Conditions: Pediatrics Muscle Spasticity Cerebral Palsy Stroke
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 235
Healthy volunteers: no

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

Detailed description:

Arms:
arm 1: Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 3 units (U) per kilogram (kg) of body weight (3 U/kg) into specified muscles of the upper limb on Day 1. Participants received weekly occupational therapy (OT). arm 2: Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 6 U per kg of body weight (6 U/kg) into specified muscles of the upper limb on Day 1. Participants received weekly OT. arm 3: Participants received intramuscular injections of normal saline (placebo) into specified muscles of the upper limb on Day 1. Participants received weekly OT.

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

Protocol document:
Prot_000.pdf: 
NCT01603602 
 
Study ID: 191622-101 
 
Title: BOTOX® Treatment in Pediatric Upper Limb Spasticity: Double-blind Study 
 
Protocol Amendment 3 Date: July 22, 2016 


Allergan Confidential 
Protocol 191622-101, 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 Upper Limb Spasticity:  Double-blind Study 
 
Protocol Number:   
191622-101 Amendment 3 
EudraCT Number: 
2012-000062-38 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 


Allergan Confidential 
Protocol 191622-101, 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. 
 


Allergan Confidential 
Protocol 191622-101, Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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INVESTIGATOR SIGNATURE PAGE 
INVESTIGATOR: 
 
STUDY LOCATION: 
 
 
I agree to: 
x Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. 
x 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 
 
 


Allergan Confidential 
Protocol 191622-101, 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 ............................ 20
1.3.2
Use of BOTOX in Upper Limb Pediatric Spasticity ............................. 20
1.4
Dose Justification ................................................................................................... 21
2.
Study Objectives and Clinical Hypotheses ...................................................................... 23
2.1
Study Objectives .................................................................................................... 23
2.2
Clinical Hypotheses ............................................................................................... 23
3.
Study Design .................................................................................................................... 24
3.1
Safety Data Review Committee ............................................................................. 24
4.
Study Population and Entry Criteria ................................................................................ 25
4.1
Number of Patients ................................................................................................. 25
4.2
Study Population Characteristics ........................................................................... 25
4.3
Inclusion Criteria .................................................................................................... 25
4.4
Exclusion Criteria................................................................................................... 26
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 ................................................................. 30
4.5.2
Prohibited Medications/Treatments....................................................... 31
4.5.3
Special Diet or Activities ....................................................................... 32
5.
Study Treatments ............................................................................................................. 33
5.1
Study Treatments and Formulations ....................................................................... 33
5.2
Control Treatment .................................................................................................. 33
5.3
Methods for Masking/Blinding .............................................................................. 33


Allergan Confidential 
Protocol 191622-101, Amendment 3 
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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
5.6.2
Determination of Principal Muscle Group for Injection ....................... 36
5.7
Storage of Study Medications/Treatments ............................................................. 38
5.8
Preparation of Study Medications/Treatments ....................................................... 39
5.9
Treatment Administration ...................................................................................... 39
6.
Response Measures and Summary of Data Collection Methods ..................................... 39
6.1
Efficacy Measures .................................................................................................. 39
6.1.1
Primary Efficacy Measures ................................................................... 39
6.1.2
Secondary Efficacy Measures ............................................................... 39
6.1.3
Other Efficacy Measures ....................................................................... 40
6.2
Safety Measures ..................................................................................................... 40
6.3
Examination Procedures, Tests, Equipment, and Techniques ................................ 40
6.4
Other Study Supplies .............................................................................................. 40
6.5
Summary of Methods of Data Collection .............................................................. 41
7.
Statistical Procedures ....................................................................................................... 41
7.1
Analysis Populations .............................................................................................. 41
7.2
Collection and Derivation of Primary and Secondary Efficacy Assessments ........ 42
7.2.1
Primary Efficacy Variables .................................................................... 42
7.2.2
Secondary Efficacy Variables ................................................................ 43
7.2.3
Other Efficacy Variables ........................................................................ 43
7.3
Hypothesis and Methods of Analysis ..................................................................... 43
7.3.1
Primary Efficacy Analyses .................................................................... 43
7.3.2
Secondary Efficacy Analyses ................................................................ 45
7.3.3
Other Efficacy Analyses ........................................................................ 45
7.3.4
Safety Analyses ..................................................................................... 46
7.4
Subgroup Analyses ................................................................................................. 46
7.5
Sample Size Calculation ........................................................................................ 47
7.6
Interim Analyses..................................................................................................... 47
7.7
Additional Analysis/Inference for US FDA ........................................................... 47
7.7.1
Primary Efficacy Analyses .................................................................... 48


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8.
Study Visit Schedule and Procedures .............................................................................. 49
8.1
Patient Entry Procedures ........................................................................................ 49
8.1.1
Overview of Entry Procedures .............................................................. 49
8.1.2
Informed Consent and Patient Privacy .................................................. 49
8.2
Procedures for Final Study Entry ........................................................................... 49
8.3
Visits and Associated Procedures ........................................................................... 50
8.3.1
Visit 1:  2 to 4 Weeks Before Day 1 (Screening) .................................. 50
8.3.2
Visit 2:  Week -2 (OT Start) – Visit with the Occupational Therapist ... 51
8.3.3
Visit 3:  Day 1 (Randomization/Treatment) .......................................... 52
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 ................................................................................................ 55
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 .......................................................................... 56
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 ............................................... 57
9.4
Procedures for Unmasking of Study Medication ................................................... 58
10. Administrative Items ....................................................................................................... 58
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 ............................................. 59
10.1.4
Compliance With Electronic Records; Electronic Signatures Regulations 
(21 CFR Part 11) ................................................................................... 59


Allergan Confidential 
Protocol 191622-101, Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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10.2 Changes to the Protocol ......................................................................................... 59
10.3 Patient Confidentiality ........................................................................................... 60
10.3.1
Patient Privacy ....................................................................................... 60
10.4 Documentation ....................................................................................................... 60
10.4.1
Source Documents ................................................................................. 60
10.4.2
Case Report Form Completion .............................................................. 61
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 .. 62
10.5.1
Labeling/Packaging ............................................................................... 62
10.5.2
Clinical Supply Inventory ..................................................................... 62
10.5.3
Return or Disposal of Study Medications/Treatments and/or Supplies 63
10.6 Monitoring by the Sponsor .................................................................................... 63
10.7 Handling of Biological Specimens......................................................................... 63
10.8 Publications ............................................................................................................ 63
10.9 Coordinating Investigator ...................................................................................... 64
11. References ........................................................................................................................ 64
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
Pregnancy Test ...................................................................................... 72
12.1.6
Barry-Albright Dystonia (BAD) Scale .................................................. 72
12.1.7
Hypertonia Assessment Tool (HAT) ...................................................... 73
12.1.8
The Manual Ability Classification System (MACS) ............................. 75
12.1.9
Gross Motor Function Classification System – Expanded and Revised 
(GMFCS–E&R) .................................................................................... 75
12.1.10
Modified Ashworth Scale - Bohannon (MAS-B) .................................. 76
12.1.11
Modified Tardieu Scale (MTS) ............................................................. 77
12.1.12
Goal Attainment Scale (GAS) by Physician ......................................... 77
12.1.13
 ................................ 78
12.1.14
 ................ 78
12.1.15
Clinical Global Impression of Overall Change (CGI) by Physician ..... 79


Allergan Confidential 
Protocol 191622-101, Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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12.1.16
 .......................... 79
12.1.17
 ..................................................... 80
12.1.18
Columbia-Suicide Severity Rating Scale (C-SSRS) ............................. 80
12.2 Package Insert/Summary of Product Characteristics ............................................. 82
12.3 Glossary of Abbreviations ...................................................................................... 83
12.4 Protocol Amendment 1 Summary .......................................................................... 85
12.5 Protocol Amendment 2 Summary .......................................................................... 87
12.6 Protocol Amendment 3 Summary (October 2015) ................................................ 91
12.7 Protocol Amendment 3 Summary (January 2016) ................................................. 92
 
List of Tables 
Table 1
Schedule of Visits and Procedures .................................................................. 14
Table 2
Dilution of Study Drug ................................................................................... 34
Table 3
Number of BOTOX Units per Kilogram, Maximum Dose, and Number of 
Injection Sites by Muscle ................................................................................ 38
Table 4
Sample Size Assumptions and Power Calculations ........................................ 47
Table 5
Reference Ranges for Alkaline Phosphatase and Glucose .............................. 71
 
List of Figures 
Figure 1
Determination of Muscle Group(s) for Injection ............................................ 37
 


