BOTOX® Treatment in Pediatric Upper Limb Spasticity: Open-label Study
Phase: PHASE3
Conditions: Pediatrics, Muscle Spasticity, Cerebral Palsy, Stroke
Sponsor: Allergan

NCT01603615 
 
Study ID: 191622-105 
 
Title: BOTOX® Treatment in Pediatric Upper Limb Spasticity: Open-label Study 
 
Protocol Amendment 4 Date: 01 August 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Approval Date: 
 
01-Aug-2016
Allergan Confidential 
Protocol 191622-105 Amendment 4 
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:  Open-label Study 
 
Protocol Number:   
191622-105 Amendment 4 
EudraCT Number: 
2012-000043-27 
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 
 
  
 
 
 
   
 
 
 
 
 
 

 
 
Approval Date: 
 
01-Aug-2016
Allergan Confidential 
Protocol 191622-105 Amendment 4 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
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Refer to the final page of this protocol for electronic 
signature and date of approval. 
 
The following information can be found on FDA Form 1572 and/or study contacts page:  
Name and contact information of Allergan study personnel and Emergency Telephone 
Numbers; name, address, and statement of qualifications of each investigator; name of each 
subinvestigator working under the supervision of the investigator; name and address of the 
research facilities to be used; name and address of each reviewing IRB; 21 CFR 312.23 
section 6(iii)b. 
 

 
 
Approval Date: 
 
01-Aug-2016
Allergan Confidential 
Protocol 191622-105 Amendment 4 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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INVESTIGATOR SIGNATURE PAGE 
INVESTIGATOR: 
 
STUDY LOCATION: 
 
 
I agree to: 
• Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. 
• Maintain all information supplied by Allergan in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Independent Ethics Committee 
(IEC) or another group, it will be submitted with a designation that the material is 
confidential. 
 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 
 

 
 
Approval Date: 
 
01-Aug-2016
Allergan Confidential 
Protocol 191622-105 Amendment 4 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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Table of Contents 
Table of Contents ...................................................................................................................... 4 
List of Tables ............................................................................................................................. 8 
List of Figures ........................................................................................................................... 8 
Protocol Summary .................................................................................................................... 9 
1. 
Background and Clinical Rationale ................................................................................. 18 
1.1 
Pediatric Spasticity ................................................................................................. 18 
1.2 
Management of Spasticity in Children ................................................................... 19 
1.3 
BOTOX for Management of Pediatric Spasticity .................................................. 20 
1.3.1 
Use of BOTOX in Pediatric Lower Limb Spasticity ............................... 21 
1.3.2 
Use of BOTOX in Pediatric Upper Limb Pediatric Spasticity ................ 21 
1.4 
Dose Justification ................................................................................................... 22 
2. 
Study Objectives and Clinical Hypotheses ...................................................................... 24 
2.1 
Study Objectives .................................................................................................... 24 
2.2 
Clinical Hypothesis ................................................................................................ 25 
3. 
Study Design .................................................................................................................... 25 
3.1 
Safety Data Review Committee ............................................................................. 28 
4. 
Study Population and Entry Criteria ................................................................................ 28 
4.1 
Number of Patients ................................................................................................. 28 
4.2 
Study Population Characteristics ........................................................................... 28 
4.3 
Inclusion Criteria .................................................................................................... 29 
4.4 
Exclusion Criteria................................................................................................... 31 
4.5 
Permissible and Prohibited Medications/Treatments ............................................. 34 
4.5.1 
Permissible Medications/Treatments ....................................................... 34 
4.5.1.1  Acceptable Contraceptive Methods and Definition of Females of 
Childbearing Potential ................................................................. 34 
4.5.2 
Prohibited Medications/Treatments ......................................................... 35 
4.5.3 
Special Diet or Activities ......................................................................... 36 
5. 
Study Treatments ............................................................................................................. 36 
5.1 
Study Treatments and Formulations ....................................................................... 36 
5.2 
Methods for Blinding ............................................................................................. 36 
5.3 
Method for Assignment to Treatment Groups ........................................................ 36 

 
 
Approval Date: 
 
