, or muscle relaxants 
should be instructed to take their medications at approximately the same time each day 
during the study, especially on the days of office visits.  Efforts should be made to keep the 
same interval from the time of the medication to the time of the spasticity assessments during 
the office visits throughout the study.  Patients using scopolamine patches must not wear their 
patches at least 2 days prior to an office visit (except for the screening and week -2 visits). 
Patients will be permitted to initiate the use of soft splints, including ankle-foot-orthosis 
(AFO), during the study at the investigator’s discretion.  However, patients should be asked 
not to wear the splint for at least 30 minutes before a spasticity measure at the office visits. 
Therapy considered necessary for the patient’s welfare may be given at the discretion of the 
investigator.  If concurrent medications may have an effect on study outcomes, those 
medications should be administered in dosages that remain constant throughout the course of 
the trial.  If the permissibility of a specific medication/treatment is in question, please contact 
Allergan. 
4.5.1.1 
Acceptable Contraceptive Methods and Definition of Females 
of Childbearing Potential 
At the time of screening, if a female patient is approaching puberty but is not yet of 
childbearing potential, then the patient and/or her legally authorized representative must be 
advised that if she becomes of childbearing potential (defined as females post menarche) 
during the study, she and/or her legally authorized representative must notify the site of this 
change.  A urine pregnancy test must be performed at the patient’s next scheduled visit.  
Upon receiving this notification, the site personnel must advise the patient and/or her legally 


 
 
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authorized representative of the protocol requirement that any female of childbearing 
potential must use a reliable method of contraception, as described below. 
For females of childbearing potential who may participate in the study, the following 
methods of contraception, if properly used, are generally considered reliable:  oral 
contraceptives, patch contraceptives, injection contraceptives, implantable contraceptives, 
male condom with intravaginal spermicide, diaphragm or cervical cap with spermicide, 
vaginal contraceptive ring, intrauterine device, surgical sterilization (bilateral tubal ligation 
or removal of both ovaries), vasectomized partner, or sexual abstinence. 
The investigator and each patient (and/or her legally authorized representative) will 
determine the appropriate method of contraception for the patient during the participation in 
the study.  The method of contraception must be documented in the patient’s medical record 
and electronic case report forms (eCRFs).  At each study visit, the investigator must counsel 
female patients of childbearing potential and/or their legally authorized representative 
regarding the importance of maintaining their agreed-upon method of contraception. 
If a female patient of childbearing potential becomes pregnant during the study, the 
investigator will notify Allergan immediately after the pregnancy is confirmed and the patient 
will be exited from the study after appropriate safety follow-up.  The investigator will (1) 
notify the patient’s physician that the patient was being treated with BOTOX or placebo and 
(2) follow the progress of the pregnancy.  The investigator must document the outcome of the 
pregnancy and provide a copy of the documentation to Allergan. 
4.5.2 
Prohibited Medications/Treatments 
Patients should not be permitted to initiate the following therapy during the study: 
• Anti-spastic medications or muscle relaxants (eg, benzodiazepines, vigabatrin, 
baclofen [oral or pump], scopolamine [oral or patch], tizanidine, or dantrolene)  
• Anti-epileptic medication 
Patients who enter the study on any of the above concomitant medications should remain on 
a stable dose throughout the study. 


 
 
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In addition, the following treatments or therapy are not permitted during the study: 
• Botulinum toxin therapy of any serotype (except for the study treatment) 
• Phenol or alcohol injection to any limb(s) 
• Baclofen pump therapy 
• Planned surgery in any limb(s) 
• General anesthesia (drug-induced depression of consciousness) or deep 
sedation/analgesia (drug-induced loss of consciousness) as defined in “Practice 
guidelines for sedation and analgesia by non-anesthesiologists” (American Society of 
Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists, 
2002) is prohibited regardless of the medication used.  Minimal sedation (anxiolysis) 
or moderate sedation/analgesia (conscious sedation) in addition to local anesthesia is 
allowed for injection of the study medication. 
• Casts or dynamic splints (UltraFlex, DynaSplint) for spasticity in the study limb or 
the affected upper limb 
• OT/PT modalities such as ultrasound, transcutaneous electrical nerve stimulation, 
electrical stimulation, or acupuncture 
Co-administration of aminoglycosides or other agents that could interfere with 
neuromuscular transmission (eg, curare-like agents) should only be used with caution as the 
effects of toxin theoretically could be potentiated. 
The decision to administer a prohibited medication/treatment is done with the safety of the 
patient as the primary consideration.  Patients may stay in the study even if a prohibited 
medication is administered.  When possible, Allergan should be notified before the prohibited 
medication/treatment is administered. 
4.5.3 
Special Diet or Activities 
Protocol-specific standardized PT will be provided to all enrolled patients.  For the purposes 
of this protocol, PT is defined as “physical interventions performed by a licensed therapist 
(or equivalent per local regulations) to facilitate functional improvement in the lower 
extremity(ies).” 


 
 
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Patients will initiate their protocol-specified standardized PT approximately 2 weeks prior to 
the day 1 (randomization) visit.  Patients who are on concurrent PT at the time of screening 
must modify their existing PT to comply with the protocol-specified standardized PT.  After 
randomization, patients will be required to follow the same standardized PT protocol for the 
entire duration of the study.  The standardized PT protocol will consist of weekly sessions of 
approximately 1 hour that will include the following modalities: 
• Elongation (approximately 20 minutes) 
• Strengthening (approximately 20 minutes) 
• Gait-oriented and/or functional mobility (approximately 20 minutes) 
For each of the 3 modalities, the specific duration and activity options will depend on the 
patient’s age, affected muscles, level of ability, and individual treatment goals (refer to the 
Standardized PT Reference Manual for further details). 
Standardized PT scheduled on the day of an office visit should not be performed prior to any 
efficacy assessments.  The last PT session should be scheduled during week 11. 
If applicable, patients who are undergoing or will undergo school-based therapy as per 
relevant local legislation will be allowed to receive school-based therapy during the study in 
addition to the protocol-specified standardized PT; however the school-based therapy should 
remain constant throughout the study, if possible.  Patients undergoing OT for upper limb 
spasticity at study entry should continue the same regimen during the study. 
5. 
Study Treatments  
5.1 
Study Treatments and Formulations 
The study treatment will consist of BOTOX or placebo and standardized PT.  To maintain the 
blinding of the study, an Independent Drug Reconstitutor (IDR) will be assigned at each site 
for study drug preparation.  A Pharmacy Manual will be provided with detailed information.  
 
 
 
 


 
 
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5.2 
Control Treatment 
Each vial of BOTOX placebo 
 contains 0.9 mg of sodium 
chloride in a sterile, vacuum-dried form without preservative. 
5.3 
Methods for Masking/Blinding 
Patients and all site personnel with the exception of the IDR will be blinded to the study 
medication and dose administered.  The IDR must not be involved in any study procedures 
other than study drug preparation and accountability (eg, proper drug storage). 
The physician investigator will be responsible for identifying the muscles and doses to be 
injected. 
Following randomization, to ensure that the injector remains blinded to the treatment group 
assignment, the IDR will be responsible for preparing the study medication according to the 
specific dilution requirements depending on the randomization assignment.  A dosing 
summary will be provided to the IDR by the investigator or other site personnel for 
preparation of the study medication and injection syringes for each eligible muscle to be 
injected. 
The study drug will be diluted according to the schedule below (Table 2) and in accordance 
with the randomization assignment received from the interactive voice response 
system/interactive web response system (IVRS/IWRS). 
Table 2 
Dilution of Study Drug  
Treatment Group 
Placebo 
BOTOX 
4 U/kga 
BOTOX 
8 U/kga 
Volume of preservative-free saline used for dilution 
2 mL 
4 mL 
2 mL 
BOTOX units  
0 U/mL 
25 U/mL 
50 U/mL 
a 
Per 100 unit (U) vial 
 
This dilution requirement will ensure that the same volume is injected into each of the 
muscles irrespective of the BOTOX dose group assignment.  The randomization assignment 
documentation received from the IVRS/IWRS must be placed in the pharmacy file in a 
secure location with limited access to prevent inadvertent unblinding of other study personnel. 


 
 
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5.4 
Treatment Allocation Ratio and Stratification 
A centralized randomization scheme stratified by age and baseline MAS-B ankle score will 
be prepared by Allergan.  Patients will be randomized to 1 of 3 treatment groups in a 1:1:1 
ratio within each combination of strata.  Randomization will be dispensed by the 
IVRS/IWRS.  The stratification categories are as follows: 
• Age (≤ 6 years and > 6 years) 
• Baseline (day 1) MAS-B score of the ankle with knee extended (MAS-B = 2 and 
MAS-B > 2)  
5.5 
Method for Assignment to Treatment Groups/Randomization 
At the screening visit, after the patient and/or legally authorized representative has signed the 
informed consent and minor assent (as applicable), the site will call the IVRS or log onto the 
IWRS to obtain the patient number that will serve as the patient identification number on all 
study documents.  The automated IVRS/IWRS will be used to manage the randomization and 
treatment assignment based on the randomization scheme prepared by Allergan Biostatistics.  
At the study day 1 visit, the site will access the IVRS/IWRS to randomize the patient/assign 
treatment.   
The system will monitor the distribution of baseline (randomization) MAS-B ankle score 
throughout enrollment of the study to ensure that approximately 30% of the patients enrolled 
have a baseline MAS-B in the ankle of > 2.  If necessary, enrollment of patients with baseline 
MAS-B of 2 will be closed and enrollment will continue for patients with baseline MAS-B of 
> 2.   
The study will also aim to enroll approximately 20% botulinum toxin-naïve patients in the 
subgroup ≤ 6 years of age and at least some botulinum toxin-naïve patients in the subgroup 
> 6 years of age.  This will also be monitored by the IVRS/IWRS. 
Study medication will be labeled with medication kit numbers.  At the time of randomization, 
sites will call the IVRS or log onto the IWRS to obtain the specific study medication kit 
numbers for each randomized patient.  Sites will dispense study medication according to the 
IVRS/IWRS instructions.  Sites will receive an IVRS/IWRS confirmation notification for 
each transaction.  All notifications must be maintained in the pharmacy file in a secure 
location to prevent inadvertent unblinding of other study personnel. 


 
 
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5.6 
Treatment Regimen and Dosing 
This study will include 1 treatment of the study limb. 
The volume and corresponding dose for each identified muscle and the total dose will be 
calculated for each of the 3 potential treatment assignments to maintain blinding.  A dosing 
summary will be provided to the IDR who will prepare the study medication according to the 
randomization assignment. 
5.6.1 
Treatment Regimen/Dosage Adjustments 
For all patients enrolled, the muscles and dose for each muscle to be injected are listed in 
Table 3 according to the randomization assignment.  All muscles listed must be injected.  The 
dose for each muscle should be calculated using the patient’s body weight in kilograms 
measured at the day 1 visit multiplied by the U/kg assigned to the muscle according to the 
randomization assignment.  For purposes of dose calculation only, the patient’s weight will 
be rounded to the nearest whole kilogram.  If the calculated unit (U/kg x body weight) is 
higher than the “not to exceed” dose for that muscle, the dose must be reduced to the “not to 
exceed” dose.  No other dose adjustment is allowed in this study except for reducing the 
calculated dose to the maximum per muscle (“not to exceed”) dose level. 
The dose for each muscle must be evenly distributed across the number of injection sites 
specified for each muscle.  The total dose across all injections must not exceed the maximum 
doses of 4 U/kg (not to exceed 150 U) or 8 U/kg (not to exceed 300 U) for the BOTOX 
groups.  The dose volume will be the same for all treatment groups, including the placebo 
group. 
In addition to BOTOX or placebo, patients will receive standardized PT consisting of 
approximately 1-hour weekly sessions from week -2 through week 11. 
5.6.1.1 
Dosing Paradigm  
Eligible patients will receive injections to the study limb in the gastrocnemius (both medial 
and lateral heads), soleus, and tibialis posterior muscles.  Doses listed in Table 3 must be 
followed according to the randomization assignment.   
 


 
 
 
 
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5.7 
Storage of Study Medications/Treatments 
The study medication must be stored in a secure area and administered only to patients 
entered into the clinical study, at no cost to the patients, in accordance with the conditions 
specified in this protocol.  To prevent possible unblinding, access to study medication during 
the reconstitution process is prohibited for staff involved in the care and evaluation of study 
patients or the handling of study data throughout the study. 
The lyophilized vials of study medication must be stored immediately upon receipt in a 
  Reconstituted study medication must be stored in the vial 
.  If not used 
, study medication may not be used.  Refer to the Pharmacy 
Manual for additional instructions. 
5.8 
Preparation of Study Medications/Treatments 
To ensure that the same volume is injected into each of the muscles irrespective of the 
treatment group assignment, BOTOX (100 U vial) and placebo will be reconstituted by the 
IDR according to Table 2.   
5.9 
Treatment Administration 
Patients will be injected according to the protocol-required dosing regimen. 
Muscles will be injected using muscle localization techniques such as e-stimulation, 
sonography, and/or electromyography (EMG).  Muscle localization using palpation alone is 
not permitted.  Motor endplate targeting injection techniques are recommended 
(Van Campenhout and Molenaers, 2011). 
The study medication may be administered in conjunction with appropriate local anesthesia 
according to each investigator’s standard practice and must be documented in the patient’s 
medical record and appropriate eCRF.  General anesthesia (drug-induced depression of 
consciousness) or deep sedation/analgesia (drug-induced loss of consciousness) as defined in 
“Practice guidelines for sedation and analgesia by non-anesthesiologists” (American Society 
of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists, 2002) 
is prohibited regardless of the medication used.  Minimal sedation (anxiolysis) or moderate 
sedation/analgesia (conscious sedation) in addition to local anesthesia is allowed. 


 
 
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6. 
Response Measures and Summary of Data Collection Methods 
6.1 
Efficacy Measures 
6.1.1 
Primary Efficacy Measures 
• MAS-B ankle score with knee extended  
• CGI by Physician (for US FDA only) 
6.1.2 
Secondary Efficacy Measures 
• CGI by Physician (for non-US FDA analyses) 
• Goal Attainment Scale (GAS) by Physician 
• Modified Tardieu Scale (MTS) of the ankle with knee extended and knee flexed 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
6.1.4 
Safety Measures 
• Adverse events 
• Physical examination 
• Urine pregnancy tests (for all females of childbearing potential) 


 
 
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• Hematology and serum chemistry 
• Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) 
• Body weight  
• Immunogenicity testing (for patients who weigh at least 15 kg at the screening visit) 
• C-SSRS (for patients ≥ 6 years of age at day 1) 
6.2 
Examination Procedures, Tests, Equipment, and Techniques  
The procedures are described in Attachment 12.1.   
6.3 
Other Study Supplies 
The following study supplies will be provided by Allergan or a vendor contracted by 
Allergan: 
• Laboratory kits for the collection and shipment of hematology, biochemistry, 
immunogenicity, and urine samples (including pregnancy kits) will be provided by a 
vendor (eg, central laboratory) contracted by Allergan.  
• Calibrated temperature recorder for monitoring drug storage refrigerator temperature 
• Syringe labels 
• Goniometer 
• 
 
 
• Kilogram-only weight scale for selected sites (note that weight must be measured and 
collected in kilograms) 
The study sites will be responsible for providing the following supplies/equipment: 
• Needles and syringes for study drug reconstitution and injection 


 
 
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• Sterile saline (0.9% without preservative) for study drug reconstitution 
• Surgical gloves for study drug reconstitution 
• 
 
• Access to a computer with internet connection (high-speed connection for eCRF 
completion) 
• Standard 12-lead ECG 
• Weight scale with height measure (if not supplied by Allergan) 
• Centrifuge for processing lab samples 
• Ultrasound and/or e-stimulation or EMG device for muscle localization techniques 
6.4 
Summary of Methods of Data Collection 
An IVRS/IWRS will be used to screen, randomize, and manage study medication inventory.  
Data will be collected using eCRFs via a validated electronic data capture system (EDC).  
Source documents will be used and stored at the sites, and may include a patient’s medical 
records, hospital charts, clinical charts, patient chart, copy of the EDC file, as well as the 
results of diagnostic tests such as laboratory tests, ultrasounds, x-rays, and ECGs.  The 
videotapes captured for the Edinburgh Visual Gait assessment will be shipped or 
electronically transferred to Allergan and stored into an Image Repository.  For patients 
≥ 6 years of age at day 1, the C-SSRS will be collected as a clinical interview and the scores 
will be collected from the designated site staff using an electronic data collection method 
(eg, electronic tablet). 
A central laboratory will be used for the analysis of all blood samples.  Blood samples for 
immunogenicity tests will be shipped by the central laboratory, analyzed by a specialty 
laboratory using validated assays, and the data will be transferred to Allergan. 
7. 
Statistical Procedures 
The database will be locked when all patients have completed the study.  A detailed analysis 
plan will be generated prior to the final database lock.  All planned analyses will be 
performed after the database has been locked and randomization data released.   