Allergan Confidential 
Protocol 191622-101, 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 is 
onabotulinumtoxinA) 
Phase:  3 
Study Objectives:  To evaluate the safety and efficacy of a single treatment of 2 doses (3 U/kg and 6 U/kg) of 
BOTOX with standardized occupational therapy (OT) in pediatric patients with upper limb spasticity 
Clinical Hypotheses: 
1) 
A single treatment of BOTOX at doses of 3 U/kg and 6 U/kg in the upper limb has an 
acceptable safety profile. 
2) 
BOTOX with standardized OT is more effective than placebo with standardized OT 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 OT is more effective than placebo with standardized OT 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) 
3 U/kg BOTOX + OT 
6 U/kg BOTOX + OT 
Placebo + OT 
Control:  Placebo 
Dosage/Dose Regimen: 
There will be 1 treatment cycle in the study.  Only 1 affected upper limb (referred to as the study limb) 
will be treated. 
Patients will be randomized among the following treatment groups in a 1:1:1 ratio: 3 U/kg (not to 
exceed 100 U) + OT, 6 U/kg (not to exceed 200 U) + OT, or placebo + OT.  The randomized doses are 
to be administered to the principal muscle group. 
Each patient will have either the elbow flexors or the wrist flexors designated as the principal muscle 
group for analysis purposes.  If wrist flexors are designated as the principal muscle group, finger 
flexors in the study limb must also be injected.  See Figure 1 for a flowchart for determining the 
muscle group(s) for injection and Table 3 for the dose requirements. 
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: 
x 
Age (≤ 6 years and > 6 years) 
x 
Designated principal muscle group (elbow flexors and wrist flexors) 
x 
Baseline (day 1) MAS-B score of principal muscle group (MAS-B = 2 and MAS-B > 2) 


Allergan Confidential 
Protocol 191622-101, Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
10 
 
 
Visit Schedule: 
There will be 8 visits and approximately 13 weekly OT sessions during the study: 
Visit 1: Week -4 to week -2 (screening) 
Visit 2: Week -2 (initiation of standardized weekly OT) 
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 224 patients will be enrolled to ensure that at least 213 patients (71 per treatment 
group) will complete the study. 
Condition/Disease: 
Medically stable monoplegic, hemiplegic, or triplegic children with spasticity of the upper limb 
involving the elbow and/or wrist flexor muscles with single-arm sparing due to cerebral palsy or stroke. 
Key Inclusion Criteria: 
x 
Male or female, 2 to 16 years and 11 months of age (prior to 17th birthday) at the day 1 visit 
x 
Minimum weight of 10 kg at the screening and day 1 visits 
x 
Upper limb monoplegic, hemiplegic, or triplegic spasticity (spasticity confirmed by Hypertonia Assessment 
Tool [HAT]) with single-arm sparing (only 1 arm requiring botulinum toxin treatment for spasticity during 
the study) resulting from cerebral palsy, or post-stroke with the stroke onset prior to age 2 and at least 
12 months prior to the day 1 visit 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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x 
 
 
 
 
 
 
 
 
 
Key Exclusion Criteria: 
x 
 
x 
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 
x 
 
x 
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  
x 
 
 
  
 
 
 
 
 
x 
 
 
x 
Botulinum toxin therapy of any serotype for any condition within 6 months prior to the day 1 visit 
x 
 
 
 
 
 
 
x 
History of surgical intervention 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. 
x 
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 lower limb(s), or planned casting or splinting with a dynamic splint (eg, Dynasplint or UltraFlex) 
for spasticity of the study limb or affected lower limb(s) during the study 
x 
 
 
 
 
 
 
 
 


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Response Measures 
Efficacy: 
Primary efficacy measures: 
x 
MAS-B of the principal muscle group (elbow or wrist) 
x 
CGI by Physician (co-primary efficacy measure for US FDA only) 
Secondary efficacy measures: 
x 
CGI by Physician (for non-US FDA analyses) 
x 
MAS-B of the finger flexor muscle group 
x 
Goal Attainment Scale (GAS) by Physician 
x 
Modified Tardieu Scale (MTS) of the principal muscle group 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety: 
x 
Adverse events 
x 
Physical examination 
x 
Urine pregnancy tests (for all females of childbearing potential) 
x 
Hematology and serum chemistry 
x 
Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, and body temperature) 
x 
Body weight 
x 
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 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.  The primary efficacy endpoint will be the average grade change from baseline in the MAS-B of the 
principal muscle group at weeks 4 and 6.  For US FDA only, the average grade change from baseline in MAS-B 
of the principal muscle group at weeks 4 and 6 and the average CGI by Physician at weeks 4 and 6 will be 
analyzed as co-primary endpoints.  Analysis of covariance (ANCOVA) will be performed with factors of age 
group, principal muscle group, treatment group, study center, and previous botulinum toxin exposure, and a 
covariate of baseline MAS-B.  Continuous secondary and other efficacy variables will be summarized by 
treatment group and analyzed by ANCOVA.  Categorical efficacy 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. 
 


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Sample Size Calculation: 
Approximately 224 patients will be enrolled to ensure that at least 213 patients (71 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 86% (PASS, Hintze, 2008).  The calculation is based on 
assumptions for the 6 U/kg group and the placebo group.  Since there are 2 co-primary endpoints for the US 
FDA analysis, for the 6 U/kg group the power for CGI by Physician is calculated to be 94%, and the overall 
power for the US FDA co-primary endpoints will be at least 81%.  The assumptions for MAS-B and CGI 
treatment differences were based on completed Studies 191622-008, BTOX-133/134/8051, 
BTOX-418/422-8051, BTX108509 and 112958, with standard deviation assumptions based on observed 
masked data from this ongoing study. 
 
Endpoint 
Average difference  
between 6 U/kg BOTOX group and 
placebo group at Weeks 4 and 6 
Standard 
Deviation 
Power 
MAS-B Change from 
Baseline 
-0.5 
0.98 
86% 
CGI by Physician (Co-
primary for US FDA 
Analysis) 
0.6 
1.02 
94% 
Overall Power 
 
81% 
CGI = Clinical Global Impression of Overall Change; MAS-B = Modified Ashworth Scale - Bohannon 


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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 is characterized by spasticity of both legs with relative 
sparing of the arms.  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 
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. 


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A less prevalent type of disorder associated with pediatric spasticity is stroke.  Information 
on the prevalence of childhood post-stroke spasticity in published literature is limited.  The 
United States (US) mortality rate attributable to stroke in children (1 to 5 years of age) is 
0.6 per 100,000.  The case fatality rate for childhood stroke is reported to range from 7% to 
28% (Lynch et al, 2002).  Based on studies evaluating the effects of stroke by degree of 
motor impairment, the rate of motor deficit in pediatric post-stroke patients ranges from 40% 
to about 70% (Brower et al, 1996; De Schryver et al, 2000; Keidan et al, 1994).  Given the 
low incidence of stroke in children and assuming the lowest case-fatality rate (7%) along 
with the worst case scenario of 70% prevalence of motor deficits, the maximum number of 
children with post-stroke spasticity in the US is estimated to be less than 1500. 
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, 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 


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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 
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. 


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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 
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. 
1.3.2 
Use of BOTOX in Upper Limb Pediatric Spasticity 
Allergan has supported several investigator-initiated trials evaluating the effect of BOTOX in 
children with upper limb spasticity associated with cerebral palsy.  Boyd et al conducted a 
single-center study in Australia, enrolled 30 children (15 pairs with matched age, gender, and 
side of hemiplegia) aged 5 to 15 years (mean 9 years) with hemiplegic cerebral palsy 
(Boyd et al, 2003).  This study was a single treatment study with 3 months follow-up and 
compared training alone to training combined with BOTOX injections.  Doses of 0.5 to 
2.0 U/kg per muscle were injected into selected upper limb muscles with a mean BOTOX 
dose of 4.9 ± 1.6 U/kg (range 3.1 to 8.4 U/kg).  BOTOX was significantly more effective 


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than the control (training alone) at week 3 (p = 0.002) and at week 12 (p = 0.0001) based on 
the Melbourne Assessment score. 
Koman et al enrolled 50 patients with cerebral palsy ages 3 to 18 years (mean age 9 years) in 
a 26-week double-blind, placebo-controlled study (Koman et al, 2004a).  Enrollment 
included patients with hemiplegia (n = 30), diplegia (n = 7), or quadriplegia (n = 13).  The 
patients were randomized to BOTOX (n = 28) or placebo (n = 22).  Three injections of 
BOTOX were administered at weeks 0, 8, and 20 at a dose based on the patient’s weight, the 
size of the target muscle(s), and the total number of muscles to be injected.  The mean dose 
of BOTOX was 4.9 U/kg for the first treatment session, 4.4 U/kg for the second treatment 
session, and 4.6 U/kg for the third treatment session.  The results on the Melbourne 
Assessment showed a significantly improved total score with BOTOX compared to placebo 
at 20 weeks (p = 0.04) and 26 weeks (p < 0.0001). 
Lowe et al conducted a randomized, controlled study in 42 children with hemiplegic cerebral 
palsy aged 2 to 8 years (mean 4 years; Lowe et al, 2006).  The study compared the effect of a 
single injection of BOTOX (1 to 2 U/kg per muscle group, maximum total body dose 8 U/kg) 
plus OT to OT alone (control).  The follow-up period was 6 months.  At the primary efficacy 
timepoint of month 6, both groups improved from baseline on the Quality of Upper 
Extremity Skills Test (QUEST) but the between-group difference was not significant.  At 
week 4, however, 67% of children treated with BOTOX had a clinically significant 20% 
improvement in total QUEST and 71% had a clinically significant improvement at week 12, 
compared with 19% of control children at week 4 and 33% at week 12 (between-group 
comparisons p = 0.004 and p = 0.03, respectively).  Spasticity, as measured by the Modified 
Ashworth Scale-Bohannon (MAS-B) (Bohannon and Smith, 1987), was significantly reduced 
in the BOTOX group compared to the control group at weeks 4 and 12. 
The above studies, and additional published studies, provide evidence of the clinical utility 
and safety of BOTOX in the management of upper and lower limb pediatric spasticity. 
1.4 
Dose Justification 
The purpose of this study is to further investigate the safety and efficacy of BOTOX 
treatment in pediatric patients with upper limb spasticity caused by cerebral palsy or stroke. 