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Allergan Confidential 
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5.4 
Treatment Regimen and Dosing ............................................................................. 37 
5.4.1 
Treatment Cycle 1 for De Novo Patients ................................................. 37 
5.4.2 
Treatment Cycle 1 for Rollover Patients ................................................. 38 
5.4.3 
Treatment Cycles 2 Through 5 for All Patients (Rollover and De Novo) 38 
5.4.4 
Treatment Regimen/Dosage Adjustment ................................................. 40 
5.4.4.1  Retreatment Criteria ..................................................................... 40 
5.4.5 
Retreatment Visits ................................................................................... 40 
5.5 
Storage of Study Medications/Treatments ............................................................. 41 
5.6 
Preparation of Study Medications/Treatments ....................................................... 41 
5.7 
Treatment Administration ...................................................................................... 41 
6. 
Response Measures and Summary of Data Collection Methods ..................................... 42 
6.1 
Efficacy Measures .................................................................................................. 42 
6.1.1 
Primary Efficacy Measure ....................................................................... 42 
6.2 
Safety Measures ..................................................................................................... 42 
6.3 
Examination Procedures, Tests, Equipment, and Techniques ................................ 42 
6.4 
Other Study Supplies .............................................................................................. 43 
6.5 
Summary of Methods of Data Collection .............................................................. 43 
7. 
Statistical Procedures ....................................................................................................... 44 
7.1 
Analysis Populations .............................................................................................. 44 
7.2 
Collection and Derivation of Primary and Secondary Efficacy Assessments ........ 44 
7.2.1 
Efficacy Variables .................................................................................... 45 
7.2.2 
Primary Efficacy Variable ....................................................................... 45 
7.3 
Hypothesis and Methods of Analysis ..................................................................... 45 
7.3.1 
Efficacy Analyses .................................................................................... 45 
7.3.2 
Safety Analyses ....................................................................................... 46 
7.4 
Subgroup Analyses ................................................................................................. 46 
7.5 
Sample Size Calculation ........................................................................................ 46 
7.6 
Interim Analyses..................................................................................................... 47 
 
 
 
 
 
 
 
 
 
 

 
 
Approval Date: 
 
01-Aug-2016
Allergan Confidential 
Protocol 191622-105 Amendment 4 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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8.4 
Instructions for the Patients .................................................................................... 54 
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 ............................................... 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 
(US 21 CFR Part 11) ............................................................................... 59 
10.2  Changes to the Protocol ......................................................................................... 59 
10.3  Patient Confidentiality ........................................................................................... 60 
10.3.1 
Patient Privacy ......................................................................................... 60 
10.4  Documentation ....................................................................................................... 60 

 
 
Approval Date: 
 
01-Aug-2016
Allergan Confidential 
Protocol 191622-105 Amendment 4 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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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 ....................................................................... 63 
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 ............................................................................................................ 64 
10.9  Coordinating Investigator ...................................................................................... 64 
11.  References ........................................................................................................................ 64 
12.  Attachments ..................................................................................................................... 69 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.2  Package Insert/Summary of Product Characteristics ............................................. 81 
12.3  Glossary of Abbreviations ...................................................................................... 82 
12.4  Protocol Amendment 1 Summary .......................................................................... 84 

 
 
Approval Date: 
 
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Allergan Confidential 
Protocol 191622-105 Amendment 4 
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12.5  Protocol Amendment 2 Summary .......................................................................... 86 
12.6  Protocol Amendment 3 Summary .......................................................................... 91 
12.7  Protocol Amendment 4 Summary .......................................................................... 93 
 
 
 
 
 
 
 
 

 
 
Approval Date: 
 
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Allergan Confidential 
Protocol 191622-105 Amendment 4 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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Protocol Summary 
 