 
 
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7.1 
Analysis Populations 
Safety data will be analyzed on the basis of all treated patients based on the treatment 
received, defined as the safety population.  Efficacy data, demographics, and background 
information will be analyzed on the basis of the modified intent-to-treat (mITT) population, 
defined as all randomized patients with a valid baseline MAS-B ankle score with knee 
extended and at least one post-baseline measurement at weeks 2, 4, or 6 for the MAS-B ankle 
score with knee extended and the CGI by Physician. 
7.2 
Collection and Derivation of Primary and Secondary Efficacy 
Assessments 
At each scheduled office visit at weeks 2, 4, 6, 8, and 12, the patient’s spasticity of the ankle 
will be evaluated using the MAS-B.  MAS-B scores of 0, 1, 1+, 2, 3, or 4 will be coded as 
grades of 0, 1, 2, 3, 4, or 5, respectively.  The MAS-B grade change from baseline to each 
post-randomization office visit and the primary endpoint, average change at weeks 4 and 6 
using observed cases without imputation of missing values, will be derived for each patient.  
Additionally, a responder status will be determined according to whether or not a patient has 
at least a 1 grade reduction from baseline on the MAS-B.  
The secondary efficacy measure CGI by Physician (for US FDA, CGI by Physician is a co-
primary measure) will be measured at weeks 2, 4, 6, 8, and 12.  CGI is a 9-point scale 
from -4 (very marked worsening) to +4 (very marked improvement).  Each assessment is 
evaluated relative to the patient’s baseline status obtained at day 1.  The average of scores at 
weeks 4 and 6 using observed cases without imputation of missing values will be derived for 
CGI by Physician. Additionally, a responder status will be determined according to whether 
or not a patient has at least +1 score of CGI by Physician.   
The secondary efficacy measures of MTS and GAS will also be collected at scheduled office 
visits according to the Schedule of Visits and Procedures in Table 1.  The difference between 
slow (R2) and fast (R1) range of motion (R2 - R1; see Attachment 12.1.11 for a detailed 
description of the MTS) and respective change from baseline to each posttreatment office 
visit on the MTS will be derived.  Multiple imputation (MI) method is only intended for 
MAS-B ankle score and the CGI by Physician as a sensitivity analysis.  Missing values for 
other variables will not be imputed. 


 
 
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7.2.1 
Primary Efficacy Variables  
The primary efficacy variable is the grade change of MAS-B of the ankle plantar flexors with 
knee extended.  The primary efficacy endpoint will be the average grade change from 
baseline in MAS-B at weeks 4 and 6.  For US FDA only, the co-primary efficacy variables 
are the average grade change of MAS-B of the ankle plantar flexors with knee extended and 
the CGI by Physician.  The co-primary efficacy endpoints will be the average grade change 
from baseline in MAS-B and the average CGI by Physician at weeks 4 and 6. 
7.2.2 
Secondary Efficacy Variables 
CGI by Physician (for non-US FDA analyses) will be evaluated at weeks 2, 4, 6, 8, and 12.  
In addition to each timepoint, the average of the weeks 4 and 6 CGI by Physician will be 
analyzed.  Functional goals, active and passive, using GAS by Physician will be evaluated 
separately relative to baseline at weeks 8 and 12.  Secondary efficacy variables of MTS 
include the difference between slow (R2) and fast (R1) range of motion (R2 - R1) as well as 
respective change from baseline on the MTS for the ankle plantar flexors (with knee 
extended and knee flexed) at weeks 2, 4, 6, 8, and 12.  Additionally changes from baseline 
for each R1 and R2 at each assessment point will be evaluated.   
 
 
 
 
 
 
 
7.3 
Hypothesis and Methods of Analysis  
7.3.1 
Primary Efficacy Analyses 
The primary efficacy analyses will be based on the mITT population.  The primary analysis 
will be conducted for the average change from baseline in MAS-B score at weeks 4 and 6.  
The statistical null hypothesis is that both higher dose (8 U/kg) and lower dose (4 U/kg) have 
the same mean as placebo. The alternative hypothesis is that at least one study dose has a 
different mean than placebo.  The hypothesis will be tested based on the Least Square (LS) 
mean differences from an analysis of Mixed Model Repeated Measures (MMRM)  at 


 
 
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significance level of 0.05.  The primary variable will be summarized by treatment group.  
The difference of LS means of each dose group and the placebo group from MMRM model 
will be used to test the null hypothesis.  The analysis will include observed data at weeks 2, 4, 
6, 8, 12. The model will include baseline MAS-B as a covariate and factors of age group, 
treatment group, visit, treatment-by-visit interaction, study center, and previous botulinum 
toxin exposure.  Age group is represented by stratification categories (≤ 6 years and > 6 years 
for age group). Baseline MAS-B grade is a continuous variable included as a covariate.  
Unstructured covariance structure will be used. Two tests will be performed based on the 
pairwise comparisons:  8 U/kg versus placebo and 4 U/kg versus placebo, each at a 0.05 
significance level.    
To control the type I error rate for the endpoint of the average change from baseline in MAS-
B score at weeks 4 and 6,  a gatekeeping approach will be used for this variable 
(Dmitrienko et al, 2005).  Specifically, for average change from baseline in MAS-B, the LS 
mean difference of 8 U/kg versus placebo from the MMRM will be tested first.  If the test is 
not statistically significant at the level of 0.05, the test of the LS mean of difference of 4 U/kg 
versus placebo will not be considered statistically significant regardless of its p-value. 
Otherwise, if the test for 8 U/kg is statistically significant, then the test for 4 U/kg versus 
placebo will be evaluated based on its p-value.   
For sensitivity analysis purposes to supplement the primary analyses, an analysis of 
covariance (ANCOVA) model using MI for missing values will be conducted.  A summary of 
the percentage of missing MAS-B scores by visit will also be provided.  The ANCOVA will 
include baseline MAS-B score as a covariate and factors of age group, treatment group, study 
center and previous botulinum toxin exposure. Additional sensitivity analyses for the MAS-B 
changes from baseline at each assessment timepoint will also be performed using ANCOVA 
with the same model as specified above with observed data, and linear contrasts will be used 
to estimate the treatment differences between each study dose and placebo.  In addition, the 
frequency distribution of the grade changes from baseline in the MAS-B, as well as the 
percentage of responders (with at least a 1 grade reduction in MAS-B), will be summarized 
by treatment group at each posttreatment office visit.  A logistic regression analysis will also 
be performed on the responder status at each posttreatment visit with a covariate of baseline 
MAS-B and factors of age group, treatment group, study center, and previous botulinum 
toxin exposure, if applicable.  The additional analyses will be conducted using observed 
cases unless stated otherwise. 
For US FDA only, CGI by Physician will be a co-primary variable (see Section 7.7 for 
description of analyses). 


 
 
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7.3.2 
Secondary Efficacy Analyses  
The observed cases will be used for secondary efficacy analyses unless stated otherwise.  
CGI by Physician will be rated at study weeks 2, 4, 6, 8 and 12.  CGI by Physician will be 
summarized and analyzed by MMRM as the average of values at weeks 4 and 6 as well as 
ANCOVA at each assessment timepoint using observed cases.  The frequency distribution of 
the CGI scores, as well as the percentage of responders (CGI score of at least +1), will be 
summarized by treatment group at each posttreatment timepoint.  A logistic regression 
analysis will also be performed on the responder status at each posttreatment timepoint with 
factors age group, treatment group, study center, and previous botulinum toxin exposure, if 
applicable. For GAS by Physician, scores for each of the 2 goals at weeks 8 and 12 will be 
summarized by treatment group and analyzed by ANCOVA as specified in Section 7.3.1 to 
assess the treatment differences.  For MTS of the ankle of the study lower limb with knee 
extended and knee flexed, the difference between slow and fast motion (R2 - R1) and the 
individual R2 and R1 values in degree, as well as the respective changes from baseline, will 
be summarized by treatment group and analyzed by ANCOVA.   
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  


 
 
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7.3.4 
Safety Analyses 
Safety variables, including the incidence of adverse events, the incidence of suicide-related 
events using the C-SSRS (for patients ≥ 6 years of age at day 1), laboratory test values and 
changes from baseline, as well as vital signs and their change from baseline, will be 
summarized by treatment group using the safety population.  The Medical Dictionary for 
Regulatory Activities (MedDRA) nomenclature will be used to code adverse events and 
medical history.  The incidence of adverse events (both pretreatment events and treatment-
emergent events) will be tabulated by primary system organ class and preferred term for each 
treatment group.  Possible distant spread of toxin adverse events will be assessed using a 
standardized methodology. 
Descriptive statistics will be presented for vital signs and numeric laboratory tests and the 
respective changes from baseline.  All laboratory values will be presented by descriptive 
statistics.  In addition, laboratory values outside the normal reference ranges for each patient 
at each applicable visit will be identified and evaluated against baseline via shift table 
analysis.  Potentially clinically significant abnormal values may be identified or summarized 
descriptively. 
Immunogenicity results for each patient will be reported as positive, negative, or 
inconclusive.  Correlations between immunogenicity results and other variables may be 
performed if warranted. 
7.4 
Subgroup Analyses 
Among the efficacy variables, the primary and selected secondary efficacy variables will be 
summarized by baseline MAS-B score (2 and > 2), age (≤ 6 years and > 6 years) and 
previous exposure to botulinum toxin. 
7.5 
Sample Size Calculation 
Approximately 412 patients will be enrolled to ensure that at least 351 patients (117 per 
treatment group) will complete the study. 


 
 
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Using a 2-sample t-test, a significance level of 0.05, and the assumptions in Table 4, the 
power for MAS-B change from baseline is 94% (PASS, Hintze, 2008).  The calculation is 
based on assumptions for 8 U/kg group and placebo group.  Since there are 2 co-primary 
endpoints for the US FDA analysis, for 8 U/kg group the power for CGI by Physician is 
calculated to be 97%, and the overall power for the US FDA co-primary endpoints will be at 
least 91%.  The assumptions for MAS-B were based on results of completed Studies 
BTX108509 and BTX108512; the estimates for CGI were based on results of completed 
Study 191622-021.   
Table 4 
Sample Size Assumptions and Power Calculations 
Endpoint 
Average of 
Week 4 and 6 
for 8 U/kg group
Average of 
Week 4 and 6 
for Placebo group
Standard 
Deviation 
Power
MAS-B Change from Baseline 
-0.8
-0.45
0.75 
94%
CGI by Physician (Co-primary for US 
FDA Analysis) 
1.2 
0.6 
1.2 
97% 
Overall Endpoints 
91%
CGI = Clinical Global Impression of Overall Change; MAS-B = Modified Ashworth Scale – Bohannon; US FDA = United 
States Food and Drug Administration 
7.6 
Interim Analyses 
There is no planned interim analysis.  
7.7 
Additional Analysis/Inference for US FDA 
Analyses are as described in all preceding sections except for the items described below. 
7.7.1 
Primary Efficacy Analyses 
There are 2 co-primary endpoints:  the average grade change from baseline in the MAS-B 
ankle score at weeks 4 and 6 and the CGI by Physician at weeks 4 and 6.  For both the co-
primary endpoints, the statistical null hypothesis is that both the higher dose (8 U/kg) and the 
lower dose (4 U/kg) have the same mean as placebo.  The alternative hypothesis is that at 
least one study dose has a different mean than placebo. 
In addition to the primary statistical analyses cited in Section 7.3.1 for the average of the 
observed grade change from baseline in MAS-B, the average observed CGI by Physician at 
weeks 4 and 6 will also be analyzed using the same statistical method (with the same 
MMRM model). 


 
 
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The Hochberg procedure (Hochberg and Tamhane, 1987) will be used to control the family-
wise type I error rate.  With 2 doses and 2 co-primary endpoints in each dose, the maximum p 
value for the 2 co-primary endpoints in each dose will be used in the Hochberg procedure.  
We first define the following values: 
• 
p11:  p value for Botox 8 U/kg vs placebo comparing MAS-B  
• 
p12:  p value for Botox 4 U/kg vs placebo comparing MAS-B  
• 
p21:  p value for Botox 8 U/kg vs placebo comparing CGI  
• 
p22:  p value for Botox 4 U/kg vs placebo comparing CGI  
• 
p1 = max(p11, p21), p2 = max(p12, p22).  
p1 and p2 will be sorted in an increasing order to get p(1) ≤ p(2).  The following decision 
rule will then be applied: 
Step 1:  If p(2) ≤ 0.05, both doses are considered efficacious; otherwise go to step 2. 
Step 2:  If p(1) ≤ 0.025, its corresponding dose is considered efficacious; otherwise go to
 
step 3. 
Step 3:  Neither dose is considered efficacious. 
For sensitivity analysis purposes to supplement the co-primary analyses, ANCOVA using MI 
for missing values will be conducted for the co-primary endpoints of MAS-B and CGI. The 
model will include baseline MAS-B as a covariate and factors of age group, treatment group, 
study center, and previous botulinum toxin exposure.  A summary of the percentages of 
missing MAS-B and CGI scores by visit will also be provided.  Additional sensitivity 
analyses for the MAS-B changes from baseline and CGI scores at each assessment time point 
will also be performed using ANCOVA with observed data, and linear contrasts will be used 
to estimate the treatment differences between each study dose and placebo.  The secondary 
efficacy analyses will be the same as the statistical analyses cited in Section 7.3.2 except for 
the analyses for CGI by Physician which is described above. 
8. 
Study Visit Schedule and Procedures 
Please see Table 1 for a schematic of the schedule of visits and procedures.  


 
 
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8.1 
Patient Entry Procedures  
8.1.1 
Overview of Entry Procedures 
Prospective patients as defined by the criteria in Sections 4.3 and 4.4 (inclusion/exclusion 
criteria) will be considered for entry into this study. 
8.1.2 
Informed Consent and Patient Privacy 
The study will be discussed with the patient/legally authorized representative and a patient/ 
wishing to participate or his/her legally authorized representative must give informed consent 
and, when applicable, minor assent prior to any study-related procedures or change in 
treatment.  The patient/legally authorized representative must also give authorization (US 
only), data protection consent (Europe only), and other written documentation in accordance 
with the relevant country and local privacy requirements (where applicable) prior to any 
study-related procedures or change in treatment.   
Further information is provided in Section 10.1. 
Each patient who provides informed consent and/or assent will be assigned a patient number 
that will be used on patient documentation throughout the study.   
8.2 
Procedures for Final Study Entry 
At visit 3 (randomization) patients must meet all of the inclusion criteria and must not meet 
any of the exclusion criteria.  Also, all females of childbearing potential must have a negative 
urine pregnancy test. 
The patient is considered to have entered this study at the time of randomization to treatment 
on day 1.  See Section 5.5 for the method for assignment to treatment groups/randomization. 
8.3 
Visits and Associated Procedures  
Ideally, the CGI by Physician should be performed prior to administering the MAS-B and 
MTS to reduce the likelihood of the CGI being influenced by the spasticity evaluations.  An 
alternative is to have different evaluators rate the CGI and perform the spasticity assessments 
(MAS-B and MTS).  Whenever possible each procedure should be performed by the same 
evaluator for an individual patient throughout the trial.  Study personnel should avoid 


 
 
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reviewing or discussing the MAS-B, MTS, or CGI scores from previous visits when they are 
completing these assessments. 
 