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Three treatment groups were selected for the study: 
x 3 U/kg not to exceed 100 U + OT 
x 6 U/kg not to exceed 200 U + OT 
x Placebo + OT 
The assigned dose is required to be injected solely into the principal muscle group. 
The BOTOX doses were selected based on Allergan clinical trial experience in pediatric 
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, 
OCUL-120-8051, BTOX-121-8051, and 191622-021).  Pediatric upper limb studies 
supported by Allergan (investigator-initiated) used doses from 5 to 8 U/kg.  All of these 
studies demonstrated an acceptable safety profile and all but 1 study (191622-021) 
documented statistically significant improvement in a variety of efficacy outcomes. 
The higher dose of 6 U/kg to the principal muscle group in the present study is further 
supported by the dose ranges described in the literature.  All of the randomized, controlled 
studies in upper limb pediatric spasticity that were reviewed have used total body doses of 
8 U/kg or less with the exception of 3 studies.  Wallen et al (2007) and Russo et al (2007) 
evaluated doses up to 13 U/kg (mean 8.1 ± 2.9 U/kg) and 11.6 U/kg (mean 8.0 ± 2.2 U/kg), 
respectively; however, those studies included injections to additional upper limb muscles 
such as the shoulder muscles that are not eligible for injection in this study.  
Pieber et al (2011) evaluated doses up to 12 U/kg but the dosing details are not provided in 
the publication. 
The doses in the present study are further supported by the consensus guidelines issued by 
several expert bodies, which are based on many of the published studies as well as clinical 
experience.  The Cochrane review focused on the effect of botulinum toxin type A in the 
management of upper limb spasticity in children and concluded that doses of BOTOX from 
0.5 to 16 U/kg or up to a total of 220 to 410 U in a broad range of upper limb muscles, 
including shoulder muscles for the studies reporting higher doses, are safe (Hoare et al, 2010).  
The European consensus paper recently recommended a dose range of 1 to 20 U/kg with a 
maximum total dose of 400 U, regardless of location of injection (Heinen et al, 2010).  The 
higher dose ranges were based on studies that allowed injections to multiple muscles of 


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varying size in the upper and/or lower limbs (Heinen et al, 2006; Molenaers et al, 2009).  
Nevertheless the per-site maximum recommended dose was 50 U, which is consistent with 
the per-site maximum dose in the present study.  In an evidence-based review, the American 
Academy of Neurology 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 upper limb doses from the studies supporting the recommendation for upper limb 
treatment do not exceed the per-muscle doses (U/kg) in the 6 U/kg dose group in the current 
study.  The international consensus statement published in 2010 recommends per-muscle 
doses ranging from 0.5 to 4 U/kg with a total dose per treatment session not to exceed 
16 U/kg or 400 U.  The per-muscle dose for the muscles in the principal muscle groups 
(elbow and wrist ) in the 6 U/kg dose group in the present study is within these recommended 
dose ranges (Fehlings et al, 2010).  The 3 and 6 U/kg doses are therefore considered to be 
appropriate doses in this study. 
In addition, the safety of the proposed doses in this study is 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 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. 
Based on the above considerations, the doses in this study for the treatment of the upper limb 
are considered to be safe and appropriate to evaluate efficacy in this population. 
2. 
Study Objectives and Clinical Hypotheses 
2.1 
Study Objectives 
To evaluate the safety and efficacy of a single treatment of 2 doses (3 U/kg and 6 U/kg) of 
BOTOX with standardized OT in pediatric patients with upper limb spasticity. 
2.2 
Clinical Hypotheses 
1. A single treatment of BOTOX at doses of 3 U/kg and 6 U/kg in the upper limb has an 
acceptable safety profile. 


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2. BOTOX with standardized OT is more effective than placebo with standardized OT as 
measured by a reduction in muscle tone on the MAS-B.  For US Food and Drug 
Administration (FDA) only, the hypothesis is that BOTOX with standardized OT is 
more effective than placebo with standardized OT 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, 3 U/kg and 6 U/kg, and placebo with standardized OT 
for the treatment of monoplegic, hemiplegic, or triplegic children with upper limb spasticity.  
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 191622-105 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 OT (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 OT sessions from week -2 through week 11. 
There will be 1 treatment cycle in the study.  Only 1 affected upper limb (referred to as the 
study limb) will be treated.  Patients will be randomized in a 1:1:1 ratio to one of the 
following treatment groups:  3 U/kg BOTOX (not to exceed 100 U) + OT, 6 U/kg BOTOX 
(not to exceed 200 U) + OT, or placebo + OT. 
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. 


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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 224 patients will be enrolled to ensure that at least 213 patients (71 per 
treatment group) will complete the study. 
4.2 
Study Population Characteristics 
Medically stable monoplegic, hemiplegic, or triplegic children with spasticity of the upper 
limb involving the elbow and/or wrist flexor muscles with single-arm sparing due to cerebral 
palsy or stroke are eligible for enrollment in this study. 
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 
2. Minimum weight of 10 kg at the screening and day 1 visits 
3. Upper limb monoplegic, hemiplegic, or triplegic spasticity (spasticity confirmed by 
Hypertonia Assessment Tool [HAT]) with single-arm sparing (only 1 arm requiring 
botulinum toxin treatment for spasticity during the study) resulting from cerebral palsy, 
or post-stroke with the stroke onset prior to age 2 and at least 12 months prior to the 
day 1 visit 
4. 
 
 
 
 
 
 
 
 


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6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 


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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. 
 
 
4. 
 
 
 
 
 
 
 
 
11. 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 
12. 
 
 
 
  


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13. 
 
 
 
 
 
 
 
 
 
 
16. 
 
 
 
 
17. Botulinum toxin therapy of any serotype for any condition within 6 months prior to 
the day 1 visit 
18. 
 
 
 
 
 
 
 
21. History of surgical intervention 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. 
22. 
 
23. 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 lower limb(s), or planned casting or 
splinting with a dynamic splint (eg, Dynasplint or UltraFlex) for spasticity of the study 
limb or affected lower limb(s) during the study 


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24. 
 
 
 
 
 
 
 
 
 
 
 
29. 
 
 
 
 
 
 
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 or pump], 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 who are on baclofen pumps must be on 
a continuous infusion with a stable dose and their baclofen treatment regimen must not 
include bolus infusions.  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). 


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Patients will be permitted to initiate the use of soft splints 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 
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 


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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: 
x Anti-spastic medications or muscle relaxants (eg, benzodiazepines, vigabatrin, 
baclofen [oral or pump], scopolamine [oral or patch], tizanidine, or dantrolene) 
x Anti-epileptic medication 
Patients who enter the study on any of the above concomitant medications should remain on 
a stable dose throughout the study. 
In addition, the following treatments or therapy are not permitted during the study: 
x Botulinum toxin therapy of any serotype (except for the study treatment) 
x Phenol or alcohol injection to any limb(s) 
x Planned surgery in any limb(s) 
x 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. 
x Casts or dynamic splints (UltraFlex, DynaSplint) for spasticity in the study limb or 
the affected lower limb(s) 
x Occupational/physical therapy modalities such as ultrasound, transcutaneous 
electrical nerve stimulation, electrical stimulation, or acupuncture 
x Constraint-induced movement therapy will not be permitted during the study. 
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. 


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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 OT will be provided to all enrolled patients.  For the purposes 
of this protocol, OT is defined as “physical interventions performed by a licensed therapist 
(or equivalent per local regulations) to facilitate functional improvement in the upper 
extremities.” 
Patients will initiate their protocol-specified standardized OT approximately 2 weeks prior to 
the day 1 (randomization) visit.  Patients who are on concurrent OT at the time of screening 
must modify their existing OT to comply with the protocol-specified standardized OT.  After 
randomization, patients will be required to follow the same standardized OT protocol for the 
entire duration of the study. 
The standardized OT protocol will consist of weekly sessions of approximately 1 hour that 
will include the following modalities: 
x Elongation (approximately 20 minutes) 
x Strengthening (approximately 20 minutes) 
x Task-oriented functional therapy (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 based on the MACS, and individual treatment 
goals (refer to the Standardized OT Reference Manual for further details). 
Standardized OT scheduled on the day of an office visit should not be performed prior to any 
efficacy assessments.  The last OT 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 OT; however, the school-based therapy should 
remain constant throughout the study if possible.  Patients undergoing PT for lower limb 
spasticity at study entry should continue the same regimen during the study. 