In addition to the procedures outlined below, patients are to complete approximately 1-hour 
weekly standardized PT sessions (see Section 4.5.3) from week -2 through week 11. 
8.3.1 
Visit 1:  2 to 4 Weeks Before Day 1 (Screening) 
• Obtain written informed consent and minor assent and data protection from the 
patient and/or legally authorized representative prior to performing any study-related 
procedures.  
• Obtain patient identification number from the IVRS/IWRS. 
• Obtain demographic information, including date of birth.  Ensure that the patient will 
be ≥ 2 years and ≤ 16 years and 11 months (prior to 17th birthday) on projected day 1, 
randomization visit. 
• Obtain medical and surgical history, ensuring that the patient is monoplegic or 
hemiplegic with dynamic muscle contracture of the ankle plantar flexors.  Include 
details on histories of dysphagia, drooling, aspiration pneumonia, seizure, and 
epilepsy.   
• Obtain past (in the last 3 months) and current concomitant medication use (including 
prescription, non-prescription, and herbal medications) and procedures.  Previous use 
of botulinum toxin, phenol, and alcohol injections should be included. 
• Perform C-SSRS (for patients ≥ 6 years of age on day 1). 
• Perform physical examination, including measurement of height and weight. 
• Obtain vital signs (blood pressure, pulse rate, respiratory rate, and body temperature). 
• Perform ECG. 
• Collect blood sample for hematology, serum chemistry, and HbA1c analysis after 
informed consent is signed.  Fasting blood samples should be collected unless the 
patient is not able to fast for approximately 8 hours.  Patients who are willing to fast 


 
 
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and did not come to the visit in a fasting state may return prior to the day 1 visit for 
blood sample collection as long as the laboratory results can be received and 
reviewed at or before the day 1 visit. 
• For patients who weigh at least 15 kg, collect blood sample for immunogenicity 
testing. 
• Perform urine pregnancy test for all females of childbearing potential. 
• Discuss choice of contraceptive method with female patients of childbearing potential 
and/or their caregivers and document method of contraception in the source 
documentation and the eCRF.  Counsel such female patients/caregivers regarding the 
importance of maintaining their agreed upon method of contraception throughout the 
study. 
• Ascertain spasticity only in the study lower limb using the HAT.  
• Assess dystonia only in the study lower limb using the BAD scale. 
• Assess gross motor function using the GMFCS-E&R. 
• Assess spasticity in the ankle (with knee extended and knee flexed) and the knee of 
the study limb using the MAS-B. 
• Perform MTS in the ankle of the study limb with knee extended and knee flexed.  
Note that the angle of slow stretch (R2) of MTS in the ankle with knee extended may 
be used to ensure the patient meets the inclusion criterion for acceptable minimal 
range of dorsiflexion. 
• Evaluate inclusion and exclusion criteria. 
o For patients who are not eligible for the study (screen failures), depending on 
the reason(s) for screen failure, collect detailed information regarding 
spasticity, contracture, respiratory condition or functions associated with 
increased risk of aspiration, seizure, and epilepsy. 
• Query patient for any adverse event that has occurred and any related medication 
used or procedure performed since signing the informed consent.   


 
 
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• Instruct patient/caregiver to initiate approximately 1-hour weekly standardized PT 
session with the therapist at week -2 and schedule through the last session at week 11. 
• Schedule the next visit, if applicable. 
8.3.2 
Visit 2:  Week -2 (PT Start) – Visit with the Physical Therapist 
• Establish with each patient/caregiver 2 goals for the GAS (1 functional active and 
1 functional passive) and define each level of patient-specific goal achievement for 
each of the 2 goals using the GAS by Physician. 
• With the patient/caregiver, review protocol-specified standardized weekly PT and 
develop a patient-tailored PT plan. 
• If patient reports adverse events to the therapist, the therapist should inform the Study 
Coordinator for further follow-up regarding adverse events and related medication 
used or procedures performed.  
• Schedule the next weekly PT session. 
8.3.3 
Visit 3:  Day 1 (Randomization/Treatment) 
• The following procedures must be performed prior to the study treatment: 
o 
 
o Note any update to medical and surgical history, if needed.  Query 
patient/caregiver for any adverse events prior to study treatment. 
o Perform C-SSRS (for patients ≥ 6 years of age at day 1). 
o For patients who are not eligible for the study (screen failures), depending on 
the reason(s) for screen failure, collect detailed information regarding 
spasticity, contracture, respiratory condition or functions associated with 
increased risk of aspiration, seizure, and epilepsy. 
o Obtain any update to concomitant medication use. 
o Obtain any information on new medical procedures or tests since the last visit. 


 
 
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o Obtain vital signs (blood pressure, pulse rate, respiratory rate, and body 
temperature). 
o Obtain weight in kilograms. 
o Review the results of the screening safety laboratory tests. 
o Perform urine pregnancy test for all females of childbearing potential. 
o Assess spasticity in the ankle (with knee extended and knee flexed) and the 
knee of the study limb using the MAS-B. 
o Perform MTS for the ankle of the study limb with knee extended and knee 
flexed.  Note that the angle of slow stretch (R2) of MTS in the ankle with 
knee extended may be used to ensure the patient meets the inclusion criterion 
for acceptable minimal range of dorsiflexion. 
o Confirm the 2 goals selected and the definitions of patient-specific goal 
achievement using the GAS by Physician. 
o 
 
 
 
o If applicable, counsel female patients and/or caregivers of childbearing 
potential regarding the importance of maintaining their agreed upon method of 
contraception throughout the study. 
o Confirm patient continues to meet study inclusion and exclusion criteria.  
o Calculate the dose for study treatment using the dose calculation worksheet 
and dose verification eCRF.   
o Access the IVRS/IWRS to randomize the patient and obtain a study 
medication kit number. 
• Inform IDR that patient is qualified for the study treatment and send blinded dosing 
summary to the IDR for study drug preparation. 
• Inject assigned study treatment as per protocol (see Section 5.9). 


 
 
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• Query patient/caregiver for any adverse events and related medication used or 
procedure performed.  
• Remind patient/caregiver of the importance of the weekly PT session.  
• Schedule the next visit. 
8.3.4 
Visits 4, 5, 6, and 7:  Weeks 2, 4, 6, and 8 (Follow-up Visits) 
• 
 
 
 
 
 
  
• Query patient/caregiver for any adverse events.  
• Perform C-SSRS (for patients ≥ 6 years of age at day 1). 
• Obtain any update to concomitant medication use. 
• Obtain any information on new medical procedures or tests since the last visit. 
• Rate the CGI by Physician before performing the spasticity assessments (MAS-B and 
MTS).   
• Assess spasticity in the ankle (with knee extended and knee flexed) of the study limb 
using the MAS-B. 
• Perform MTS for the ankle of the study limb with knee extended and knee flexed. 
• Only at visit 7/week 8, evaluate the patient’s performance for each of the 2 goals 
using the GAS by Physician. 
• 
 
 
• Remind patient/caregiver of the importance of the weekly PT session.  


 
 
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• Schedule the next visit. 
8.3.5 
Visit 8:  Week 12 or Early Termination (Exit Visit) 
• 
 
  
 
 
• Query patient/caregiver for any adverse events.  
• Perform C-SSRS (for patients ≥ 6 years of age at day 1). 
• Obtain any update to concomitant medication use. 
• Obtain any information on new medical procedures or tests since the last visit. 
• Perform physical examination, including measurement of weight. 
• Obtain vital signs (blood pressure, pulse rate, respiratory rate, and body temperature). 
• Collect blood sample for hematology, serum chemistry, and hemoglobin A1c analysis 
for all patients.  Fasting blood samples should be collected unless the patient is not 
able to fast for approximately 8 hours. 
• For patients who weighed at least 15 kg at the screening visit, collect blood sample 
for immunogenicity testing. 
• Perform urine pregnancy test for all females of childbearing potential. 
• Rate the CGI by Physician before performing the spasticity assessments (MAS-B and 
MTS).   
• Assess spasticity in the ankle (with knee extended and knee flexed) of the study limb 
using the MAS-B. 
• Perform MTS for the ankle of the study limb with knee extended and knee flexed. 
• Evaluate the patient’s performance for each of the 2 goals using the GAS by 
Physician.  


 
 
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• 
 
 
• Any adverse event that is marked “ongoing” at the exit visit must be followed-up as 
appropriate. 
• Enter patient exit status in the IVRS/IWRS. 
• If the patient/legally authorized representative agrees to participate the follow on 
Study 191622-112 have the patient/legally authorized representative sign the 
consent/assent/privacy form and proceed with the day 1 visit for that study. 
8.4 
Instructions for the Patients 
Patients/caregivers will be instructed to strictly follow the study visit schedule and report any 
changes in condition to the investigative site.   
Patients/caregivers will be instructed to complete the approximately 1-hour weekly 
standardized PT sessions (see Section 4.5.3) from week -2 through week 11. 
8.5 
Unscheduled Visits 
Unscheduled visits can be performed if safety concerns arise and at the discretion of the 
investigator.  Additional examinations may be performed as necessary to ensure the safety 
and well being of patients during the study.  eCRFs will be completed for each unscheduled 
visit.   
8.6 
Compliance With Protocol 
At each post-baseline visit, patients/caregivers will be questioned on concomitant medication 
use and procedures or tests since the last visit to ensure protocol compliance.   
8.7 
Early Discontinuation of Patients 
Patients may voluntarily withdraw from the study at any time or may be withdrawn at the 
discretion of the investigator and Allergan due to clinically significant findings including, but 
not limited to, adverse events and clinical laboratory abnormalities.  Allergan will be notified 
of early patient discontinuation from the study and the reason for discontinuation will be 
clearly documented on the appropriate eCRF. 


 
 
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The last visit for the patient will be considered the study exit visit.  Procedures for week 12 
will be performed if the study exit visit occurs earlier than week 12.   
8.8 
Withdrawal Criteria  
Patients have the right to withdraw from the study at any time and for any reason without 
prejudice to his or her future medical care by the physician or the institution.  The 
investigator and Allergan also have the right to withdraw a patient from the study at any time 
for any reason. Patients who withdraw from the study will not be replaced.  
8.9 
Study Termination 
The study may be stopped at his/her study site at any time by the site investigator.  Allergan 
may stop the study (and/or the study site) for any reason with appropriate notification.  
9. 
Adverse Events  
Adverse events occurring during the study will be recorded on an adverse event eCRF.  If 
adverse events occur, the first concern will be the safety of the study participants.  
9.1 
Definitions 
9.1.1 
Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.  In addition, during the screening period, adverse events 
will be assessed regardless of the administration of a pharmaceutical product.   
Adverse events will be assessed and documented, as appropriate, throughout the study (ie, 
after informed consent has been obtained).  At each visit, the investigator will begin by 
querying for adverse events by asking each patient/caregiver a general, non-directed question 
such as “How have you been feeling since the last visit?”  Directed questioning and 
examination will then be done as appropriate.  All reported adverse events will be 
documented on the appropriate eCRF.   


 
 
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9.1.2 
Serious Adverse Event 
A serious adverse event is any adverse event occurring at any dose that results in any of the 
following outcomes:  death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a 
congenital anomaly/birth defect.  Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  (See Section 9.3 for procedures for reporting a serious adverse event.) 
Note:  Allergan considers all cancer adverse events as serious adverse events.  In addition, 
Allergan considers any abortion (spontaneous or nonspontaneous) as a serious adverse event. 
9.1.3 
Severity 
A clinical determination will be made of the intensity of an adverse event.  The severity 
assessment for a clinical adverse event must be completed using the following definitions as 
guidelines: 
Mild 
Awareness of sign or symptom, but easily tolerated 
Moderate 
Discomfort enough to cause interference with usual activity 
Severe 
Incapacitating with inability to work or do usual activity 
Not applicable 
In some cases, an adverse event may be an ‘all or nothing’ finding 
which cannot be graded 
 
9.1.4 
Relationship to Study Drug or Study Procedure 
A determination will be made of the relationship (if any) between an adverse event and the 
study drug or study procedure, as applicable.  A causal relationship is present if a 
determination is made that there is a reasonable possibility that the adverse event may have 
been caused by the drug or study procedure.   
9.2 
Procedures for Reporting Adverse Events 
Any adverse event must be recorded on the appropriate eCRF. 


 
 
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All adverse events that are drug-related and unexpected (not listed as treatment-related in the 
current Investigator’s Brochure) must be reported to the governing IRB/IEC as required by 
the IRB/IEC, local regulations, and the governing health authorities.  Any adverse event that 
is marked “ongoing” at the exit visit must be followed-up as appropriate. 
9.3 
Procedures for Reporting a Serious Adverse Event 
Any serious adverse event occurring during the study period (beginning with informed 
consent) and for at least 28 days after the last dose of study drug must be immediately 
reported no later than 24 hours after learning of a serious adverse event.  Serious adverse 
events must be reported to Allergan or its designee as listed on the Allergan Study Contacts 
Page and recorded on the serious adverse event form.  All patients with a serious adverse 
event must be followed and the outcomes reported.  The investigator must supply Allergan 
and the IRB/IEC with any additional requested information (eg, autopsy reports and terminal 
medical reports).  
In the event of a serious adverse event, the investigator must: 
1. Notify Allergan immediately by fax or email using the serious adverse event form 
(contact details can be found on page 1 of the serious adverse event form); phone 
numbers and relevant Allergan personnel contacts are also on the front page of 
protocol. 
2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of 
the patient. 
3. Provide Allergan with a complete, written case history (adverse event report form) 
which includes a statement as to whether the event was or was not related to the use 
of the investigational drug. 
4. Promptly inform the governing IRB/IEC of the serious adverse event as required by 
the IRB/IEC, local regulations, and the governing health authorities. 
9.4 
Procedures for Unmasking of Study Medication 
When necessary for the safety and proper treatment of the patient, the investigator can 
unmask the patient’s treatment assignment to determine which treatment has been assigned 
and institute appropriate follow-up care.  When possible, the sponsor (Allergan Medical 


 
 
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Safety Physician) should be notified prior to unmasking study medication.  The investigator 
must inform the sponsor (Allergan Medical Safety Physician) of the unmasking if there is no 
notification prior to the unmasking.   
The treatment assignment for the patient can be determined by designated site personnel 
calling into the IVRS/IWRS system via password protected access.  The reason for breaking 
the code must be recorded in the patient’s source documents. 
10. 
Administrative Items 
This protocol is to be conducted in accordance with the applicable Good Clinical Practice 
(GCP) regulations and guidelines, eg, the International Conference on Harmonisation (ICH) 
Guideline on GCP. 
10.1 
Protection of Human Subjects 
10.1.1 
Compliance with Informed Consent Regulations (US 21 CFR 
Part 50) and Relevant Country Regulations 
Written informed consent is to be obtained from each patient prior to enrollment into the 
study, and/or from the patient’s legally authorized representative.  If the patient is under the 
legal age of consent, the consent form must be signed by the legally authorized representative 
in accordance with the relevant country and local regulatory requirements. 
Written parental/legally authorized representative informed consent in addition to a separate 
written minor consent and/or assent (in accordance with any applicable state and local 
laws/regulations) are required for each minor study patient prior to study enrollment or any 
study-related procedures in the study. 
10.1.2 
Compliance With IRB or IEC Regulations 
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) 
or applicable IEC regulations.  The investigator must obtain approval from a properly 
constituted IRB/IEC prior to initiating the study and re-approval or review at least annually.  
Allergan is to be notified immediately if the responsible IRB/IEC has been disqualified or if 
proceedings leading to disqualification have begun.  Copies of all IRB/IEC correspondence 
with the investigator should be provided to Allergan. 


 
 
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10.1.3 
Compliance With Good Clinical Practice 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines.  
10.1.4 
Compliance With Electronic Records; Electronic Signatures 
Regulations (21 CFR Part 11) 
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature. 
10.2 
Changes to the Protocol 
The investigator must not implement any deviation from or changes of the protocol without 
approval by Allergan and prior review and documented approval/favorable opinion from the 
IRB/IEC of a protocol amendment, except where necessary to eliminate immediate hazards 
to study patients, or when the changes involve only logistical or administrative aspects of the 
study (eg, change in monitors, change of telephone numbers). 
10.3 
Patient Confidentiality 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
patient’s name will not be disclosed in these documents.  The patient’s name may be 
disclosed to the Sponsor of the study, Allergan, or the governing health authorities or the 
FDA if they inspect the study records.  Appropriate precautions will be taken to maintain 
confidentiality of medical records and personal information. 
10.3.1 
Patient Privacy 
Written authorization (US sites only), data protection consent (European sites only), and 
other documentation in accordance with the relevant country and local privacy requirements 
(where applicable) is to be obtained from each patient prior to enrollment into the study, 
and/or from the patient’s legally authorized representative in accordance with the applicable 
privacy requirements (eg, the Health Insurance Portability and Accountability Act Standards 
for Privacy of Individually Identifiable Health Information (“HIPAA”), European Union Data 
Protection Directive 95/46/EC [“EU Directive”]). 


 
 
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In accordance with HIPAA requirements, additional purposes of this study include the 
following: 
• to publish anonymous patient data from the study, and 
• to create and maintain a data repository 
10.4 
Documentation 
10.4.1 
Source Documents 
Source documents may include a patient’s medical records, hospital charts, clinic charts, the 
investigator’s patient study files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and electrocardiograms.  The investigator’s copy of the case report forms 
serves as part of the investigator’s record of a patient’s study-related data.   
The following information should be entered into the patient’s medical record: 
• Patient’s name 
• Patient’s contact information 
• The date that the patient entered the study, patient number, and medication kit number 
• The study title and/or the protocol number of the study and the name of Allergan 
• A statement that informed consent and/or assent, if applicable was obtained 
(including the date).  A statement that written authorization (US sites only), data 
protection consent (EU sites only), or other country and local patient privacy required 
documentation for this study has been obtained (including the date). 
• A statement that patient meets all the inclusion criteria and does not meet any of the 
exclusion criteria.  If a patient does not qualify for the study, a screen failure reason 
must be noted. 
• Dates of all patient visits 
• Medical and surgical history  
• Documentation of results of all procedures conducted during the course of the trial, 
including the dose determination process.  
 