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5. 
Study Treatments 
5.1 
Study Treatments and Formulations 
The study treatment will consist of BOTOX or placebo and standardized OT.  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. 
 
 
 
 
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). 


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Table 2 
Dilution of Study Drug 
Treatment Group 
Placebo 
BOTOX 
3 U/kga 
BOTOX 
6 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. 
5.4 
Treatment Allocation Ratio and Stratification 
A centralized randomization scheme stratified by age group, principal muscle group, and 
baseline MAS-B will be prepared by Allergan.  Patients will be randomized to 1 of the 
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: 
x Age (≤ 6 years and > 6 years) 
x Designated principal muscle group (elbow flexors and wrist flexors) 
x Baseline (day 1) MAS-B score of the principal muscle group (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.  Following enrollment, patient distribution will be monitored by the system as 
follows: 
1. Principal muscle group – to ensure that at least 40% of the patients enrolled have 
elbow flexors spasticity and 40% have wrist/finger flexors spasticity.  If necessary, one 
or both of the following modifications may be implemented: 


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a. For patients with the same MAS-B score for the elbow and the wrist at baseline 
(day 1), the wrist will be selected instead of the elbow 
b. Enrollment may be limited to patients with one of the principal muscle groups (eg, 
wrist ) if the majority of the patients enrolled have the other muscle group (eg, 
elbow) designated as the principal muscle group 
2. Baseline (day 1) MAS-B score – to ensure that approximately 30% of the patients 
enrolled have a baseline MAS-B of 3 or greater in the principal muscle group.  If 
necessary, enrollment of patients with baseline MAS-B = 2 will be closed and 
enrollment will continue for patients with baseline MAS-B > 2. 
The study will also aim to enroll approximately 20% botulinum toxin-naïve patients in the 
subgroup d 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. 
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.  For patients who weigh 40 kg or more, 
the maximum per-muscle dose must be used.  For patients who weigh less than 40 kg, 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 


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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 3 U/kg (not to exceed 100 U) or 6 U/kg (not to exceed 200 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 OT consisting of 
approximately 1-hour weekly sessions from week -2 through week 11. 
5.6.2 
Determination of Principal Muscle Group for Injection 
Each patient will have either the elbow flexors or the wrist flexors designated as the principal 
muscle group for analysis purposes (see Figure 1).  The principal muscle group must have a 
MAS-B score of 2 or greater.  If wrist flexors are identified as the principal muscle group 
then the wrist must have a MAS-B of 2 or greater but finger flexors need only have MAS-B 
of 1+. 
If both the wrist and elbow flexors meet the minimum MAS-B score of 2 at baseline (day 1), 
then the muscle group with the higher MAS-B score will be designated as the principal 
muscle group.  If both the wrist and elbow flexors have exactly the same MAS-B score, then 
the elbow flexors will be designated as the principal muscle group.  Note that the last 
algorithm in the case of equal MAS-B score in wrist and elbow may be changed based on 
enrollment activity (see Section 5.5). 
All muscles specified for the principal muscle group must be injected.  If the elbow flexors 
are designated as the principal muscle group, then the biceps, brachialis, and brachioradialis 
must all be injected exactly according to the dose requirements specified in Table 3.  If the 
wrist flexors are designated as the principal muscle group, both the wrist and finger flexors, 
which also contribute to spasticity at the wrist level, will be injected; ie, flexor carpi ulnaris 
and flexor carpi radialis, flexor digitorum superficialis, and flexor digitorum profundus must 
all be injected exactly according to the dose requirements specified in Table 3. 


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Figure 1 
Determination of Muscle Group(s) for Injection 
 
 
 
 
 
 
 
 
MAS-B = Modified Ashworth Scale – Bohannon 
 
Collect MAS-B scores 
on all muscle groups 
Wrist MAS-B > Elbow MAS-B 
Elbow MAS-B ≥ Wrist MAS-B 
Principal Muscle Group 
= Wrist 
Assign doses for both 
wrist and finger flexors 
Principal Muscle Group 
= Elbow 
Assign doses for elbow 
flexors 


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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. 


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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. 
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. 
6. 
Response Measures and Summary of Data Collection Methods 
6.1 
Efficacy Measures 
6.1.1 
Primary Efficacy Measures 
x MAS-B of the principal muscle group (elbow or wrist) 
x CGI by Physician (for US FDA only) 
6.1.2 
Secondary Efficacy Measures 
x CGI by Physician (for non-US FDA analyses) 
x MAS-B of the finger flexor muscle group 
x Goal Attainment Scale (GAS) by Physician 
x Modified Tardieu Scale (MTS) of the principal muscle group 


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6.2 
Safety Measures 
x Adverse events 
x Physical examination 
x Urine pregnancy tests (for all females of childbearing potential) 
x Hematology and serum chemistry 
x Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) 
x Body weight 
x C-SSRS (for patients ≥ 6 years of age at day 1) 
6.3 
Examination Procedures, Tests, Equipment, and Techniques 
The procedures are described in Attachment 12.1. 
6.4 
Other Study Supplies 
The following study supplies will be provided by Allergan or a vendor contracted by 
Allergan: 
x Laboratory kits for the collection and shipment of hematology, biochemistry, and 
urine samples (including pregnancy kits) will be provided by a vendor (eg, central 
laboratory) contracted by Allergan. 
x Calibrated temperature recorder for monitoring drug storage refrigerator temperatures 
x Syringe labels 
x Goniometer 
x Kilogram-only weight scale for selected sites (weight must be measured and collected 
in kilograms only) 
The study sites will be responsible for providing the following supplies/equipment: 


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x Needles and syringes for study drug reconstitution and injection 
x Sterile saline (0.9% without preservative) for study drug reconstitution 
x Surgical gloves for study drug reconstitution 
x 
 
 
x Access to a computer with internet connection (high-speed connection for eCRF 
completion) 
x Standard 12-lead ECG 
x Weight scale with height measure (if not supplied by Allergan) 
x Centrifuge for processing lab samples 
x Ultrasound and/or e-stimulation or EMG device for muscle localization techniques 
6.5 
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.  A central 
laboratory will be used for the analysis of all blood samples.  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). 
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. 
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 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.  


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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 
designated principal muscle group 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 the multiple imputation (MI) method, 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 the MI method for 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 MAS-B of the 
finger flexor muscle group, GAS, and MTS 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.  The MI method is only intended for MAS-B scores of the 
principle muscle group and the CGI by Physician.  Missing values for other variables will not 
be imputed. 
7.2.1 
Primary Efficacy Variables 
The primary efficacy variable is the grade change from baseline in MAS-B of the principal 
muscle group.  The primary efficacy endpoint will be the average grade change from baseline 
in the MAS-B of the principal muscle group at weeks 4 and 6.  For US FDA only, the 
average grade change from baseline in the MAS-B of the principal muscle group and the 
average CGI by Physician are co-primary efficacy variables.  Grade change from baseline in 
the MAS-B of the principal muscle group and the CGI by Physician will be analyzed as co-
primary endpoints for the average of weeks 4 and 6 (see Section 7.7). 


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7.2.2 
Secondary Efficacy Variables 
The secondary efficacy variables are CGI by Physician (for non-US FDA analyses), the grade 
change of MAS-B of the finger flexors, GAS by Physician, and MTS.  The secondary 
efficacy variables of CGI by Physician and the MAS-B change from baseline for finger 
flexors will be evaluated at weeks 2, 4, 6, 8, and 12.  The MAS-B change from baseline for 
finger flexors will be analyzed using the subgroup of patients with wrist identified as the 
principal muscle group.  Functional goals (active and passive) using GAS by Physician will 
be evaluated separately relative to baseline at weeks 8 and 12, and MTS including the 
difference between slow (R2) and fast (R1) range of motion (R2 - R1) as well as respective 
change from baseline on the MTS of the principal muscle group at weeks 2, 4, 6, 8, and 12.  
Additionally changes from baseline for each R1 and R2 at each assessment point will be 
evaluated.  In addition to each timepoint, the average of the weeks 4 and 6 MAS-B change 
from baseline of the finger flexors and CGI by Physician will be analyzed. 
 