  


 
 
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• 
 
• The results of laboratory tests performed by the site (eg, results of hematology, serum 
chemistry, HbA1c, urine pregnancy, and immunogenicity tests).   
• All concurrent medications (list all prescription, non-prescription and herbal 
medications being taken 3 months prior to or at the time of enrollment).  At each 
subsequent visit, changes to the list of medications and concurrent procedures should 
be recorded. 
• Occurrence and status of any adverse events 
• The date the patient exited the study, and a notation as to whether the patient 
completed the study or reason for discontinuation 
10.4.2 
Case Report Form Completion 
The investigator is responsible for ensuring that data are properly recorded in each patient’s 
eCRF and related documents.  An investigator who has signed the protocol signature page 
should personally sign for the eCRFs (as indicated in the eCRFs) to ensure that the 
observations and findings are recorded in the eCRFs correctly and completely.  The eCRFs 
are to be completed in a timely manner. 
10.4.3 
Study Summary 
An investigator’s summary will be provided to Allergan within a short time after the 
completion of the study, or as designated by Allergan.  A summary is also to be provided to 
the responsible IRB/IEC. 
10.4.4 
Retention of Documentation 
All study-related correspondence, patient records, consent forms, patient privacy 
documentation, records of the distribution and use of all investigational products, and 
electronic copies of eCRFs must be maintained on file. 
For countries falling within the scope of the ICH guidelines, the Allergan-specific essential 
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 contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents 


 
 
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should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or if needed by Allergan. 
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation. 
Allergan requires that it be notified in writing if the investigator wishes to relinquish 
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of 
ownership to a suitably qualified, responsible person. 
10.5 
Labeling, Packaging, and Return or Disposal of Study 
Medications/Treatments 
10.5.1 
Labeling/Packaging 
The investigational materials will be packaged and labeled in identically appearing vials.  
The study treatment will be identified as an investigational compound.  The study number 
and kit number will be identified on the unit label. 
10.5.2 
Clinical Supply Inventory 
The investigator must keep an accurate accounting of the number of investigational units 
received from Allergan, dispensed to the patients, and the number of units returned to 
Allergan or Allergan designee during and at the completion of the study.  A detailed 
inventory must be completed for the study medication.  The study medication must be 
reconstituted and administered only by appropriately qualified persons to patients in the study.  
The medication is to be used in accordance with the protocol under the direct supervision of 
an investigator. 
10.5.3 
Return or Disposal of Study Medications/Treatments and/or 
Supplies 
All clinical study medications/treatments and/or supplies will be returned to Allergan or 
Allergan designee for destruction. 


 
 
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10.6 
Monitoring by the Sponsor 
A representative of Allergan will monitor the study on a periodic basis.  The determination of 
the extent and nature of monitoring will be based on considerations such as the objective, 
purpose, design, complexity, blinding, size, and endpoints of the study.   
Authorized representatives of Allergan or regulatory authority representatives will conduct 
on-site visits to review, audit and copy study-related documents.  These representatives will 
meet with the investigator(s) and appropriate staff at mutually convenient times to discuss 
study-related data and questions. 
10.7 
Handling of Biological Specimens 
Laboratory specimens for blood chemistry panel, hematology, and HbA1c will be sent to a 
centralized clinical laboratory with certification from a recognized accreditation agency (eg, 
College of American Pathology [CAP] or Clinical Laboratory Improvement Amendments 
[CLIA] certification) to be assayed using validated methods.  Samples for immunogenicity 
will be sent to the central laboratory for temporary storage and will then be sent to a specialty 
laboratory for analysis.  Allergan shall have full ownership rights to any biological 
specimens/samples derived from the study.   
Approximately 14 mL of blood is estimated to be collected at a given visit for children 15 kg 
and above (7 mL for hematology and chemistry and 7 mL for immunogenicity testing).  
Approximately 7 mL of blood will be collected at a given visit for children under 15 kg in 
weight.  Please refer to the Laboratory Manual for details regarding specimen sample 
collection, processing, storage, and shipping procedures.   
10.8 
Publications 
Allergan as the sponsor, has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and 
Allergan personnel.  Authorship will be established prior to the writing of the manuscript.  As 
this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Allergan.   
10.9 
Coordinating Investigator 
A signatory Coordinating Investigator will be designated prior to the writing of the Clinical 
Study Report. 


 
 
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11. 
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Barry MJ, Van Swearingen JM, Albright AL.  Reliability and responsiveness of the Barry-
Albright Dystonia scale.  Dev Med Child Neurol. 1999;41:404-411. 
Beckung E, Hagberg G.  Neuroimpairment, activity limitations, and participation restrictions 
in children with cerebral palsy.  Dev Med Child Neurol. 2002;44:309-316. 
Bohannon RW, Smith MB.  Interrater reliability of a modified Ashworth scale of muscle 
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Butler C, Darrah J.  Effects of neurodevelopmental treatment (NDT) for cerebral palsy:  an 
AADPDM evidence report.  Dev Med Child Neurol. 2001;43:778-790. 
Chambers HG.  The surgical treatment of spasticity.  Muscle Nerve Suppl. 1997;6:S121-128. 
Cobeljic G, Bumbasirevic M, Lesic A, Bajin Z.  The management of spastic equinus in 
cerebral palsy. Orthop Trauma. 2009;23:201-209. 
Delgado MR, Hirtz D, Aisen M, Ashwal S, Fehlings DL, McLaughlin J, et al.  Practice 
parameter:  pharmacologic treatment of spasticity in children and adolescents with cerebral 
palsy (an evidence-based review).  Neurology. 2010;74:336-343. 
Detrembleur C, Lejeune TM, Renders A, Van Den Bergh PY.  Botulinum toxin and short-
term electrical stimulation in the treatment of equinus in cerebral palsy.  Mov Disord. 
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Dmitrienko A, Molenberghs G, Chuang-Stein C, Offen W.  Analysis of clinical trials using 
SAS: a practical guide. Cary N.C.: SAS Institute Inc.; 2005:104-120. 
Dumas HM, O’Neil ME, Fragala MA.  Expert consensus on physical therapist intervention 
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Dunne JW, Heye N, Dunne SL.  Treatment of chronic limb spasticity with botulinum toxin A.  
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Gracies JM, Elovic E, McGuire J, Simpson D.  Traditional pharmacological treatments for 
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The updated European Consensus 2009 on the use of botulinum toxin for children with 
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Heinen F, Schroeder AS, Fietzek U, Berweck S.  When it comes to botulinum toxin, children 
and adults are not the same: multimuscle option for children with cerebral palsy.  Mov Disord. 
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Hintze J.  PASS (Power Analysis and Sample Size) 2008.  Kaysville, Utah: NCSS, LLC; 
2008.  Available at: www.ncss.com. 
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Jethwa A, Jonathan M, Macarthur C, Knights S, Fehlings T, Fehlings D.  Development of the 
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Koman IA, Smith BP, Shilt JS.  Cerebral palsy.  Lancet. 2004;363:1619-1631.   
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Lannin N, Scheinberg A, Clark K.  AACPDM systematic review of the effectiveness of 
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Love SC, Novak I, Kentish M, Desloovere K, Heinen F, Molenaers G, et al.  Botulinum toxin 
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toxin type A on the functional ability of the child with spastic hemiplegia: a randomized 
controlled trial.  Eur J Neurol. 2001;8(Suppl 5):50-58. 


 
 
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Molenaers G, Desloovere K, Fabry G, de Cock P.  The effects of quantitative gait assessment 
and botulinum toxin A on musculoskeletal surgery in children with cerebral palsy.  J Bone 
Joint Surg. 2006;88:161-170. 
Molenaers G, Schörkhuber V, Fagard K, Van Campenhout A, De Cat J, Pauwels P, et al.  
Long-term use of botulinum toxin type A in children with cerebral palsy: treatment 
consistency.  Eur J Paediatr Neurol. 2009;13:421-429. 
Odding E, Roebroeck ME, Stam HJ.  The epidemiology of cerebral palsy: incidence, 
impairments and risk factors.  Disabil Rehabil. 2006;28:183-191. 
O’Flaherty S, Waugh MC.  Pharmacologic management of the spastic and dystonic upper 
limb in children with cerebral palsy.  Hand Clin. 2003;19:585-589. 
Palisano R, Rosenbaum P, Bartlett D, Livingston M.  GMFCS – E&R: Gross motor function 
classification system expanded and revised.  2007. Available from: 
http://motorgrowth.canchild.ca/en/GMFCS/resources/GMFCS-ER.pdf. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al.  The 
Columbia- Suicide Severity Rating Scale (C-SSRS):  Initial validity and internal consistency 
findings from three multi-site studies with adolescents and adults.  Am J Psychiatry.  
2011;168:1266-1277. 
Read HS, Hazlewood ME, Hillman SJ, Prescott RJ, Robb JE.  Edinburgh Visual Gait Score 
for use in cerebral palsy.  J Pediatr Orthopaed.  2003;23:296-301. 
Rodda J, Graham HK.  Classification of gait patterns in spastic hemiplegia and spastic 
diplegia: a basis for a management algorithm.  Eur J Neurol. 2001;8 (Suppl 5):98-108. 
Russman BS, Tilton AH, Gormley Jr ME.  Cerebral palsy:  a rational approach to a treatment 
protocol and the role of botulinum toxin in treatment.  In:  Brashear A, Mayer NH, eds.  
Spasticity and other forms of muscle overactivity in the upper motor neuron syndrome.  
Etiology, evaluation, management and the role of botulinum toxin.  New York, New York:  
WeMove; 2008:  Chapter 12. 
Scheinberg A, Hall K, Lam LT, O’Flaherty S.  Oral baclofen in children with cerebral palsy:  
A double-blind cross-over pilot study.  J Paediatr Child Health. 2006;42:715-720. 


 
 
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Stanley F, Blair E, Alberman E.  Cerebral Palsy: epidemiology and causal pathways.  Clinics 
in Developmental Medicine, No 151. London, England: Mac Keith Press; 2000:4-21. 
Steinbok P.  Selection of treatment modalities in children with spastic cerebral palsy.  
Neurosurg Focus. 2006;21:1-8. 
Van Campenhout A, Molenaers G.  Localization of the motor endplate zone in human skeletal 
muscles of the lower limb: anatomical guidelines for injection with botulinum toxin.  Dev 
Med Child Neurol. 2011;53:108-119. 
von Baeyer CL, Spagrud LJ.  Systematic review of observational (behavioral) measures of 
pain for children and adolescents aged 3 to 18 years.  Pain. 2007;127:140-150.  
Wallen M, Waugh M-C, O’Flaherty S.  Functional outcomes of intramuscular botulinum 
toxin type A and occupational therapy in the upper limbs of children with cerebral palsy:  
a randomized controlled trial.  Arch Phys Med Rehab. 2007;88:1-10. 
 
 


 
 
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12. 
Attachments 
12.1 
Examination Procedures, Tests, Equipment, and Techniques  
Further details are provided in the Study Procedure Manual. 
12.1.1 
Physical Examination 
The investigator physician will examine the patient for any detectable abnormalities of the 
following body systems:  general appearance, head/eyes/ears/nose/throat, lungs, 
heart/cardiovascular, abdomen, neurologic, extremities, back (including spinal deformity), 
musculoskeletal, lymphatic, skin, and other.  Weight in kilograms and height (height 
measured at screening visit only) should be measured consistently throughout the study using 
a ruler and calibrated scale; patients should wear similar clothing and remove items such as 
splints, orthotics, braces, shoes, heavy clothes, and wet diapers for each weight measurement. 
12.1.2 
Vital Signs 
Systolic and diastolic blood pressure, pulse rate, and respiratory rate will be taken after 
patients have been at rest (seated) for at least 2 minutes.  Blood pressure will be recorded in 
mm Hg.  Pulse rate and respiratory rate will be measured in beats or breaths per minutes, 
respectively, by counting over 30 seconds and multiplying by 2. 
Oral, axillary, temporal, rectal, or tympanic body temperature may be taken.  The same route 
should be used throughout the study.  If oral temperature is taken, the patient should not have 
any oral intake for at least 5 minutes prior to the measurement. 
12.1.3 
Electrocardiogram 
A standard 12-lead ECG will be performed at screening to ensure that a patient does not have 
a clinically significant condition that may indicate an unacceptable safety risk for study 
participation. 
12.1.4 
Hematology and Serum Chemistry 
During screening, patients will need to have a blood sample for laboratory evaluations 
collected after informed consent is signed.  Another blood sample will be collected at the 
study exit visit.  Blood specimens will be collected using standard laboratory instructions and 
procedures provided by the central laboratory.  Fasting blood samples should be collected 


 
 
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unless the patient is not able to fast for approximately 8 hours.  Patients who are willing to 
fast and did not come to the screening visit in a fasting state may return prior to the day 1 
visit for blood sample collection as long as the laboratory results can be received and 
reviewed at or before the day 1 visit.  The blood specimens will be analyzed for the 
following: 
 
Hematology 
hemoglobin 
hematocrit 
red blood cells 
 
white blood cells 
neutrophils 
bands 
 
lymphocytes 
monocytes 
basophils 
 
eosinophils 
platelets 
 
 
Electrolytes 
sodium 
potassium 
bicarbonate 
 
chloride 
phosphorus 
calcium 
 
Chemistry 
glucose 
creatinine 
urea nitrogen 
 
total bilirubin 
alkaline phosphatase 
(total plus bone and 
liver fractions) 
aspartate 
aminotransferase 
(serum glutamic 
oxaloacetic 
transaminase) 
 
alanine 
aminotransferase 
(serum glutamic 
pyruvic 
transaminase) 
albumin 
 
 
Other 
HbA1c 
25 hydroxyl 
vitamin D 
Parathyroid hormone 
if alkaline 
phosphatase bone 
fraction is abnormal 
 
 
Reference ranges for alkaline phosphatase and glucose are shown in Table 5. 


 
 
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Table 5 
Reference Ranges for Alkaline Phosphatase and Glucose 
Parameter 
Age (Years) 
Range 
Alkaline phosphatase 
 
 
 Female 
1 to 3 
125 to 320 U/L 
 
4 to 6 
150 to 370 U/L 
 
7 to 9 
150 to 440 U/L 
 
10 to 11 
150 to 530 U/L 
 
12 to 13 
110 to 525 U/L 
 
14 to 15 
55 to 305 U/L 
 
16 to 19 
40 to 120 U/L 
 Male 
1 to 3 
125 to 320 U/L 
 
4 to 6 
150 to 370 U/L 
 
7 to 9 
150 to 440 U/L 
 
10 to 11 
150 to 470 U/L 
 
12 to 13 
160 to 500 U/L 
 
14 to 15 
130 to 530 U/L 
 
16 to 19 
60 to 270 U/L 
Bone-specific alkaline 
phosphatase (ostase) 
 
 
 Female 
1 to 6 
0 to 189 U/L 
 
7 to 9 
0 to 246 U/L 
 
10 to 13 
0 to 340 U/L 
 
14 to 15 
0 to 91 U/L 
 
≥ 16 
0 to 55 U/L 
 Male 
1 to 6 
0 to 208 U/L 
 
7 to 9 
0 to 264 U/L 
 
10 to 15 
0 to 340 U/L 
 
16 to 19 
0 to 165 U/L 
Glucose 
All ages 
70 to 100 mg/dL, 
3.9 to 5.6 mmol/L 
Note:  Reference ranges were received from Covance Laboratory as of 16 January 2012. 
 