 
 
 
 
 
 
 
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 for the principal 
muscle group at weeks 4 and 6 using the MI method for missing values.  The statistical null 
hypothesis is that both higher dose (6 U/kg) and lower dose (3 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 covariance (ANCOVA) at a 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 the ANCOVA model will be used to test the null hypothesis.  The 
ANCOVA will be performed using the following model statement: 


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Primary variable = baseline MAS-B + age group + principal muscle group + treatment group 
+ study center + previous botulinum toxin exposure, where age group and principal muscle 
group are represented by stratification categories (≤ 6 years and > 6 years for age group, 
elbow flexors and wrist flexors for designated principal muscle group).  Baseline MAS-B 
grade is a continuous variable included as a covariate.  Two tests will be performed based on 
the pairwise comparisons:  6 U/kg versus placebo and 3 U/kg versus placebo, each at a 0.05 
significance level. 
To control the type I error rate for the primary endpoint of the average change from baseline 
in MAS-B score of the principal muscle group at weeks 4 and 6, a gatekeeping approach will 
be used for this variable (Dmitrienko et al, 2005).  Specifically, for the average of the grade 
change from baseline in MAS-B at weeks 4 and 6, the LS mean difference of 6 U/kg versus 
placebo from the ANCOVA will be tested first.  If the test is not statistically significant at the 
level of 0.05, the test of the LS mean difference of 3 U/kg versus placebo will not be 
considered statistically significant regardless of its p value.  Otherwise if the test for 6 U/kg 
versus placebo is statistically significant, then the test for 3 U/kg versus placebo will be 
evaluated based on its p value.  
For sensitivity analysis purposes to supplement the primary analyses, Mixed Model Repeated 
Measures (MMRM) with an unstructured covariance matrix will be conducted.  The model 
will include baseline MAS-B as a covariate and factors of age group, principal muscle group, 
treatment group, visit, treatment-by-visit interaction, study center, and previous botulinum 
toxin exposure.  A summary of the percentage of missing MAS-B scores by visit will also be 
provided.  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, and linear contrasts will be used to estimate the treatment differences 
between each study dose and placebo.  The sensitivity analyses will be conducted using 
observed data. 
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, principal muscle group, treatment 
group, study center, and previous botulinum toxin exposure, if applicable.  The additional 
analyses will be conducted using observed cases unless stated otherwise. 


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For US FDA only, CGI by Physician will be a co-primary variable (see Section 7.7 for 
description of analyses). 
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 ANCOVA as the average of values at weeks 4 and 6 using the 
MI method for missing values, as well as 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, principal muscle group, treatment group, 
study center, and previous botulinum toxin exposure, if applicable. 
The average grade change from baseline for weeks 4 and 6 in the MAS-B for finger flexor 
muscle groups will be summarized by treatment group and analyzed by ANCOVA using the 
subgroup of patients with wrist identified as the principal muscle group.  The grade change 
from baseline in the MAS-B for finger flexor muscle groups at each timepoint will also be 
summarized by treatment group and analyzed by ANCOVA using the same subgroup.  The 
ratings for each of the 2 goals using GAS 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, the difference between slow and fast motion (R2 - R1) and the 
individual R2 and R1 values in degrees for the principal muscle group, 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 pre-treatment 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. 
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), designated 
principal muscle group, and previous exposure to botulinum toxin.   
The analyses of adverse events will be presented by type of anesthesia, previous exposure to 
botulinum toxin, and age group, if appropriate. 


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7.5 
Sample Size Calculation 
Approximately 224 patients will be enrolled to ensure that at least 213 patients (71 per 
treatment group) will complete the study. 
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 86% (PASS, Hintze, 2008).  The calculation is 
based on assumptions for the 6 U/kg group and the placebo group.  Since there are 2 
co-primary endpoints for the US FDA analysis, for the 6 U/kg group the power for CGI by 
Physician is calculated to be 94%, and the overall power for the US FDA co-primary 
endpoints will be at least 81%.  The assumptions for MAS-B and CGI treatment differences 
were based on completed Studies 191622-008, BTOX-133/134/8051, BTOX-418/422-8051, 
BTX108509 and 112958, with standard deviation assumptions based on observed masked 
data from this ongoing study.  The conservative overall power is calculated assuming that the 
MAS-B and CGI are independent.  Note that the improvements in MAS-B were generally 
positively correlated with CGI scores based on completed adult spasticity studies. 
Table 4 
Sample Size Assumptions and Power Calculations 
Endpoint 
Average difference  
between 6 U/kg BOTOX group 
and placebo group at 
Weeks 4 and 6 
Standard 
Deviation 
Power 
MAS-B Change from Baseline 
-0.5 
0.98 
86% 
CGI by Physician (Co-primary for US 
FDA Analysis) 
0.6 
1.02 
94% 
Overall Power 
 
81% 
CGI = Clinical Global Impression of Overall Change; MAS-B = Modified Ashworth Scale - Bohannon 
 
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.  


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7.7.1 
Primary Efficacy Analyses 
There are 2 co-primary endpoints:  the average grade change from baseline in the MAS-B of 
the principal muscle group 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 (6 U/kg) and the lower dose (3 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 grade change 
from baseline in MAS-B score of the principal muscle group at weeks 4 and 6, the average 
CGI by Physician at weeks 4 and 6 will be analyzed using the same statistical method (with 
the same ANCOVA model and the MI method). 
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: 
x p11:  p value for Botox 6 U/kg vs placebo comparing MAS-B  
x p12:  p value for Botox 3 U/kg vs placebo comparing MAS-B  
x p21:  p value for Botox 6 U/kg vs placebo comparing CGI  
x p22:  p value for Botox 3 U/kg vs placebo comparing CGI  
x 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, MMRM with 
unstructured covariance matrices will be conducted for the co-primary endpoints of MAS-B 
and CGI.  The models will include a covariate of baseline MAS-B and factors of age group, 
principal muscle group, treatment group, visit, treatment-by-visit interaction, 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 


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changes from baseline and CGI scores at each assessment time point will also be performed 
using ANCOVA with the same model as specified for the primary analysis, and linear 
contrasts will be used to estimate the treatment differences between each study dose and 
placebo.  The sensitivity analyses will be conducted using observed data. 
8. 
Study Visit Schedule and Procedures 
Please see Table 1 for a schematic of the schedule visits and procedures. 
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. 


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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 
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 OT 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) 
x 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. 
x Obtain patient identification number from the IVRS/IWRS. 
x 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. 
x Obtain medical and surgical history, ensuring that the patient has upper limb 
monoplegic, hemiplegic, or triplegic spasticity with single-arm sparing resulting from 
cerebral palsy, or is post-stroke with the stroke onset prior to age 2 and at least 
12 months prior to the day 1 visit.  Include details on histories of dysphagia, drooling, 
aspiration pneumonia, seizure, and epilepsy. 
x 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. 
x Perform C-SSRS (for patients ≥ 6 years of age at day 1). 
x Perform physical examination, including measurement of height and weight. 
x Obtain vital signs (blood pressure, pulse rate, respiratory rate, and body temperature). 
x Perform ECG. 
x Collect blood sample for hematology, serum chemistry, and HbA1c analysis after 
informed consent is signed.  Fasting blood samples should be collected unless the 


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patient is not able to fast for approximately 8 hours.  Patients who are willing to fast 
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. 
x Perform urine pregnancy test for all females of childbearing potential. 
x 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. 
x Ascertain spasticity only in the study upper limb using the HAT. 
x Assess dystonia only in the study upper limb using the BAD scale. 
x Assess manual ability only in the study upper limb using the MACS. 
x Assess gross motor function using the GMFCS-E&R. 
x Assess spasticity in the elbow, wrist, and finger in the study limb using the MAS-B. 
x Perform MTS in the elbow, wrist, and finger in the study limb.  Passive range of 
motion for the elbow, wrist, and finger for can be performed during the MTS 
assessment in order to verify inclusion criteria. 
x 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. 
x Query patient for any adverse event that has occurred and any related medication 
used or procedure performed since signing the informed consent. 
x Instruct patient/caregiver to initiate approximately 1-hour weekly standardized OT 
session with the therapist at week -2 and schedule through the last session at week 11. 
x Schedule the next visit, if applicable. 
8.3.2 
Visit 2:  Week -2 (OT Start) – Visit with the Occupational 
Therapist 
x 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. 


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x With the patient/caregiver, review protocol-specified standardized weekly OT and 
develop a patient-tailored OT plan. 
x 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. 
x Schedule the next weekly OT session. 
8.3.3 
Visit 3:  Day 1 (Randomization/Treatment) 
x 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. 
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 elbow, wrist, and finger in the study limb using the MAS-
B. 
o Perform MTS in the elbow, wrist, and finger in the study limb.  Passive range of 
motion for the elbow, wrist, and finger can be performed during the MTS 
assessment in order to verify inclusion criteria. 
o Confirm the 2 goals selected and the definitions of patient-specific goal 
achievement using the GAS by Physician. 