 
 
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12.1.5 
Immunogenicity Testing 
Blood samples (approximately 7 mL per visit) for immunogenicity testing will be collected at 
the screening visit and study exit from patients who weigh at least 15 kg at the screening visit.  
A 2-stage assay approach will be used for the detection of binding antibodies against 
BoNT-A and neutralizing antibodies against BOTOX in patients’ serum. In stage 1, serum 
samples will be screened for reactivity using a validated enzyme-linked immunosorbent 
assay (ELISA).  The reactive serum samples will be subsequently titered to assess the extent 
of antibodies present and immunodepleted to confirm that the reactivities are specific to 
BoNT-A.  In stage 2, only samples that are confirmed positive in the ELISA will be tested for 
neutralizing antibodies to BOTOX using a validated assay.   
Additional information on handling samples for immunogenicity testing is provided in the 
Laboratory Manual. 
12.1.6 
Pregnancy Test 
Females of childbearing potential will have urine pregnancy tests performed at screening, 
day 1 (randomization) prior to injection, and the exit visit.  Pregnancy test kits will be 
provided by Allergan or an Allergan contracted central laboratory and will be administered 
according to the instructions provided with the tests.  A female of childbearing potential is 
defined as a female who is post menarche. 
12.1.7 
Barry-Albright Dystonia (BAD) Scale 
The BAD scale (Barry et al, 1999) is used to assess the level of dystonia, which is a 
comorbid condition in patients with cerebral palsy.  This scale contains a 5-point, criterion-
based, ordinal scale assessing dystonia in 8 body regions: eyes, mouth, neck, trunk, and the 
4 extremities.    
In this study, the investigator will only assess the patient’s dystonia level in the study limb 
identified for this study using the BAD scale at the screening visit.  Patients with dystonia 
defined as level 3 or greater by the BAD for the study limb will not be eligible from the study.  
Below is the specific scoring description for the lower extremities:  
Signs of dystonia of the lower extremities include sustained muscle contractions causing 
abnormal posturing of the lower extremities.  The scale for lower extremities is: 


 
 
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0 – Absence of lower extremity dystonia 
1 –Slight.  Dystonia less than 10% of the time and does not interfere with normal 
positioning and/or functional activities 
2 – Mild.  Dystonia less than 50% of the time and does not interfere with normal 
positioning and/or functional activities 
3 – Moderate.  Dystonia more than 50% of the time and/or dystonia that interferes 
with normal positioning and/or lower extremity weight bearing or function 
4 – Severe.  Dystonia more than 50% of the time and/or dystonia that prevents normal 
positioning and/or lower extremity weight bearing and/or function (eg, cannot 
maintain standing due to severe dystonia at ankles) 
* – Unable to assess lower extremity movements 
12.1.8 
Hypertonia Assessment Tool (HAT) 
The HAT is a clinical assessment tool developed to differentiate subtypes of hypertonia in the 
pediatric population.  This scale contains 7 items and each item can be scored as 0 (negative) 
or 1 (positive).  The results determine if a patient has spasticity, dystonia, rigidity, or mixed 
tone (Jethwa et al, 2010). 
For this study, HAT will be performed on the study lower limb to ensure the presence of 
spasticity. 


 
 
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12.1.9 
Gross Motor Function Classification System – Expanded and 
Revised (GMFCS–E&R) 
The Gross Motor Function Classification System (GMFCS-E&R) for cerebral palsy is based 
on self-initiated movement (Palisano et al, 2007).  The emphasis of this scale is on sitting, 
transfers, and mobility, and focuses on determining which level best represents the child’s 
present ability and limitations in gross motor function.  Instead of reflecting what the child 
can do best (capability), this scale focuses on his or her usual performance in home, school, 
and community settings.  Five levels are included in this scale: 
Level I – Walks without limitations 
Level II – Walks with limitations 
Level III – Walks using a hand-held mobility device 
Level IV – Self-mobility with limitations; may use powered mobility 
Level V – Transported in a manual wheelchair  
Detailed descriptions are provided for each level of classification by age groups (before 2nd 
birthdays, between 2nd and 4th birthdays, between 4th and 6th birthdays, between 6th and 
12th birthdays, and between 12th and 18th birthdays).  The investigator will assess the 
patient’s motor function using GMFCS-E&R at the screening visit.  Patients with 
GMFCS-E&R levels I to IV will be eligible for the study. 
12.1.10 
Modified Ashworth Scale-Bohannon (MAS-B) 
The MAS-B will be used to evaluate spasticity based on grading the resistance encountered 
in a specific muscle group by means of passively moving a limb through its range of motion 
at a study-specified velocity.  The resistance encountered to passive stretch is graded from 
0 = no increase in muscle tone to 4 = affected part(s) rigid in flexion or extension 
(Bohannon and Smith, 1987).  The same investigator should perform this measure at each 
visit, if possible. 
0 
No increase in muscle tone 
1 
Slight increase in muscle tone, manifested by a catch and release, or by 
minimal resistance at the end of the range of motion when the affected part(s) 
is moved in flexion or extension 


 
 
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1+ 
Slight increase in muscle tone, manifested by a catch, followed by minimal 
resistance throughout the remainder (less than half) of the range of motion 
2 
More marked increase in muscle tone through most of the range of motion, 
but affected part(s) easily moved.  There can be a catch, but movement should 
be stiff through most of range. 
3 
Considerable increase in muscle tone, passive movement difficult 
4 
Affected part(s) rigid in flexion or extension 
Please refer to the Study Procedure Manual for detailed instructions on performing the 
MAS-B. 
12.1.11 
Modified Tardieu Scale (MTS) 
The MTS will be used to determine the passive range of movement for the ankle of the study 
limb at different movement velocities, V1 (as slow as possible) and V3 (as fast as possible), 
with the relative difference between a slow and a fast velocity passive stretch determining the 
dynamic component of the muscle contracture (Love et al, 2001).   
At each visit, the same investigator (when possible) will measure 2 joint angles by 
goniometer:  the R1 angle, which is the “angle of catch” after a fast velocity (V3) stretch, and 
the R2 angle, which is defined as the passive joint range of movement following a slow 
velocity (V1) stretch.  The R2 – R1 value indicates the level of dynamic contracture in the 
joint.  Measurements of R1 and R2 should be done at approximately the same time of day at 
each visit using a constant position for the study limb being evaluated.  The R1 angle should 
be measured prior to the R2 angle. 
Please refer to the Study Procedure Manual for detailed instructions on performing the MTS. 
 
 
 
 
 
 
 
 


 
 
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12.1.14 
Goal Attainment Scale (GAS) by Physician 
The GAS by Physician will be used to measure functional goal attainment relative to the 
effect of the study intervention.  Goals should be specific, measurable, achievable and 
realistic, resource sensitive, and timed (SMART).  At week -2, two goals will be selected by 
the patient and family in consultation with the physician investigator and/or treating therapist 
relative to the lower limb impairment due to spasticity.  These goals will be confirmed at the 
day 1 visit.  Two functional goals will be established for each patient:  a functional active 
goal and a functional passive goal.  After the functional goals (active and passive) are set, 
they should remain the same throughout the study.  It is crucial to define all the levels of the 
goal.  Goal achievement will be assessed by the physician investigator taking into 
consideration input from the treating therapist, caregiver, and/or patient. 
The following scale will be used to evaluate the level of achievement of the 2 goals:  
-3 
Worse than start  
-2 
Equal to start:  the patient’s initial condition; no change  
-1 
Less than expected:  slight improvement, but below the defined therapeutic 
goal 
0 
Expected goal:  attains the defined therapeutic goal 
+1 
Somewhat more than expected:  improvement slightly exceeds the defined 
therapeutic goal 
+2 
Much more than expected:  improvements clearly exceed the defined 
therapeutic goal 


 
 
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12.1.15 
Clinical Global Impression of Overall Change (CGI) by 
Physician 
Ideally, the CGI by Physician should be performed prior to administering the MAS-B and 
MTS to reduce the likelihood of the CGI being influenced by the spasticity evaluations.  An 
alternative is to have different evaluators rate the CGI and perform the spasticity assessments 
(MAS-B and MTS).  Whenever possible each procedure should be performed by the same 
evaluator for an individual patient throughout the trial.  Study personnel should avoid 
reviewing or discussing the MAS-B, MTS, or CGI scores from previous visits when they are 
completing these assessments. 
Each assessment should be evaluated relative to the patient’s condition prior to entering the 
study.  The physician investigator should make an assessment of the change (improvement or 
worsening) from baseline (day 1) taking into account the patient’s clinical condition and 
severity of side effects.  The investigator should choose a score that indicates his/her 
assessment about any therapeutic effects from the study intervention.  Several factors can be 
considered when assigning a score including but not limited to assessment of any specific 
benefit/detriment to the patient, adverse events, risk/benefit of the study intervention, any 
effects on the patient’s social and/or psychological status.  
“How is the subject doing in his/her life since he/she received the study medication?”: 
-4 
Very marked worsening 
-3 
Marked worsening 
-2 
Moderate worsening 
-1 
Slight worsening 
-0 
Unchanged 
+1 
Slight improvement 
+2 
Moderate improvement 
+3 
Marked improvement 
+4 
Very marked improvement 
 
 
 
 
  


 
 
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12.1.18 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS (Posner et al, 2011) is a semistructured interview designed to assess the severity 
and intensity of suicidal ideation, suicidal behavior, and non-suicidal self-injurious behavior 
over a specified time period (eg, prior year, since last visit).  The measurement of suicidal 
ideation is based on 5 “yes” or “no” questions (plus a description if answered “yes”) arranged 
in order of increasing severity.  If the patient answers “yes” to either question 1 or 2, the 
intensity of ideation will then assessed in 5 additional questions relating to the frequency, 
duration, controllability, deterrents, and reasons for the most severe ideation.  Suicidal 
behavior is then assessed by asking further questions to categorize the behaviors into actual, 
aborted, and interrupted attempts; preparatory behavior; and non-suicidal self-injurious 
behavior.  The interview is used in full only if the initial questions are positive; this 
assessment is completed at all scheduled clinic visits at which other clinical assessments are 
to be carried out. 
If any item(s) on the C-SSRS are answered with “yes”, a physician investigator must review 
patient’s responses in order to: 
a) at screening and baseline determine patient’s study eligibility and potential need for 
 
referral to  a mental health professional, and  
b) during the study evaluate patient’s need for appropriate medical management such as 
 
referral to a mental health professional.  


 
 
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A  significant risk of suicide is defined as a “yes” in answer to: a) questions 4 or 5 on the 
suicidal ideation section; or b) any questions on any item in the suicidal behavior section.  
This must be reported as a serious adverse event and followed up accordingly (see 
Sections 9.1.2 and 9.3 of the study protocol).  Additionally, if a patient responds “yes” to any 
of the suicidal ideation questions 1 to 3, the investigator should apply clinical judgment to 
determine the need for reporting as an adverse event or serious adverse event and the need 
for any referral. 
The C-SSRS is available in several versions designed for use in clinical trials.  Appropriate 
versions of the scale will be used in this trial. 


 
 
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12.2 
Package Insert/Summary of Product Characteristics 
The appropriate package insert or Summary of Product Characteristics will be supplied to 
investigators in countries where the product is marketed. 


 
 
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12.3 
Glossary of Abbreviations  
Term/Abbreviation 
Definition 
AFO 
ankle-foot-orthosis 
ANCOVA 
analysis of covariance 
BAD 
Barry Albright Dystonia scale 
BoNT-A 
botulinum neurotoxin type A 
BOTOX® 
botulinum toxin type A purified neurotoxin complex (US Adopted 
Name, onabotulinumtoxinA) 
CFR 
Code of Federal Regulations (US) 
CGI 
Clinical Global Impression of Overall Change 
CNS 
central nervous system 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EMG 
electromyography 
EU 
European Union 
FDA 
Food and Drug Administration 
GAS 
Global Attainment Scale 
GCP 
Good Clinical Practices 
GMFCS-E&R 
Gross Motor Function Classification System Expanded and 
Revised 
HAT 
Hypertonia Assessment Tool 
HbA1c 
glycosylated hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act Standards for 
Privacy of Individually Identifiable Health Information 
ICH 
International Conference on Harmonisation 
IDR 
Independent Drug Reconstitutor 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
 
 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LS 
least square 


 
 
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MAS-B 
Modified Ashworth Scale - Bohannon 
MI 
multiple imputation 
MMRM 
Mixed Model Repeated Measures 
mITT 
modified intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTS 
Modified Tardieu Scale 
NA 
not applicable 
No. 
number 
NOAEL 
no-observable-adverse-effect level 
OT 
occupational therapy 
PASS 
power analysis and sample size 
PT 
physical therapy 
R1 
fast range of motion (R1 angle is the “angle of catch” after a fast 
velocity [V3] stretch) 
R2 
slow range of motion (R2 angle is the passive joint range of 
movement following a slow velocity [V1] stretch 
Random 
randomization 
SDRC 
Safety Data Review Committee 
U 
unit, corresponding to the median lethal dose (LD50) in mice 
US 
United States 
V1 
slow velocity 
V3 
fast velocity 
 


 
 
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12.4 
Protocol Amendment 1 Summary 
Title:  BOTOX® Treatment in Pediatric Lower Limb Spasticity:  Double-blind Study 
Protocol 191622-111, Amendment 1 
Date of Amendment:  30 March 2012 
Amendment Summary 
This summary includes changes made to Protocol 191622-111 (02 December 2011) to 
provide clarifications, updated information, and corrections.   
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section(s) 
Revision 
Rationale 
Title page 
Added EudraCT number and 
changed Allergan Medical Safety 
Physician.  
Updated information. 
7.3.1, Primary 
Efficacy Analyses 
Added wording to specify that if a 
pairwise comparison in MAS-B is 
not statistically significant, the 
corresponding pairwise comparison 
in CGI will not be considered 
statistically significant regardless 
of the actual p-value. 
Additional details added for 
clarification. 
7.7, Additional 
Analysis/Inference 
for US FDA 
Section 7.7 added to the protocol to 
clarify when dose effectiveness 
will be concluded.  
Clarification added to address 
comments by US FDA during 
Special Protocol Assessment 
review.   
Table 1 
(schedule), 
Footnote “i”; 8.3, 
Visits and 
Associated 
Procedures; and 
12.1.16, CGI by 
Physician 
Revised to clarify the ideal order of 
CGI and spasticity assessments.  
Emphasis on these points was 
increased to reduce potential 
bias in CGI and spasticity 
assessments. 


 
 
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Section(s) 
Revision 
Rationale 
10.7, Handling of 
Biological 
Specimens 
Revised approximate volume of 
blood collection for hematology 
and chemistry regardless of weight 
from 5 to 7 mL and total for 
children 15 kg and above from 
12 to 14 mL. 
Based on the revised central 
laboratory (
) 
requirements. 
12.1.4, 
Hematology and 
Serum Chemistry 
Revised reference ranges for 
alkaline phosphatase in Table 4. 
Corrected values based on 
revised reference ranges 
provided by central laboratory 
(
). 
12.1.5, 
Immunogenicity 
Testing 
Deleted reference to mouse 
protection assay (MPA). 
Modified the language to allow 
either the MPA or other 
appropriate and validated 
assays to be used. 
12.1.17, Patient-
reported Onset of 
Spasticity 
Symptom Relief 
Revised the question from “have 
you noticed any treatment 
effect…” to “have you noticed any 
effect…”  
Corrected reference to limb from 
arm to leg. 
Revised based on central IRB 
requirement to minimize 
potential bias in response and 
corrected limb.  


 
 
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12.5 
Protocol Amendment 2 Summary 
Title:  BOTOX® Treatment in Pediatric Lower Limb Spasticity:  Double-blind Study 
Protocol 191622-111, Amendment 2 
Date of Amendment:  January 2014 
Amendment Summary 
This summary includes changes made to Protocol 191622-111 Amendment 1 (e-signature 
date 02 April 2012).  This protocol was amended primarily to add assessment of suicidal 
ideation and behavior using the C-SSRS as a standard safety measure required by the US 
FDA’s Division of Neurology Products for all ongoing or planned clinical studies, and to 
incorporate changes in statistical procedures. 
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section(s) 
Revision 
Rationale 
Title page 
Referred to the Study Contacts Page for 
emergency telephone numbers on pages 1 
and 2 
Per new Allergan protocol 
template 
Protocol Summary; 
2.2 
Added distinction between US FDA and 
non-US FDA clinical hypotheses and 
analyses 
Clarification 
Protocol Summary; 
Table 1; 6.1.3; 
7.2.3; 7.3.3; 8.3.4; 
8.3.5; 12.1.17 
 
 
Protocol Summary; 
Table 1; 6.1.4; 6.4; 
7.3.4; 8.3.1; 8.3.3; 
8.3.4; 8.3.5; 11; 
12.1.18; 12.3 
Specified that the C-SSRS is to be 
performed as a safety measure for patients 
≥ 6 years of age at day 1, and provided 
description of scale, data handling, and 
reference information 
As requested by US FDA’s 
Division of Neurology Products 
Table 1 
Added “Review safety lab results” to visit 3 
In agreement with Section 8.3.3 
 
Added “Access IVRS/IWRS” and clarified 
in new footnote (k) how and when 
IVRS/IWRS is used 
Clarification 


 
 
Approval Date: 
 
25-Jul-2016
Allergan Confidential 
Protocol 191622-111, Amendment 3 
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87 
 
 
 
Section(s) 
Revision 
Rationale 
Protocol Summary; 
4.3; 8.3.1 
Revised Inclusion Criterion 3 and screening 
procedure to remove requirement of true 
equinus foot deformity referenced in Rodda 
and Graham 
Clarification that gait pattern 
analysis is not required to 
confirm equinus foot deformity 
3.1 
Changed “member” to “participant” and 
removed “or investigator” from the 
examples given of ad hoc SDRC 
participants 
Clarification 
Protocol Summary; 
4.4 
Revised Exclusion Criterion 3 to remove 
the definition of significant knee spasticity  
Clarification 
 
Modified Exclusion Criterion 13a regarding 
seizure frequency for exclusion 
Clarification 
 
Added Exclusion Criterion 31 to exclude 
patients with significant suicidality from 
treatment 
To avoid confounding the safety 
data 
4.5.2 
Added “or pump” to forms of baclofen that 
are prohibited 
Clarification 
 
Added that patients may stay in the study 
even if a prohibited medication is 
administered. 
Clarification 
4.5.3 
Moved and amended sentence regarding 
school-based therapy 
Clarification that school-based 
therapy, if relevant per local 
legislation, is permitted during 
the study. 
5.3 
Amended first paragraph regarding IDR 
To clarify responsibilities of the 
IDR  
5.5 
Inserted sentence in first paragraph 
regarding IVRS/IWRS 
To clarify that the site will 
access the system on day 1 
5.6.1 
Amended the first paragraph regarding 
patient’s weight and dose calculation 
To clarify that patient’s weight 
in kilograms will be rounded to 
the nearest kilogram for dose 
calculation only 
6.1.1; 6.1.2; 7.2; 
7.2.1; 7.2.2; 7.3.1 
Made the distinction between US FDA 
measures and non-US FDA measures 
Clarification 
6.3 
Corrected second bullet by removing 
“freezer” from the equipment needing 
temperature monitoring  
Correction 
 
Added bullet that Allergan will supply a 
kilogram-only weight scale for selected 
sites, and that the site will supply it only if 
it is not already supplied by Allergan 
To ensure that patient’s weight 
is collected in kilograms only 


 
 
Approval Date: 
 
25-Jul-2016
Allergan Confidential 
Protocol 191622-111, Amendment 3 
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88 
 
 
 
Section(s) 
Revision 
Rationale 
 
Removed: “Non-frost-free -20°C freezer for 
storage of serum neutralizing antibody 
samples” 
Correction 
 
Corrected last bullet by adding “or EMG to 
the devices for muscle localization 
techniques 
Correction 
Table 1; 7.2.2; 
7.3.2; 8.3.1; 8.3.3; 
8.3.4; 8.3.5 
Added “with knee extended and knee 
flexed” to the description of the MTS scale 
Clarification 
7.3.1 
The multiple testing procedure was changed 
to a gatekeeping procedure 
To control type I error rate 
 
Pairwise comparison for higher dose versus 
lower dose was removed 
To incorporate US FDA 
recommendation 
 
Overall test for among group comparison 
was removed 
Gatekeeping procedure for the 2 
pairwise comparisons is 
sufficient to control type I error 
rate 
 
Principal muscle group by stratification 
categories was removed from ANOVA 
model explanation 
Correction 
 
CGI by Physician was removed for non-US 
FDA analyses 
Clarification 
7.3.1 and 11 
Removed Saville citation and reference 
No longer applicable due to the 
multiple testing procedure 
change 
7.3.2 
CGI by Physician was added for non-US 
FDA analyses 
Clarification 
7.4 
Removed subgroup efficacy analyses by 
type of anesthesia 
The distribution and number of 
patients in each type of 
anesthesia will not produce 
meaningful efficacy results. 
Protocol summary; 
7.5 
Revised sample size calculation to base the 
calculation on 2 sample t test 
Since the overall test for among 
group comparison was removed 
7.7 
Added separate sections (7.7.1 and 7.7.2) to 
specify the primary and secondary efficacy 
analyses for FDA and added a table for 
efficacy claim 
Clarification and to incorporate 
US FDA recommendation  
Table 1; 8.3.1; 8.3.3 
Removed passive range of motion bullet to 
indicate that assessment of passive range of 
motion can be performed as part of the 
MTS using the angle of slow stretch (R2) 
Clarification 
 
Added “in kilograms” to weight 
measurement 
Clarification 


 
 
Approval Date: 
 
25-Jul-2016
Allergan Confidential 
Protocol 191622-111, Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
89 
 
 
 
Section(s) 
Revision 
Rationale 
8.3.1; 12.1.4 
Specified that patients may return to the 
clinic for fasting blood sample collection as 
long as the laboratory results can be 
received and reviewed at or before the day 
1 visit 
Clarification 
8.3.3 
Removed the requirement that the urine 
pregnancy test must be performed prior to 
study treatment 
Clarification 
 
 
  
 
 
 
 
Added bullets for review of screening 
laboratory results and accessing 
IVRS/IWRS to randomize patients, and 
notification/scheduling follow-up visits 
Clarification of day 1 
procedures 
8.3.5 
Added bullet regarding IVRS/IWRS 
Clarification of visit 8 
procedures 
9.3 
Updated serious adverse event reporting 
procedures 
Per new Allergan protocol 
template 
10.7, 12.1.5 
Amended Study Procedure Manual to 
Laboratory Manual 
Correction 
12.1.1 
Amended second sentence regarding weight 
measurements  
Clarification on requirements 
for weight measurements and 
that weight must be measured in 
kilograms  
12.1.2  
Added “temporal, rectal” to body 
temperature 
As per common practices 
12.1.10 
Deleted “physician” 
To clarify that other qualified 
site personnel can perform the 
MAS-B 
 
Revised MAS-B description to say “study-
specified” instead of “non-study-specified” 
velocity 
To clarify that we do instruct 
the sites on a specific velocity 
 
Added referral to Study Procedure Manual 
for detailed instructions on performing the 
MAS-B 
Clarification 
12.1.11 
Merged sections 12.1.11 and 12.1.12 to 
indicate that assessment of passive range of 
motion can be performed as part of the 
MTS using slow stretch (V1) 
Clarification 
12.1.14; 12.1.15 
Amended “investigator” to “physician 
investigator” 
Clarification 
 


 
 
Approval Date: 
 
25-Jul-2016
Allergan Confidential 
Protocol 191622-111, Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
90 
 
 
 
12.6 
Protocol Amendment 3 Summary 
Title:  BOTOX® Treatment in Pediatric Lower Limb Spasticity:  Double-blind Study 
Protocol 191622-111, Amendment 3 
Date of Amendment:  July 2016 
Amendment Summary 
This summary includes changes made to Protocol 191622-111 Amendment 2 (January 2014).  
This protocol was amended primarily to modify the statistical methods (introduction of the 
Hochberg procedure, changes in imputation methods and sensitivity analyses) to reflect the 
simultaneous changes being made to Protocol 191622-101. 
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section(s) 
Revision 
Rationale 
Title page 
Updated Allergan Medical Safety Physician 
and Allergan signatory information 
Change in staff 
Protocol Summary 
(General Statistical 
Methods and Types 
of Analyses); 7.1 
(Analysis 
Populations); 7.3 
(Hypothesis and 
Methods of 
Analysis) 
The intent-to-treat (ITT) population was 
replaced with the mITT population, which is 
defined as all randomized patients with a valid 
MAS-B baseline score of the principle muscle 
group and at least one post-baseline 
measurement at weeks 2, 4, or 6 for the 
MAS-B of the principle muscle group and the 
CGI by Physician. 
Revised based on FDA 
recommendation 
Protocol Summary 
(General Statistical 
Methods and Types 
of Analyses) 
Text describing sensitivity analyses was 
edited to spell out the covariate and factors in 
the MMRM model 
For clarification 
7.2 (Collection and 
Derivation of 
Primary and 
Secondary Efficacy 
Assessments) 
A responder status based on +1 score of CGI 
by Physician was added 
To further characterize 
treatment response 


 
 
Approval Date: 
 
25-Jul-2016
Allergan Confidential 
Protocol 191622-111, Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
91 
 
 
 
Section(s) 
Revision 
Rationale 
7.2 (Collection and 
Derivation of 
Primary and 
Secondary Efficacy 
Assessments) 
The sensitivity analyses of MAS-B and CGI 
were changed to use the multiple imputation 
method for missing values instead of observed 
cases; sensitivity analyses using last 
observation carried forward (LOCF) were 
removed. 
Based on FDA feedback on 
handling missing data for the 
primary analysis 
7.3 (Hypothesis and 
Methods of 
Analysis) 
The primary MAS-B analysis and FDA co-
primary MAS-B and CGI analyses were 
changed to use MMRM with observed data; 
ANCOVA with MI and observed data was 
used as sensitivy analyses; analyses of co-
primary endpoints for US FDA were moved 
to Section 7.7 
To obtain more consistent 
results and increase model 
power per FDA feedback 
7.4 (Subgroup 
Analyses) 
Subgroup analyses of AEs were deleted 
Subgroup analyses of AEs 
will not be conducted in this 
study as deemed unnecessary 
7.7 (Additional 
Analysis/Inference 
for US FDA) 
Multiple testing procedure (gatekeeping 
procedure) was changed to Hochberg 
procedure for the co-primary analysis for US 
FDA 
To control type I error rate 
7.7 (Additional 
Analysis/Inference 
for US FDA) 
Sensitivity analyses using MMRM and 
ANCOVA to support the co-primary analysis 
for US FDA are now described in this section 
For clarification 
 

SAP_000.pdf: 
NCT01603628 
 
Study ID: 191622-111 
 
Title: BOTOX® Treatment in Pediatric Lower Limb Spasticity: Double-blind Study 
 
Statistical Analysis Plan Date: August 16, 2017 


Study 191622-111 Analysis Plan 
GDD-BSP-T-001 v2012.5 
1 
16.1.9 Statistical Methods 
 
Allergan 
Biostatistics 
Analysis Plan 
Study ID: 
191622-111 
Study Title: 
BOTOX® Treatment in Pediatric Lower limb Spasticity:  Double-blind Study  
 
 
 
 
 
 


Study 191622-111 Analysis Plan 
GDD-BSP-T-001 v2012.5 
2 
Table of Contents 
1 
Introduction ..............................................................................................................................4 
1.1  Primary Study Objectives and Design .............................................................................4 
1.2  Secondary and Other Objectives .....................................................................................5 
2 
Analysis Populations and Data Conventions ............................................................................5 
2.1  Analysis Populations .......................................................................................................5 
2.2  Treatment Visits ...............................................................................................................5 
2.3  Data Conventions ............................................................................................................6 
3 
Disposition and Exit Status ......................................................................................................9 
3.1  Screening Log Data .........................................................................................................9 
3.2  Disposition and Exit Status .............................................................................................9 
4 
Demographics and Other Baseline Characteristics ................................................................10 
4.1  Demographics ................................................................................................................10 
4.2  Disease Characteristics ..................................................................................................10 
4.3  Prior Medications ..........................................................................................................10 
4.4  Concomitant Medications and Concurrent Procedures .................................................10 
4.5  Medical History .............................................................................................................10 
4.6  Pre-treatment Adverse Events ....................................................................................... 11 
4.7  Pre-treatment Serious Adverse Events .......................................................................... 11 
5 
Efficacy Analyses ................................................................................................................... 11 
5.1  Collection and Derivation of Efficacy Assessments .....................................................12 
5.2  Primary Efficacy Analyses ............................................................................................14 
5.2.1  Primary Analyses of Primary Efficacy Variable ................................................14 
5.2.2  Other Analyses of Primary Efficacy Variable....................................................15 
5.3  Secondary Efficacy Analyses ........................................................................................16 
5.3.1  CGI by Physician ...............................................................................................16 
5.3.2  Global Attainment Scale by Physician ..............................................................17 
5.3.3  Modified Tardieu Scale (MTS) of Ankle ...........................................................17 


Study 191622-111 Analysis Plan 
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3 
5.4  Other Efficacy Analyses ................................................................................................17 
 
 
 
 
 
 
 
 
 
 
 
 
5.5  Subgroup Analyses for Efficacy Variables ....................................................................19 
6 
Safety Analyses ......................................................................................................................19 
6.1  Exposure to Study Treatments .......................................................................................19 
6.2  Treatment Emergent Adverse Events ............................................................................19 
6.3  Serious Adverse Events .................................................................................................22 
6.4  Clinical Laboratory Evaluations ....................................................................................22 
6.5  Vital Signs .....................................................................................................................23 
6.6  Columbia-Suicide Severity Rating Scale ......................................................................23 
6.7  Immunogenicity Testing ................................................................................................24 
6.8  Other Safety Analyses ...................................................................................................24 
6.8.1  Physical Examination ........................................................................................24 
6.8.2  Pregnancy Test ...................................................................................................24 
7 
Interim Analyses .....................................................................................................................25 
8 
Pharmacokinetic Data Analyses .............................................................................................25 
9 
Health Outcomes Data Analyses ............................................................................................25 
10  Analysis for US FDA HFD-550 .............................................................................................25 
10.1  Primary Efficacy Analyses ............................................................................................25 
10.2  Secondary Efficacy Analyses ........................................................................................26 
11  Data Collected but not Analyzed ............................................................................................26 
12  Deviations from Protocol .......................................................................................................26 
13  References ..............................................................................................................................26 


Study 191622-111 Analysis Plan 
GDD-BSP-T-001 v2012.5 
4 
1 
Introduction 
This analysis plan details the analyses that will be performed for BOTOX® (Botulinum Toxin 
Type A) Study 191622-111, a phase 3 study designed to evaluate the safety and efficacy of 2 
doses (4 U/kg and 8 U/kg) of BOTOX with standardized physical therapy in the treatment of 
pediatric lower limb spasticity involving the ankle plantar flexors in monoplegic and hemiplegic 
children. 
1.1 
Primary Study Objectives and Design 
The primary objective of the study is to evaluate the safety and efficacy of a single treatment of 
2 doses (4U/kg and 8U/kg) of BOTOX with standardized physical therapy (PT) in pediatric 
patients with lower limb spasticity. 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 12-week 
study evaluating 2 doses of BOTOX, 4 and 8 U/kg, and placebo with standardized PT for the 
treatment of spasticity involving the ankle plantar flexors in monoplegic and hemiplegic children. 
Patients who successfully complete this study without major protocol deviations (eg, 
noncompliance to protocol-required procedures) will be given the option of enrolling in the 
open-label extension Study 191622-112 if they meet eligibility criteria. 
A centralized randomization scheme stratified by age group, and baseline modified Ashworth 
Scale – Bohannon (MAS-B) will be used.  Patients will be randomized in a 1:1:1 ratio ratio to 
one of the following treatment groups: 4 U/kg (not to exceed 150 U) + PT, 8 U/kg (not to exceed 
300 U) + PT, or placebo + PT within each combination of strata.  The stratification categories are 
as follows: 
1. 
Age (≤ 6 years and > 6 years) 
2. 
Baseline (day 1) MAS-B ankle score with knee extended (MAS-B = 2 and MAS-B  > 
2) 
There will be 1 treatment cycle in the study.  Only 1 affected lower limb (referred to as the study 
limb) will be treated. The maximum study duration per patient will be approximately 16 weeks 
(including up to 4 weeks in the screening period).  Patients will complete 8 study visits as 
follows:  screening (week -4 to week -2), initiation of standardized PT (week -2), randomization 
and treatment visit (day 1), and post-injection follow-up visits at weeks 2, 4, 6, 8, and 12.  All 
patients will receive weekly PT sessions from week -2 through week 11. 