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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 Identify principal muscle group and 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. 
x Inform IDR that patient is qualified for the study treatment and send blinded dosing 
summary to the IDR for study drug preparation. 
x Inject assigned study treatment as per protocol (see Section 5.9). 
x Query patient/caregiver for any adverse events and related medication used or 
procedure performed. 
x Remind patient/caregiver of the importance of the weekly OT session. 
x Schedule the next visit. 
8.3.4 
Visits 4, 5, 6, and 7:  Weeks 2, 4, 6, and 8 (Follow-up Visits) 
x 
 
x 
 
x 
 
 
x Query patient/caregiver for any adverse events. 
x Perform C-SSRS (for patients ≥ 6 years of age at day 1). 
x Obtain any update to concomitant medication use. 
x Obtain any information on new medical procedures or tests since the last visit. 
x Rate the CGI by Physician before performing the spasticity assessments (MAS-B and 
MTS). 
x Assess spasticity in the elbow, wrist, and finger in the study limb using the MAS-B. 
x Perform MTS on the elbow, wrist, and finger in the study limb. 
x Only at visit 7/week 8, evaluate the patient’s performance for each of the 2 goals 
using the GAS by Physician. 


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x 
 
 
x Remind patient/caregiver of the importance of the weekly OT session. 
x Schedule the next visit. 
8.3.5 
Visit 8:  Week 12 or Early Termination (Exit Visit) 
x 
 
 
 
 
x Query patient/caregiver for any adverse events. 
x Perform C-SSRS (for patients ≥ 6 years of age at day 1). 
x Obtain any update to concomitant medication use. 
x Obtain any information on new medical procedures or tests since the last visit. 
x Perform physical examination, including measurement of weight. 
x Obtain vital signs (blood pressure, pulse rate, respiratory rate, and body temperature). 
x 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. 
x Perform urine pregnancy test for all females of childbearing potential. 
x Rate the CGI by Physician before performing the spasticity assessments (MAS-B and 
MTS). 
x Assess spasticity in elbow, wrist, and finger in the study limb using the MAS-B. 
x Perform MTS on the elbow, wrist, and finger in the study limb. 
x Evaluate the patient’s performance for each of the 2 goals using the GAS by 
Physician. 
x 
 
 
x Any adverse event that is marked “ongoing” at the exit visit must be followed-up as 
appropriate. 
x Enter patient exit status in the IVRS/IWRS. 
x If the patient/legally authorized representative agrees to participate in the follow-on 
Study 191622-105, have the patient/legally authorized representative sign the 
consent/assent/privacy form and proceed with the day 1 visit for that study. 


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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 OT 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. 
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. 


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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. 
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.) 


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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. 
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 


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event must be followed up 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 
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. 


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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. 
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 


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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”]). 
In accordance with HIPAA requirements, additional purposes of this study include the 
following: 
x to publish anonymous patient data from the study, and 
x 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. 


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The following information should be entered into the patient’s medical record: 
x Patient’s name 
x Patient’s contact information 
x The date that the patient entered the study, patient number, and medication kit number 
x The study title and/or the protocol number of the study and the name of Allergan 
x 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). 
x 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. 
x Dates of all patient visits 
x Medical and surgical history 
x Documentation of results of all procedures conducted during the course of the trial, 
including the dose determination process.  
 
 
x The results of laboratory tests performed by the site (eg, results of hematology, serum 
chemistry, HbA1c, and urine pregnancy tests). 
x 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. 
x Occurrence and status of any adverse events 
x 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 eCRF) 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. 


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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 
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 


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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. 
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.  Allergan shall have full 
ownership rights to any biological specimens/samples derived from the study. 
Approximately 7 mL of blood is estimated to be collected at a given visit.  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 


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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. 
11. 
References 
American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-
Anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. 
Anesthesiology.  2002;96:1004-1017. 
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 
spasticity. Phys Ther. 1987;67:206-207. 
Boyd R, Bach T, Morris M, Graham HK, Imms C, Johnson L, et al.  A single blind 
randomized trial of botulinum toxin A (BTX-A) and upper limb training in congenital 
hemiplegia – activity, participation, and health-related quality of life.  Dev Med Child Neurol. 
2003;45(Suppl 96):10-11 Abstract C:3. 
Brower MC, Rollins N, Roach ES.  Basal ganglia and thalamic infarction in children.  Arch 
Neurol. 1996;53:1252-1256. 
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-S128. 
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. 


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DeMatteo C, Law M, Russell D, Pollock N, Rosenbaum P , Walter S.  QUEST: quality of 
upper extremity skills test.  Manual, 1992. 
De Schryver ELLM, Kappelle LJ, Jennekens-Schinkel A, Peters ACB.  Prognosis of ischemic 
stroke in childhood: a long-term follow-up study.  Dev Med Child Neurol. 2000;42:313-318. 
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 
after botulinum toxin A injection for children with cerebral palsy.  Pediatr Phys Ther. 
2001;13:122-132. 
Dunne JW, Heye N, Dunne SL.  Treatment of chronic limb spasticity with botulinum toxin A.  
J Neurol Neuros Psy. 1995;58:232-235. 
Eliasson A-C, Krumlinde-Sundholm L, Rosblad B, Beckung E, Arner M, Ohrvall A-M, et al.  
The Manual Ability Classification System (MACS) for children with cerebral palsy: scale 
development and evidence of validity and reliability.  Dev Med Child Neurol. 
2006;48:549-554. 
Fehlings D, Novak I, Berweck S, Hoare B, Stott NS, Russo RN.  Botulinum toxin assessment, 
intervention and follow-up for paediatric upper limb hypertonicity: international consensus 
statement.  Eur J Neurol. 2010;17(Suppl. 2):38–56. 
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management of calf spasticity in children with diplegic cerebral palsy.  Eura Medicophys. 
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The updated European Consensus 2009 on the use of botulinum toxin for children with 
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Hintze J.  PASS (Power Analysis and Sample Size) 2008.  Kaysville, Utah: NCSS, LLC; 
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an adjunct to treatment in the management of the upper limb in children with spastic cerebral 
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extremity spasticity associated with cerebral palsy.  Dev Med Child Neurol. 
2004a;46(Suppl 9):10 Abstract-C:3. 
Koman IA, Smith BP, Shilt JS.  Cerebral palsy.  Lancet. 2004;363:1619-1631. 
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disordered motor control.  Chicago, Illinois:  Year Book Medical Publishers; 1980:485-494. 
Lannin N, Scheinberg A, Clark K.  AACPDM systematic review of the effectiveness of 
therapy for children with cerebral palsy after botulinum toxin A injections.  Dev Med Child 
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toxin type A on the functional ability of the child with spastic hemiplegia: a randomized 
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Lowe K, Novak I, Cusick A.  Low-dose/high-concentration localized botulinum toxin A 
improves upper limb movement and function in children with hemiplegic cerebral palsy.  
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Lynch JK, Hirtz DG, DeVeber G, Nelson KB.  Report of the National Institute of 
Neurological Disorders and Stroke Workshop on Perinatal and Childhood Stroke.  Pediatrics. 
2002;109:116-123. 
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. 
Pieber K, Herceg M, Wick F, Grim-Stieger M, Bernert G, Paternostro-Sluga T.  Functional 
electrical stimulation combined with botulinum toxin type A to improve hand function in 
children with spastic hemiparesis – a pilot study.  Wien klein Wochenschr. 2011;123:100-105. 
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. 
Russo RN, Crotty M, Miller MD, Murchland S, Flett P, Haan E.  Upper-limb botulinum toxin 
A injection and occupational therapy in children with hemiplegic cerebral palsy identified 
from a population register: a single-blind, randomized, controlled trial.  Pediatrics. 
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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. 
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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 
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 


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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 
 


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Reference ranges for alkaline phosphatase and glucose are shown in Table 5. 
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 
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. 
12.1.6 
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 upper extremities: 
Signs of dystonia of the upper extremities include sustained muscle contractions causing 
abnormal posturing of the upper extremities. 
0 
Absence of upper 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 upper extremity function 
4 
Severe.  Dystonia more than 50% of the time and/or dystonia that prevents 
normal positioning and/or upper extremity function (eg, arms restrained in 
wheelchair to prevent injury) 
* 
Unable to assess upper extremity movements 


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12.1.7 
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 upper limb to ensure the presence of 
spasticity. 


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12.1.8 
The Manual Ability Classification System (MACS) 
The MACS provides a functional description of how a child with cerebral palsy uses his or 
her hands when handling objects in daily activities.  This measure focuses on typical manual 
performances, not the maximal capacity (Eliasson et al, 2006); and is a description of 
function of both hands together.  MACS should be conducted by asking someone who is 
familiar with the child, not by performing an assessment.  The child’s level of manual ability 
can be depicted by one of the following levels: 
I. 
Handles objects easily and successfully 
II. 
Handles most objects but with somewhat reduced quality and/or speed of 
achievement 
III. 
Handles objects with difficulty; needs help to prepare and/or modify activities 
IV. 
Handles a limited selection of easily managed objects in adapted situations 
V. 
Does not handle objects and has severely limited ability to perform even simple 
actions 
While this scale is developed specifically for patients with cerebral palsy, it will be applied to 
the post-stroke patients in this study for screening purposes.  Investigators will review 
patient’s manual ability at the screening visit.  Patients with MACS level I-IV will be eligible 
for the study. 
12.1.9 
Gross Motor Function Classification System – Expanded and 
Revised (GMFCS–E&R) 
The 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. 