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5 
Approximately 412 patients will be enrolled to ensure that at least 351 patients (117 per 
treatment group) will complete the study. Details on sample size calculation and power 
consideration are presented in Section 7.5 of the study protocol. 
1.2 
Secondary and Other Objectives 
There are no secondary or other objectives for this study. 
2 
Analysis Populations and Data Conventions 
2.1 
Analysis Populations 
Two populations will be used in the statistical analysis:  safety population and modified intent-to-
treat (mITT) population.  If any patient is mis-stratified by the site at randomization on day 1, 
this patient’s data will be included in the stratum to which the patient should have been stratified 
instead of the interactive voice response system (IVRS) stratum for analysis. 
The safety population will include all treated patients based on the treatment received.  All safety 
analyses will be based on the actual treatment received by each patient in this population. 
The mITT population will include all randomized patients with a valid MAS-B baseline ankle 
score with knee extended and at least one post-baseline measurement at weeks 2, 4, or 6 for the 
MAS-B ankle score with knee extended and the Clinical Global Impression of Overall Change 
(CGI) by Physician. Here weeks 2, 4, and 6 refer to the analysis visits defined in Section 2.2. The 
mITT population will be analyzed according to randomization assignment, regardless of 
treatment actually received. Efficacy data, demographics, and background information will be 
analyzed on the basis of the mITT population. 
2.2 
Treatment Visits 
All days are referenced to day 1.  Day 1 is the randomization/treatment day.  In the cases where 
randomization and treatment happened on different days, the day of treatment will be used as 
day 1.  Visits according to the windows below will be determined for each variable analyzed 
unless noted otherwise in the following sections.  If there are values from multiple visits in a 
given window, the value collected from the visit closest to the target day will be used to represent 
the window.  If 2 visits with values fall within the same window and are equidistant from the 
target day, the value from the first of the 2 visits chronologically will be used to represent the 
window.  For clinical laboratory variables, the last non-missing observation for that visit window 
will be used.  This rule will be applied separately for each variable for non-missing data only.  


Study 191622-111 Analysis Plan 
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6 
(The exception is because re-runs of laboratory variables may only involve one or a few 
variables and would thus include missing data for many variables). 
Visit 
Target Day of the Visit 
Visit Window (Day*) 
Screening 
-28 
≤ Day -1 
Day 1 
(Randomization/Treatment) 
1 
Day 1 
Week 2 
15 
Day 2 to Day 22 
Week 4 
29 
Day 23 to Day 36 
Week 6 
43 
Day 37 to Day 50 
Week 8 
57 
Day 51 to Day 71 
Week 12 
85 
≥ Day 72 
* 
All days are referenced to day 1.  For post–treatment visits, study day = visit date – day 1 date+1 while for 
pre-treatment visits, study day = visit date - day 1 date. 
 
The visit windows will be used for by-visit analyses in both modified intent-to-treat (mITT) and safety 
population analyses. 
 
2.3 
Data Conventions 
The data conventions and definitions listed in this section are to be applied to all analyses unless 
stated otherwise in a subsequent section of this Analysis Plan. 
• Data will be analyzed according to the 3 treatment groups, ie, (1) BOTOX 8 U/kg, (2) 
BOTOX 4 U/kg, and (3) Placebo. 
• Concomitant medication and prior medication will be calculated using the following 
convention:  1) If the stop date of taking medication is prior to injection date, then it will be 
counted as prior medication;  2) If the start date of taking medication is after or on injection 
date, then it will be counted as concomitant medication;  3) If the start date of taking 
medication is prior to injection date and stop date is on or after injection date, then it will be 
counted as both prior medication and concomitant medication. 
• Concurrent procedures are defined as those taken on or after the first injection date. 
• All data will be listed with the exceptions of commonly expected results such as physical 
examination, pregnancy tests results for females when not applicable, etc. 
• The level of significance used for all statistical tests will be 0.05.  All hypotheses will be 
tested for statistical significance with 2-sided alternatives. 


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GDD-BSP-T-001 v2012.5 
7 
• Summary statistics of continuous variables will include the sample size (N), mean, standard 
deviation, median, minimum (Min), and maximum (Max). 
• Summary statistics of categorical variables will include the sample size (N) and/or frequency 
counts and percentages. 
• Medical Dictionary for Regulatory Activities (MedDRA) nomenclature will be used to code 
all adverse events and medical history. 
• World Health Organization Drug Dictionary Enhanced (WHO DDE) preferred name and 
MedDRA will be used to code all medications. 
• Metric systems will be used for all applicable measures including (kg), height (cm), and 
clinical laboratory data (SI: Standard International units). 
• Unless otherwise defined, baseline will be the last non-missing value of an analysis variable 
before treatment.  Therefore, in general values collected prior to the treatment on day 1 will 
be used as baseline except for clinical laboratory tests which will be performed at screening 
instead of day 1.  In the event a variable value is missing at the day 1 before treatment time 
point, the last non-missing value before day 1 will be used as baseline.  Change from baseline 
is calculated as follow-up minus baseline value. 
• Missing values will not be imputed. The multiple imputation (MI) method is only intended 
for sensitivity analyses of MAS-B ankle scores with knee extended and CGI by Physician.  
• Study days from randomization/day 1 will be calculated as:  
Study days = visit date – randomization/day 1 visit date + 1. 
• The study day of an event that has occurred before randomization/day 1 will be calculated as: 
Study day = date of event – randomization/day 1 visit date. 
• Partial dates occurring when calculation of study day is germane to the study outcome will be 
handled as follows: 
If the year is missing then the date is treated as missing. 


Study 191622-111 Analysis Plan 
GDD-BSP-T-001 v2012.5 
8 
If either the month or the day is missing, then the closest date to baseline possible will be 
used.  That is, an event occurring the year before baseline would use December and/or the 
last day of the month.  An event occurring the year after baseline would use January 
and/or the first day of the month. 
All partial dates will be listed “as is” in the data listings. 
• All adverse events with missing onset dates will be identified and the missing dates will be 
imputed as follows for analysis.  These imputations are only for assigning adverse events to a 
particular study phase; calculations such as days to onset will not use these imputations. All 
partial dates will be listed “as is” in the data listings. 
(a) 
For adverse event onset date:  If day and month are missing but year is available 
(../../yy) then the imputed day and month will be 01/01/yy or the injection date if 
they have the same year, whichever is later.  If the day is missing but the month and 
year are available (mm/../yy), then the imputed day will be mm/01/yy or the 
injection date if they have the same month and year, whichever is later. 
(b) 
For adverse event stop dates:  If day and month are missing but year is available 
(../../yy) then the imputed day and month will be 12/31/yy or the study exit date if 
they have the same year, whichever is earlier.  If day is missing but the month and 
year are available (mm/../yy), then the imputed day will be the last day of the month 
mm in the year yy or the study exit date if they have the same month and year, 
whichever is earlier. 
(c) 
If the adverse event onset or stop month, day, and year are missing (../../..), then the 
study entry date will be used as the adverse event onset date and the exit date will be 
used as the adverse event stop date. 
• Data from unscheduled visits or re-test visits will be treated the same way as scheduled visits, 
ie, the dates of such visits will be used in the categorization of visit window.  The algorithm 
handling multiple visits within a visit window will also be applied to unscheduled visits and 
re-test visits. 
• For the primary and secondary efficacy analyses where study center is a factor in the analysis 
model, centers that recruited only a few patients will be pooled together. The following 
algorithm for pooling study centers will be used: 
A. Pooling of study centers will by country. 
B. Within each country, the following will be conducted: 


Study 191622-111 Analysis Plan 
GDD-BSP-T-001 v2012.5 
9 
1. Study centers will be ranked in descending order of the total number of patients enrolled. 
2. Any center with at least 12 patients will stand on its own. 
3. The first center with fewer than 12 patients will be combined with the next center until the 
total number in the pooled center reaches or exceeds 12 patients. 
4. The algorithm of combining centers will continue down the list as described above. 
5. If the last pooled center still has less than 12 patients, the last pooled center will be combined 
with the previous pooled center. 
C. If there are less than 12 subjects enrolled in a country, the country will be pooled to the 
smallest center in the same region (alphabetical order if there is a tie). The regions include Asia-
Pacific, Europe, and North America. For example, if Canada enrolled less than 12 patients, 
Canada will be pooled with a smallest center in the United States. 
• The mean change from baseline for a given treatment group will be calculated by taking the 
sum of all individual changes from baseline divided by the number of patients with 
observations in that treatment group.  As a consequence, patients without the particular 
follow-up data will not be taken into account, except if there is a missing value replacement 
method used. 
 
 
3 
Disposition and Exit Status 
3.1 
Screening Log Data 
The number of subjects who are screen failures versus those who are qualified will be tabulated.  
The characteristics (sex, race, and age) of the failed and qualified subjects will be summarized. 
In addition, reasons for failure will be tabulated by “inclusion” and “exclusion”.  The screen 
failures will be listed by site.   
3.2 
Disposition and Exit Status 
A patient disposition and exit status table will be done for the all randomized subjects population.  
A cumulative frequency table showing patient disposition (enrolled, completed, and discontinued) 
in the study with sub-categorization by reason for premature discontinuation for each treatment 
group will be generated.     


Study 191622-111 Analysis Plan 
GDD-BSP-T-001 v2012.5 
10 
4 
Demographics and Other Baseline Characteristics 
4.1 
Demographics 
The demographics will be summarized for the mITT population. 
Age, race, sex will be summarized using frequency tabulations and/or summary statistics, both 
by treatment group and overall patients.  Race will be classified as Caucasian and non-Caucasian 
(black, Asian, Hispanic, and other).  In addition, race will be displayed as collected in the case 
report form (Caucasian, black, Asian, Hispanic, and other). 
4.2 
Disease Characteristics 
For the mITT population, the MAS-B ankle score with knee extended and knee flexed at baseline, 
the history of disease including the type (hemiplegia and monoplegia), onset, duration, and 
previous botulinum toxin exposure status will be summarized by treatment group for the mITT 
population.  
4.3 
Prior Medications 
Using the mITT population, the number and percent of patients who had taken prior medication 
(as defined in Section 2.3) will be presented by treatment group for the base preferred (drug) 
name according to the World Health Organization Drug Dictionary Enhanced (WHO DDE) with 
the same active ingredients by the primary system organ class (SOC) and preferred term of the 
MedDRA code.  
4.4 
Concomitant Medications and Concurrent Procedures 
Concomitant medications (as defined in Section 2.3) will be presented by WHO DDE preferred 
drug name for each treatment group by the primary SOC and preferred term of the MedDRA 
code using the mITT population. Concurrent procedures will be listed for the mITT population. 
4.5 
Medical History 
Data for medical history with onset dates prior to the initial informed consent form signed date 
will be tabulated and presented by the SOC and preferred term of MedDRA code for each 
treatment group using the mITT population.   


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11 
4.6 
Pre-treatment Adverse Events 
Data for pre-treatment adverse events, adverse events with onset date in-between informed 
consent date and randomization/day 1 visit or medical history that worsened duration this period 
will be listed.  
4.7 
Pre-treatment Serious Adverse Events 
All pre-treatment serious adverse events will be flagged in the pre-treatment adverse events 
listing.   
5 
Efficacy Analyses 
The primary, secondary, and other efficacy endpoints are listed below. The efficacy analysis for 
US FDA is described in Section 10. 
Primary efficacy endpoints: 
• The average change from baseline in MAS-B ankle score with knee extended at weeks 4 
and 6 
• The average CGI by Physician at weeks 4 and 6 (co-primary efficacy endpoint for US 
FDA only) 
Secondary efficacy endpoints: 
• The average CGI by Physician at weeks 4 and 6 (for non-US FDA analyses) 
• Goal Attainment Scale (GAS) by Physician 
• Modified Tardieu Scale (MTS) of the ankle with knee extended and knee flexed 
 
 
  
 
 
 
 
 
 


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5.1 
Collection and Derivation of Efficacy Assessments 
The MAS-B will be used to evaluate spasticity of each of the injected muscle (gastrocnemius, 
soleus, tibialis posterior) based on rating the resistance encountered in a specific muscle by 
means of passively moving a limb through its range of motion at a specified velocity. 
At day 1 and weeks 2, 4, 6, 8 and 12, the same investigator (when possible) will assess the 
patient’s ankle muscle tone with knee extended and knee flexed .  The investigator will extend 
the patient’s ankle from a position of maximum possible plantar flexion to a maximum possible 
dorsiflexion.  The resistance encountered to the passive stretch will be rated on the MAS-B as 
follows: 
0 =  
No increase in muscle tone 
1 =  
Slight increase in muscle tone, manifested by a catch and release, or by 
minimal resistance at the end of the range of motion when the affected 
part(s) is moved in flexion or extension 
1+ =  
Slight increase in muscle tone, manifested by a catch, followed by minimal 
resistance throughout the remainder (less than half) of the range of motion 
2 =  
More marked increase in muscle tone through most of the range of motion, 
but affected part(s) easily moved.  There can be a catch, but movement 
should be stiff through most of range. 
3 =  
Considerable increase in muscle tone, passive movement difficult 
4 =  
Affected part(s) rigid in flexion or extension 
 
The MAS-B scores of 0, 1, 1+, 2, 3, or 4 will be coded as a grade of 0, 1, 2, 3, 4, or 5, 
respectively.  The MAS-B ankle score change from baseline to each post-randomization visit and 
the primary endpoint, average change from baseline at weeks 4 and 6, will be derived for each 
patient.  Additionally, a responder status will be determined according to whether or not a patient 
has at least a 1-grade reduction from baseline in MAS-B ankle score. 
The CGI by Physician will be measured at weeks 2, 4, 6, 8, and 12.  There is no CGI assessment 
at baseline. The CGI is a 9-point scale from -4 (very marked worsening) to +4 (very marked 
improvement).  Each assessment is evaluated relative to the patient’s baseline status obtained at 
day 1.  The secondary endpoint for CGI will be the average of weeks 4 and 6 scores. Additionally, 


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a responder status will be determined according to whether or not a patient has at least +1 score 
of CGI by Physician. 
The secondary efficacy measures of average CGI by Physician at weeks 4 and 6, GAS, and MTS 
will also be collected at scheduled office visits according to the Schedule of Visits and 
Procedures in the protocol. 
The GAS is used to measure functional goal attainment relative to the effect of the study 
intervention.  The achievement of 2 functional goals, one active and one passive, preset at week -
2 by the patient and family in consultation with the investigator and/or treating physical therapist 
relative to the lower limb impairment due to spasticity and confirmed at day 1, will be assessed 
at weeks 8 and 12 using a scale of -3 (worse than start) to +2 (improvements clearly exceed the 
defined therapeutic goal). 
For MTS, the difference between slow and fast range of motion (R2-R1) and respective change 
from baseline to each post-treatment office visit will be derived.  The MTS of the ankle will be 
used to determine the passive range of movement at different movement velocities, V1 (as slow 
as possible) and V3 (as fast as possible) with the relative difference between a slow and a fast 
velocity passive stretch determining the dynamic component of the muscle contracture for the 
joint.  At each visit, the same investigator, when possible will measure two joint angles by 
goniometer:  the R1 angle which is the “angle of catch” after a fast velocity (V3) stretch and the 
R2 angle defined as the passive joint range of movement following a slow velocity (V1) stretch.  
The R2 – R1 value indicates the level of dynamic contracture in the joint. The difference 
between slow (R2) and fast (R1) range of motion and respective change from baseline to each 
post-treatment office visit on the MTS will be derived. 
 
 
 
 
 
 
 
 
 


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5.2 
Primary Efficacy Analyses 
5.2.1 
Primary Analyses of Primary Efficacy Variable 
The primary efficacy analyses will be based on the mITT population.  The primary analysis will 
be conducted for the average of change from baseline in MAS-B of the ankle plantar flexors with 


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knee extended at weeks 4 and 6. For the assessment of treatment groups in the primary endpoint, 
the statistical null hypothesis is that both BOTOX higher dose (8 U/kg) and lower dose (4 U/kg) 
have the same mean as placebo.  The alternative hypothesis is that at least one study dose of 
BOTOX has a different mean than placebo.  The hypothesis will be tested using Mixed Model 
Repeated Measures (MMRM) at significance level of 0.05.  The primary variable will be 
summarized by treatment group.  The differences of each BOTOX dose group and the placebo 
group will be used to test the null hypothesis.  The analysis will include weeks 2, 4, 6, 8, 12 data. 
The model will include baseline MAS-B ankle score with knee extended as a covariate and 
factors of age group, treatment group, visit, treatment-by-visit interaction, study center and 
previous botulinum toxin exposure.  Age group is represented by stratification categories 
(≤ 6 years and > 6 years). Baseline MAS-B ankle score with knee extended is a continuous 
variable included as a covariate. Pooled study center will be produced to ensure each contains at 
least 12 patients. Pooling method is described in Section 2.3. 
 