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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).  While this scale is developed 
specifically for patients with cerebral palsy, it will also be applied to the post-stroke patients 
in this study for screening purposes.  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 
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 


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Please refer to the Study Procedure Manual for detailed instructions on performing the 
MAS-B on the elbow, wrist, and finger muscle groups. 
12.1.11 
Modified Tardieu Scale (MTS) 
The MTS 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 (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 affected study upper 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 
on the elbow, wrist, and finger muscle groups. 
12.1.12 
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 upper 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. 


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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  
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.  


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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 
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 
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 
MACS 
Manual Ability Classification System 
MAS-B 
Modified Ashworth Scale – Bohannon 
Max 
maximum 


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MI 
multiple imputation 
MMRM 
Mixed Model Repeated Measures 
mITT 
modified intent-to-treat 
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 
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 Upper Limb Spasticity:  Double-blind Study 
Protocol 191622-101, Amendment 1 
Date of Amendment:  30 March 2012 
Amendment Summary 
This summary includes changes made to Protocol 191622-101 (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. 
4.4, Exclusion 
Criteria 
Deleted number 12 and 
renumbered remaining criteria 
accordingly. 
Number 12 duplicated 11b. 
5.6.1, Treatment 
Regimen 
In second paragraph, corrected 
150 U to 100 U in 
“…maximum doses of 3 U/kg 
(not to exceed 100 U)…” 
Corrected typographical error. 
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.   


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Section(s) 
Revision 
Rationale 
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. 
10.7, Handling of 
Biological 
Specimens 
Revised approximate volume of 
blood collection for hematology 
and chemistry from 5 to 7 mL  
Based on the revised central 
laboratory (Covance) 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 (Covance). 
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…”  
Revised based on central IRB 
requirement to minimize potential 
bias in response. 


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12.5 
Protocol Amendment 2 Summary 
Title:  BOTOX® Treatment in Pediatric Upper Limb Spasticity:  Double-blind Study 
Protocol 191622-101, Amendment 2 
Date of Amendment:  January 2014 
Amendment Summary 
This summary includes changes made to Protocol 191622-101 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; updated 
page 2 
Per new Allergan protocol 
template 
Protocol Summary 
Amended Visit Schedule description to state 
there will be “approximately” 13 weekly OT 
sessions 
Clarification 
Protocol Summary; 
2.2 
Added distinction between US FDA and non 
US FDA clinical hypotheses and analyses 
Clarification 
Protocol Summary; 
Table 1; 6.2; 6.5; 
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 
Protocol Summary; 
Table 1; 6.1.3; 7.2.3; 
7.3.3; 8.3.4; 8.3.5; 
12.1.17 
Added patient-reported benefit of injection 
To collect patient-reported 
data on benefit of injection 


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Section(s) 
Revision 
Rationale 
Protocol Summary; 
4.4 
Modified Exclusion Criterion 11a regarding 
seizure frequency for exclusion 
Clarification 
 
Modified Exclusion Criterion 12 regarding 
vulnerable respiratory state 
Clarification 
 
Added Exclusion Criterion 29 to exclude 
patients with significant risk of suicide from 
treatment 
To avoid confounding the 
safety data 
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 
3.1 
Changed “members” to “participants” and 
removed “or investigator” from the examples 
given of ad hoc SDRC participants 
Clarification 
4.5.2 
Added the statement 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 
Protocol Summary; 
5.6.1; 8.3; 8.3.1 
Amended to “approximately” 1-hour OT 
sessions 
Clarification 
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 
Made the distinction between US FDA 
measures and non-US FDA measures 
Clarification 
6.4 
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 


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Section(s) 
Revision 
Rationale 
 
Corrected last bullet by adding “or EMG” to 
the devices for muscle localization techniques 
Correction 
7.2.2; 7.2.3; 7.3.2; 
7.3.3 
Clarified that MAS-B and MTS for finger 
flexors will be analyzed for the subgroup of 
patients with wrist identified as the principal 
muscle group 
Clarification 
7.3.1 
The original multiple testing procedure 
(Fisher’s Protected Testing procedure) was 
changed to a gatekeeping procedure 
To control type I error rate 
 
Pairwise comparison for high dose versus low 
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 
 
CGI by Physician was removed for non-US 
FDA primary analyses 
Clarification 
7.3.1; 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 as a secondary measure 
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  
8.3.1; 12.1.4 
Amended sentence to remove time frame for 
blood sample collection  
Clarification  
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 
8.3.3 
Added bullets for review of screening 
laboratory results and accessing IVRS/IWRS 
to randomize patients 
Clarification of day 1 
procedures 
 
Added “in kilograms” to weight measurement 
Clarification 


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Section(s) 
Revision 
Rationale 
8.3.4 
 
Clarification of visit 8 
procedures 
8.3.5 
Added 
 use of 
IVRS/IWRS 
Clarification of visit 8 
procedures 
9.3 
Updated serious adverse event reporting 
procedure 
Per new Allergan protocol 
template 
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 
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 
12.1.12, 12.1.15 
Amended “investigator” to “physician 
investigator” 
Clarification 
 
 
 
 


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12.6 
Protocol Amendment 3 Summary (October 2015) 
Title:  BOTOX® Treatment in Pediatric Upper Limb Spasticity:  Double-blind Study 
Protocol 191622-101, Amendment 3 
Date of Amendment:  October 2015 
Amendment Summary 
This summary includes changes made to Protocol 191622-101 Amendment 2 (January 2014).  
This protocol was amended to decrease the sample size 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 
Updated Allergan Medical Safety Physician 
and Allergan signatory information 
Change in staff 
Protocol Summary, 
4.1 (Number of 
Patients) 
Estimated number of patients to complete 
study was decreased from 351 to 213 
Recalculated sample size 
based on adjusted treatment 
differences from upper limb 
studies 
Protocol Summary; 
7.5 (Sample Size 
Calculation) 
Number of patients and sample size 
calculations were revised 
Recalculated sample size 
based on adjusted treatment 
differences from upper limb 
studies 
7.2 (Collection and 
Derivation of 
Primary and 
Secondary Efficacy 
Assessments) 
Added sensitivity analyses (MMRM and 
summary of percentage of missing data for the 
primary variables) 
To supplement primary 
analysis using observed data, 
not imputed data for primary 
analysis 
7.3 (Hypothesis and 
Methods of 
Analysis) 
Statistical analysis method (ANOVA) was 
changed to ANCOVA (added study center 
and previous botulinum toxin exposure as 
factors) and changed baseline MAS-B to 
continuous variable 
To obtain more consistent 
results and increase model 
power 
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 
 


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12.7 
Protocol Amendment 3 Summary (January 2016) 
Title:  BOTOX® Treatment in Pediatric Upper Limb Spasticity:  Double-blind Study 
Protocol 191622-101, Amendment 3 
Date of Amendment:  January 2016 
Amendment Summary 
This summary includes changes made to Protocol 191622-101 Amendment 3 (October 2015).  This 
protocol was amended to incorporate FDA recommendations. 
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 
Personnel changes 
Protocol Summary, 
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, 
7.5 (Sample Size 
Calculation) 
The sample size assumptions and power 
calculations tables (Protocol Summary and 
Table 4) are now in agreement 
Correction 
7.2 (Collection and 
Derivation of 
Primary and 
Secondary Efficacy 
Assessments), 7.3 
(Hypothesis and 
Methods of 
Analysis), 7.7 
(Additional 
Analysis/Inference 
for US FDA) 
The primary MAS-B analysis and FDA co-
primary MAS-B and CGI analyses were 
changed to use the MI 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 


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Section(s) 
Revision 
Rationale 
7.3 (Hypothesis and 
Methods of 
Analysis) 
Text describing sensitivity analyses was 
edited to spell out the covariate and factors in 
the MMRM model; factors for logistic 
regression were updated to match the primary 
analysis model; analyses of co-primary 
endpoints for US FDA were moved to 
Section 7.7 
For clarification 
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_001.pdf: 
NCT01603602 
 
Study ID: 191622-101 
 
Title: BOTOX® Treatment in Pediatric Upper Limb Spasticity: Double-blind Study 
 
Statistical Analysis Plan Date: September 11, 2017 


Study 191622-101 Analysis Plan 
GDD-BSP-T-001 v2012.5 
1 
16.1.9 Statistical Methods 
 
Allergan 
Biostatistics 
Analysis Plan 
Study ID: 
191622-101 
Study Title: 
BOTOX® Treatment in Pediatric Upper Limb Spasticity:  Double-blind Study  