  
 
 
 
 
 
 
 
A gate-keeping approach will be used to control the type I error rate for the primary endpoint.  
Specifically, 8 U/kg versus placebo will be tested first followed by the 4 U/kg versus placebo 
comparison, each at 2-sided 0.05 level.  The 4 U/kg versus placebo comparison will only be 
performed if the test for 8 U/kg versus placebo is statistically significant. 
The co-primary analyses for US FDA only is described in Section 10. 
5.2.2 
Other Analyses of Primary Efficacy Variable 
For sensitivity analysis purposes to supplement the primary analyses, an analysis of covariance 
(ANCOVA) model using MI for missing values will be conducted.  A summary of the percentage 


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of missing MAS-B ankle scores with knee extended by visit will also be provided. The 
ANCOVA will include baseline MAS-B ankle score with knee extended as a covariate and 
factors of age group,  treatment group, study center and previous botulinum toxin exposure.  
The ANCOVA model will be used to analyze each imputation dataset obtained from MI as 
described in Section 5.1. 
 will then be used to pool the analyses results 
across the imputation datasets and produce final parameter estimates.  Additional sensitivity 
analyses for the MAS-B ankle score with knee extended changes from baseline at each 
assessment time point will also be performed using the same ANCOVA as specified above with 
observed data, and linear contrasts will be used to estimate the treatment differences between 
each study dose and placebo.   
In addition, the frequency distribution of the grade changes from baseline on the MAS-B ankle 
score with knee extended, as well as the percentage of responders (with at least a 1-grade 
reduction in MAS-B), will be summarized by treatment group at each post-treatment office visit.  
A logistic regression analysis will also be performed on the responder status at each post-
treatment visit with a covariate of baseline MAS-B ankle score with knee extended and factors of 
age group, treatment group, study center, and previous botulinum toxin exposure, if applicable.  
The additional analyses will be conducted using observed cases unless stated otherwise. 
5.3 
Secondary Efficacy Analyses 
For secondary efficacy analyses, the observed cases will be used unless stated otherwise. 
5.3.1 
CGI by Physician 
CGI by Physician will be rated at study weeks 2, 4, 6, 8, and 12.  Descriptive statistics will be 
presented by treatment group at each assessment timepoint and for the average of weeks 4 and 6.      
CGI by Physician will be summarized and analyzed by MMRM, as well as ANCOVA at each 
assessment timepoint using observed cases.  MMRM model will include baseline MAS-B ankle 
score with knee extended as a covariate and factors of age group, treatment group, visit, 
treatment-by-visit interaction, study center and previous botulinum toxin exposure.  The 
frequency distribution of the CGI scores, as well as the percentage of responders (CGI score ≥ 1), 
will be summarized by treatment group at each post-treatment visit.  A logistic regression 
analysis will also be performed on the responder status at each post-treatment visit with factors 
of age group, treatment group, study center, and previous botulinum toxin exposure, if applicable. 


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5.3.2 
Global Attainment Scale by Physician 
Each of the 2 goals for each patient at each visit will be analyzed by an ANCOVA model with 
age group, treatment group, study center and previous botulinum toxin exposure as factors and 
baseline MAS-B ankle score with knee extended as a covariate to assess treatment differences.  
The frequency distribution of raw scores for each goal will be summarized by treatment group.  
Additionally, the percentages of responders who scored 0 or higher (meet or exceed expectation) 
and the responders who scored -1 or high (slight improvement but not meet expectation) on each 
functional goal will also be summarized and responder status will be analyzed by logistic 
regression with factors of age group, treatment group, study center and previous botulinum toxin 
exposure, if applicable. 
5.3.3 
Modified Tardieu Scale (MTS) of Ankle 
The change from baseline of the angle difference, R2-R1, and the individual R1and R2 
respective changes from baseline will be derived at each post-treatment visit and summarized by 
treatment group, excluding observations where R1>R2.  An ANCOVA model with age group, 
treatment group, study center and previous botulinum toxin exposure as factors and baseline 
MTS of ankle with knee extended as a covariate will be performed to assess treatment 
differences.  The raw scores of R2-R1, R2 and R1 will also be summarized and analyzed using 
similar methods. MTS of ankle with knee flexed will be analyzed using the same method as 
MTS of ankle with knee extended. 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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5.5 
Subgroup Analyses for Efficacy Variables 
Subgroup analyses by the stratification factors of age (≤ 6 years and > 6 years), baseline MAS-B 
score (2 and > 2) and previous exposure to botulinum toxin will be performed for primary 
efficacy variable(s). The “None” subgroup for previous exposure to botulinum toxin is defined as 
the patients who never received botulinum toxin in the past.  
6 
Safety Analyses 
Safety variables including the incidence of adverse events, the incidence of suicide-related 
events using the C-SSRS (for patients ≥ 6 years of age at day 1), lab tests values and their 
changes from baseline, as well as vital signs and their change from baseline, immunogenicity 
tests will be summarized by treatment group using the safety population. 
6.1 
Exposure to Study Treatments 
Patient exposure to the study medication will be characterized by total dose in U, and dose in 
U/kg body weight.  
Duration of follow up is defined as the number of days from the first injection to exit; if the date 
of exit is missing, the date of the last visit will be used.  Data will be summarized with 
descriptive statistics for each treatment group. 
In addition, the total dose in U and dose in U/kg body weight will be summarized by individual 
muscle, as well as for all muscles combined. 
6.2 
Treatment Emergent Adverse Events  
Adverse events are collected both for the screening/baseline period prior to treatment (which are 
referred to as pre-treatment adverse events as cited in Section 4.6) and for the follow-up period 
after treatment is initiated. 
A treatment-emergent adverse event (TEAE) is a post-baseline adverse event with onset after the 
initiation of study treatment or an adverse event with onset prior to study treatment that 
worsened in severity or became serious after the initiation of study treatment. The number and 
percentage of patients reporting each event will be summarized and presented for all events and 
tabulated by treatment groups (8 U/kg, 4 U/kg, and placebo) and overall as follows: 


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i. 
By primary SOC and preferred term.  At each level of summarization (overall, 
primary SOC, and preferred term) a patient will be counted once if he/she reports 1 or 
more experiences at that level. 
ii. 
By primary SOC, preferred term and severity.  For a given adverse event of a patient, 
if more than 1 severity grade was reported, the worst severity grade will be included 
in the tabulation.   
All treatment-related TEAEs (study drug-related and injection procedure-related TEAE) will be 
presented by primary SOC and preferred term.  A listing of adverse events leading to 
discontinuation will also be provided. 
The number and percentage of patients with any of the preferred terms will be summarized for 
each primary SOC and preferred term.  All patients will be counted only once for each preferred 
term when multiple occurrences of the same preferred term are reported.  
In addition, individual patient data listings (including adverse event listings that include the 
investigator verbatim terms and MedDRA lower level terms) will be provided. 
Furthermore, the assessment of possible distant spread of toxin will be performed using the list 
of 39 MedDRA preferred terms (version 19.0 or its updated version as appropriate during the 
time of data analysis). 


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MedDRA Preferred Terms Evaluated for Possible Distant Spread of Toxin 
 
Cardiac Disorders 
          Bradycardia  
 
Eye Disorders 
          Accommodation disorder  
          Diplopia 
          Extraocular muscles paresis 
          Eyelid function disorder 
          Eyelid ptosis 
          Pupillary reflex impaired 
          Vision blurred 
 
Gastrointestinal Disorders 
          Constipation 
          Dry mouth  
          Dysphagia 
          Ileus paralytic 
 
Infections and Infestations 
          Botulism 
 
Musculoskeletal and Connective Tissue 
Disorders           
          Muscular weakness 
 
 
 
 
Nervous System Disorders 
          Bulbar palsy  
         Cranial nerve palsies multiple 
         Cranial nerve paralysis 
          Dysarthria 
          Facial paralysis 
          Facial paresis 
          Hyporeflexia 
          Hypotonia 
          Paralysis 
          Paresis cranial nerve 
          Peripheral nerve palsy 
          Peripheral paralysis 
          Speech disorder 
          Vocal cord paralysis 
          Vocal cord paresis 
 
  
Renal and Urinary Disorders 
          Urinary retention 
 
Respiratory, Thoracic and Mediastinal 
Disorders 
          Aspiration  
          Diaphragmatic paralysis 
          Dysphonia 
          Dyspnoea 
          Pneumonia aspiration 
          Respiratory arrest 
          Respiratory depression 
          Respiratory failure 
 
 
Reproductive System and Breast Disorders        
          Pelvic floor muscle weakness           
 


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6.3 
Serious Adverse Events 
The number and percent of patients with serious TEAEs will be tabulated by treatment groups (8 
U/kg, 4 U/kg, and placebo) and overall for all serious adverse events regardless of relation to 
treatment by primary SOC and preferred term.  
6.4 
Clinical Laboratory Evaluations 
Hematology and non-fasting clinical chemistry assays will be obtained at screening and exit as 
specified below. 
 
Hematology 
hemoglobin 
hematocrit 
red blood cells 
 
white blood cells 
neutrophils 
bands 
 
lymphocytes 
monocytes 
basophils 
 
eosinophils 
platelets 
 
 
Electrolytes 
sodium 
potassium 
bicarbonate 
 
chloride 
phosphorus 
calcium 
 
Chemistry 
glucose 
creatinine 
urea nitrogen 
 
total bilirubin 
alkaline phosphatase 
(total plus bone and 
liver fractions) 
aspartate 
aminotransferase 
(serum glutamic 
oxalacetic 
transaminase) 
 
alanine 
aminotransferase 
(serum glutamic 
pyruvic 
transaminase) 
albumin 
 
 
Other 
hemoglobin A1c 
25 hydroxyl 
vitamin D 
Parathyroid hormone 
if alkaline 
phosphatase bone 
fraction is abnormal 
 
These values at each visit and the change from baseline will be summarized by the treatment 
group by visits using descriptive statistics.  All laboratory values will be listed. Laboratory values 
at each visit will also be categorized as low, normal, and high according to the respective 
reference normal ranges. 


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6.5 
Vital Signs 
Vital signs are assessed at screening, day 1, and exit.  Blood pressure (diastolic and systolic 
measured in mmHg), pulse rate (beats/minute), respiratory rate (breaths/minute), and body 
temperature (°C), weight (kg) will be summarized by treatment group for each visit and change 
from baseline to exit visit will also be summarized by treatment group.  
6.6 
Columbia-Suicide Severity Rating Scale 
Suicidality for age over 6 years will be assessed using the Columbia-Suicide Severity Rating 
Scale (C-SSRS), conducted at every assessment visit.  Suicide-related events corresponding to 
the C-SSRS questions will be classified into the following 11 categories: 
• Self-injurious behavior, no suicidal intent 
• Suicidal ideation 
1. 
Wish to be dead 
2. 
Active: Nonspecific (no method, intent, or plan)  
3. 
Active: Method, but no intent or plan 
4. 
Active: Method and intent but no plan 
5. 
Active: Method, intent and plan 
• Suicidal behavior 
1. 
Preparatory acts or behaviors  
2. 
Aborted attempt 
3. 
Interrupted attempt 
4. 
Suicide attempt  
5. 
Completed suicide 
The number and percentage of patients with the above suicide-related events during treatment 
will be presented by treatment group.  If a patient has more than one suicide-related event during 
an interval, the most severe event in increasing order listed above will be used. 


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6.7 
Immunogenicity Testing  
Blood samples (approximately 7 mL per visit) will be collected for immunogenicity testing at the 
screening visit and study exit from patients who weigh at least 15 kg at the screening visit.  A 2-
stage assay approach will be used for the detection of binding antibodies against BoNT-A and 
neutralizing antibodies against BOTOX in patients’ serum.  In stage 1, serum samples will be 
screened for reactivity using a validated enzyme-linked immunosorbent assay (ELISA).  The 
reactive serum samples will be subsequently titered to assess the extent of antibodies present and 
immunodepleted to confirm that the reactivities are specific to BoNT-A.  In stage 2, only samples 
that are confirmed positive in the ELISA will be tested for neutralizing antibodies to BOTOX 
using a validated assay.  
 
Immunogenicity results of binding antibodies (BABs) against BoNT-A will be reported as 
positive or negative.  Immunogenicity results of neutralizing antibodies (NABs) against BOTOX 
will be reported as positive, negative, or inconclusive.  For NABs, the total negatives including 
patients with negative neutralizing antibody results as well as with negative binding antibody 
results will be reported.   
 
Immunogenicity findings will be tabulated with the number and percent of patients at each visit 
separately for each treatment group.  Percentages will be based on the number of treated patients 
with interpretable antibody assays in each treatment group at the specified visit.  Antibody titers 
will be summarized by median, minimum, and maximum.   
 
Depending on the timing and availability of data, immunogenicity data may be locked separately, 
at a different time point following the database lock for the main clinical data. 
 
6.8 
Other Safety Analyses 
6.8.1 
Physical Examination 
Physical examination will be performed at screening and study exit.  Abnormal findings will be 
listed.   
6.8.2 
Pregnancy Test 
The urine pregnancy test will be performed for females of childbearing potential at screening, 
day 1 prior to injection and at study exit.  Positive pregnancy test results (any pregnancies will be 
reported in the clinical study report) will be listed. 


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7 
Interim Analyses 
No interim analysis is planned for this study. 
8 
Pharmacokinetic Data Analyses 
There will be no pharmacokinetic data to be analyzed from this study. 
9 
Health Outcomes Data Analyses 
There will be no health outcomes data to be analyzed from this study. 
10 
Analysis for US FDA HFD-550 
Analyses are as described in all preceding sections except for the items described below. 
10.1 
Primary Efficacy Analyses 
There are 2 co-primary endpoints:  the average grade change from baseline in the MAS-B ankle 
score with knee extended at weeks 4 and 6 and the average CGI by Physician at weeks 4 and 6.  
For both co-primary endpoints, the statistical null hypothesis is that both the higher dose (8 U/kg) 
and the lower dose (4 U/kg) have the same mean as placebo.  The alternative hypothesis is that at 
least one study dose has a different mean than placebo.  In addition to the primary statistical 
analyses cited in Section 5.2.1 for the average grade change from baseline in MAS-B ankle score 
with knee extended at weeks 4 and 6, the average CGI by Physician at weeks 4 and 6 will be 
analyzed using the same statistical method with a same MMRM model in Section 5.3.1. 
The Hochberg procedure (Hochberg and Tamhane, 1987) will be used to control the family-wise 
type I error rate.  With 2 doses and 2 co-primary endpoints in each dose, the maximum p-value 
for the 2 co-primary endpoints in each dose will be used in the Hochberg procedure.  We first 
define the following values: 
p11:  p value for Botox 8 U/kg vs placebo comparing MAS-B  
p12:  p value for Botox 4 U/kg vs placebo comparing MAS-B  
p21:  p value for Botox 8 U/kg vs placebo comparing CGI  
p22:  p value for Botox 4 U/kg vs placebo comparing CGI  
p1 = max(p11, p21), p2 = max(p12, p22).  


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p1 and p2 will be sorted in an increasing order to get p(1) ≤ p(2).  The following decision rule 
will then be applied: 
Step 1:  If p(2) ≤ 0.05, both doses are considered efficacious; otherwise go to step 2. 
Step 2:  If p(1) ≤ 0.025, its corresponding dose is considered efficacious; otherwise go to step 3. 
Step 3:  Neither dose is considered efficacious. 
For sensitivity analysis purposes to supplement the co-primary analyses, ANCOVA using MI for 
missing values will be conducted for the co-primary endpoints of MAS-B ankle score with knee 
extended and CGI.  The model will include baseline MAS-B ankle score with knee extended as a 
covariate and factors of age group, treatment group, study center, and previous botulinum toxin 
exposure.  A summary of the percentages of missing MAS-B and CGI scores by visit will also be 
provided.  Additional sensitivity analyses for the MAS-B ankle score with knee extended 
changes from baseline and CGI scores at each assessment timepoint will also be performed using 
the same ANCOVA with observed data, and linear contrasts will be used to estimate the 
treatment differences between each study dose and placebo.   
10.2 
Secondary Efficacy Analyses 
The secondary efficacy analyses will be the same as the statistical analyses cited in Section 5.3 
except for the analyses for CGI by Physician which is described in the Section 10.1. 
11 
Data Collected but not Analyzed 
The date and signature of investigator and system required variables of electronic data capture 
(EDC) and IVRS/IWRS will not be analyzed. 
12 
Deviations from Protocol 
There are no deviations from protocol amendment 3.  
13 
References 
Hochberg Y, Tamhane A (1987). Multiple Comparison Procedures, John Wiley, New York. 
14 
Changes to Analyses  
Changes to Analyses from Previous Version of Statistical Analysis Plan 


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27 
The changes to the analyses as specified in the last approved version of the statistical analysis 
plan, dated 01 NOV 2016, are as follows: 
• Disposition summary will be performed for all randomized patients. 
• Clarification on pooling for countries with less than 12 subjects enrolled.  The country 
will be pooled to the smallest center in the same region (alphabetical order if there is a 
tie).  
 


ALLERGAN 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY)/Time (PT) 
Signed by: 
Justification 
  
 
           
 
            
 
          
 
            
 
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
191622-111 Statistical Analysis Plan