Study 191622-101 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 ............................................................................................15 
5.2.1  Primary Analyses of Primary Efficacy Variable ................................................15 
5.2.2  Other Analyses of Primary Efficacy Variable....................................................16 
5.3  Secondary Efficacy Analyses ........................................................................................16 
5.3.1  CGI by Physician ...............................................................................................16 
5.3.2  MAS-B of the Finger Flexor Muscle Group .....................................................17 
5.3.3  Global Attainment Scale by Investigator/Therapist ..........................................17 


Study 191622-101 Analysis Plan 
GDD-BSP-T-001 v2012.5 
3 
5.3.4  Modified Tardieu Scale of the Principal Muscle Groups ..................................18 
5.4  Other Efficacy Analyses ................................................................................................18 
 
 
 
 
 
 
 
 
 
 
 
 
5.5  Subgroup Analyses for Efficacy Variables ....................................................................19 
6 
Safety Analyses ......................................................................................................................20 
6.1  Exposure to Study Treatments .......................................................................................20 
6.2  Treatment Emergent Adverse Events ............................................................................20 
6.3  Serious Adverse Events .................................................................................................23 
6.4  Clinical Laboratory Evaluations ....................................................................................23 
6.5  Vital Signs .....................................................................................................................24 
6.6  Columbia-Suicide Severity Rating Scale ......................................................................24 
6.7  Other Safety Analyses ...................................................................................................25 
6.7.1  Physical Examination ........................................................................................25 
6.7.2  Pregnancy Test ...................................................................................................25 
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 ............................................................................................27 
12  Deviations from Protocol .......................................................................................................27 
13  References ..............................................................................................................................27 


Study 191622-101 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 191622-101, a phase 3 study designed to evaluate the safety and efficacy of 
2 doses (3 U/kg and 6 U/kg) of BOTOX with standardized physical therapy in the treatment of 
pediatric upper limb spasticity. 
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 (3 U/kg and 6 U/kg) of BOTOX with standardized occupational therapy (OT) in 
pediatric patients with upper limb spasticity. 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 12-week 
study evaluating 2 doses of BOTOX, 6 U/kg, 3 U/kg, and placebo with standardized OT for the 
treatment of monoplegic, hemiplegic, or triplegic children with upper limb spasticity due to 
cerebral palsy or stroke. 
A centralized randomization scheme stratified by age group, principal muscle group, and 
baseline modified Ashworth Scale – Bohannon (MAS-B) will be used.  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: 
1. 
Age (≤ 6 years and > 6 years) 
2. 
Designated principal muscle group (elbow flexors and wrist flexors) 
3. 
Baseline (day 1) MAS-B score of the principal muscle group (MAS-B = 2 and 
MAS-B  > 2) 
There will be 1 treatment cycle in the study.  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 OT 
(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 OT sessions from week 2 through week 11. 
Patients who successfully complete this study without major protocol deviations (eg, non-
compliance to protocol required procedures) will be given the option of enrolling in open-label 
extension Study 191622-105 if they meet eligibility criteria. 


Study 191622-101 Analysis Plan 
GDD-BSP-T-001 v2012.5 
5 
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 based on the patients’ actual age and baseline 
MAS-B for the age and baseline MAS-B group, and the actual injected muscle group for the 
principal muscle group instead of the interactive voice response system (IVRS) stratum for 
analysis. 
The safety population will include all treated patients.  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 score of 
the principal muscle group and at least one post-baseline measurement at weeks 2, 4, or 6 for the 
MAS-B of the principal muscle group 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 other baseline characteristics will 
be analyzed using 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 


Study 191622-101 Analysis Plan 
GDD-BSP-T-001 v2012.5 
6 
will be used.  This rule will be applied separately for each variable for non-missing data only.  
(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 6 U/kg, (2) 
BOTOX 3 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. 


Study 191622-101 Analysis Plan 
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 scores of the principal muscle group 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 191622-101 Analysis Plan 
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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: 


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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 smallest 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 Asian 
Pacific, Europe, and North America. For example, if Canada enrolled less than 12 patients, 
Canada will be pooed 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.   


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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 score at baseline, the history of disease including the type 
(monoplegic, hemiplegic, or triplegic), etiology (cerebral palsy or post-stroke), previous 
botulinum toxin exposure status, onset, and duration 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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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 score of  principal muscle group 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) 
• The average change from baseline in MAS-B of the finger flexor muscle group at 
weeks 4 and 6 
• Goal Attainment Scale (GAS) by Physician at weeks 8 and 12  
• Modified Tardieu Scale (MTS) of the principal muscle group 
 
 
 
 
 


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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 groups (elbow 
flexors, wrist flexors and finger flexors) based on rating the resistance encountered in a specific 
muscle group 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 upper limb muscle tone.  For the elbow or wrist flexor muscles, the investigator will 
passively extend the patient’s affected elbow/wrist from a position of maximum possible flexion 
to a maximal possible extension.  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 grade 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 for elbow flexors and wrist flexors muscle groups.  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. 


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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, 
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 MAS-B of the finger flexor muscle group, GAS, and MTS 
will also be collected at scheduled office visits according to the Schedule of Visits and 
Procedures in the protocol. 
MAS-B of the finger flexor muscle group will be collected and derived in the same way as the 
principal muscle groups. 
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 
occupational/physical therapist relative to the upper 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). 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 


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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 score of the principal muscle 
group 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 (6 U/kg) and lower dose (3 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 as a covariate and factors of age group, principal 
muscle group, treatment group, visit, treatment-by-visit interaction, study center, and previous 
botulinum toxin exposure.  Age group and principal muscle group are represented by 
stratification categories (≤ 6 years and > 6 years for age group, elbow flexors and wrist flexors 
for designated principal muscle group). Baseline MAS-B grade 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 the Section 2.3. 
  
 
 
 
 
 
 
 


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A gate-keeping approach will be used to control the type I error rate for the primary endpoint.  
Specifically, 6 U/kg versus placebo will be tested first followed by the 3 U/kg versus placebo 
comparison, each at 2-sided 0.05 level.  The 3 U/kg versus placebo comparison will only be 
performed if the test for 6 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 
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, principal muscle 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 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, 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 and factors of age group, principal muscle 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.      


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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 as a 
covariate and factors of age group, principal muscle 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, 
principal muscle group, treatment group, study center, and previous botulinum toxin exposure, if 
applicable. 
5.3.2 
MAS-B of the Finger Flexor Muscle Group 
MAS-B of the finger flexor muscle group will be analyzed using the subgroup of patients with 
wrist identified as the principal muscle group.  The average grade change from baseline for 
weeks 4 and 6 on the MAS-B for finger flexor muscle groups will be summarized by treatment 
group and analyzed by ANCOVA model with age group, treatment group, study center and 
previous botulinum toxin exposure as factors and baseline MAS-B of finger flexor muscle group 
as a covariate. The grade change from baseline at each time point will also be summarized and 
analyzed in the same fashion.  In addition, the frequency distribution of the grade changes from 
baseline on 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 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 of finger flexor muscle group and factors of age group, 
treatment group, study center, and previous botulinum toxin exposure, if applicable. 
5.3.3 
Global Attainment Scale by Investigator/Therapist 
Each of the 2 goals for each patient at each visit will be analyzed by an ANCOVA model with 
age group, principal muscle group, treatment group, study center and previous botulinum toxin 
exposure as factors and baseline MAS-B 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, principal muscle group, treatment group, study center and 
previous botulinum toxin exposure, if applicable. 


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5.3.4 
Modified Tardieu Scale of the Principal Muscle Groups 
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.  An ANCOVA model with age group, principal muscle group, treatment group, 
study center and previous botulinum toxin exposure as factors and baseline MTS 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. 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 


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5.5 
Subgroup Analyses for Efficacy Variables 
Subgroup analyses by the stratification factors of age (≤ 6 years and > 6 years), principal muscle 
group (elbow and wrist), and 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 


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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, 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, by each muscle group 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 (6 U/kg, 3 U/kg, and placebo) and overall as follows: 
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. 


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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 (6 
U/kg, 3 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 
Other Safety Analyses 
6.7.1 
Physical Examination 
Physical examination will be performed at screening and study exit.  Abnormal findings will be 
listed.   
6.7.2 
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. 
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 of the 
principal muscle group 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 (6 U/kg) 
and the lower dose (3 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 score of the 
principal muscle group 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. 


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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 6 U/kg vs placebo comparing MAS-B  
p12:  p value for Botox 3 U/kg vs placebo comparing MAS-B  
p21:  p value for Botox 6 U/kg vs placebo comparing CGI  
p22:  p value for Botox 3 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, principal muscle 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 
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. 


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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 
The changes to the analyses as specified in the last approved version of the statistical analysis 
plan, dated 22 AUG 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).  
• Clarification on mis-stratification where analyses will use the stratum that uses the 
subject’s actual age and baseline MAS-B score, and actual injected muscle group.  
 
 


ALLERGAN 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY)/Time (PT) 
Signed by: 
Justification 
  
 
           
 
            
 
 
            
 
           
 
            
 
         
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
191622-101 Analysis Plan