Study Compound: BOTOX® (botulinum toxin type A) purified neurotoxin complex (US Adopted Name is 
onabotulinumtoxinA) 
Phase:  3 
Study Objectives:  To evaluate the long-term safety of repeated doses of BOTOX for the treatment of pediatric 
upper limb spasticity   
Clinical Hypothesis:  Repeated doses of BOTOX (up to 8 U/kg in the upper limb alone and up to 10 U/kg in a 
combination of upper and lower limbs) have an acceptable safety profile for treating pediatric upper limb 
spasticity (with or without treatment in the lower limb)   
Study Design 
Structure:  Multicenter, open-label study  
Duration:  Approximately 60 weeks  
Study Treatment Groups:  BOTOX 
Controls:  None 
Dosage/Dose Regimen (BOTOX doses are expressed per body weight):   
There will be up to 5 treatments in the study.   
For the first treatment cycle, de novo patients (who did not participate in Allergan Study 191622-101) are to 
receive at least 6 U/kg and not to exceed 8 U/kg or 300 U in the affected upper limb (referred to as the study 
upper limb).  Patients with clinically significant lower limb spasticity may be eligible to receive BOTOX 
treatment in affected lower limb(s).  The combined upper and lower limb dose should not exceed 8 U/kg or 300 
U, whichever is lower. 
Rollover patients (who participated in Allergan Study 191622-101), during the first treatment cycle may receive 
up to a maximum of 8 U/kg (not to exceed 300 U) in the same upper limb that was treated in Study 191622-101 
(referred to as the study upper limb).  Patients with clinically significant lower limb spasticity may be eligible to 
receive BOTOX treatment in affected lower limb(s) up to a maximum of 8 U/kg (not to exceed 300 U).  The 
combined upper and lower limb dose should not exceed 8 U/kg or 300 U, whichever is lower, during the first 
cycle. 
For treatment cycles 2 through 5, the maximum dose for the study upper limb only remains the same as in 
treatment cycle 1; the maximum dose for combined upper and lower limbs or for both lower limbs only for 
triplegic patients can be increased to 10 U/kg (not to exceed 340 U). 
If a patient meets the retreatment criteria, including no indication of an unacceptable safety risk, and it is 
considered clinically appropriate by the investigator, the patient should receive at least 6 U/kg in the study 
upper limb every 12 to 14 weeks, with the total dose not to exceed the maximum specified for each treatment 
cycle. 
Randomization/Stratification:   
No randomization or stratification will be performed for this open-label study. 
   
 
 
 
 

 
 
Approval Date: 
 
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Allergan Confidential 
Protocol 191622-105 Amendment 4 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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Study Population Characteristics 
Patients who successfully completed Study 191622-101 without major protocol deviations (eg, noncompliance 
to protocol-required procedures) and have not experienced an adverse event that, in the investigator’s opinion, 
may indicate an unacceptable safety risk for additional BOTOX treatments may be eligible for enrollment in 
this study (referred to as rollover patients).  Patients who became pregnant during Study 191622-101 cannot be 
enrolled in this study.  
Additionally, de novo patients (who did not participate in Study 191622-101) who meet the inclusion criteria 
and do not meet the exclusion criteria may be enrolled in this study. 
Number of Patients:   
Approximately 213 patients will be enrolled. 
Condition/Disease:   
Medically stable monoplegic, hemiplegic, or triplegic pediatric patients with upper limb spasticity involving the 
elbow and/or wrist flexor muscles with single-arm sparing (only 1 arm requiring treatment for spasticity during 
the study) due to cerebral palsy or stroke 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
De novo patients:  
• 
Male or female, 2 to 16 years and 11 months of age (prior to 17th birthday) at the day 1 visit 
• 
Minimum weight of 10 kg at the screening and day 1 visits 
 
 
 
 
 
 
 
 
 
  
 
 

 
 
Approval Date: 
 
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Key Exclusion Criteria (all patients except where noted otherwise): 
 
 
• 
Any medical condition that may put the patient at increased risk with exposure to Botulinum Toxin Type A 
Purified Neurotoxin Complex, including diagnosed muscular dystrophy (eg, Duchenne’s muscular 
dystrophy), myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, mitochondrial 
disease, or any other significant disease that might interfere with neuromuscular function  
 
 
• 
Uncontrolled epilepsy 
 
 
  
 
 
 
 
 
  
 
 
 
• 
Botulinum toxin therapy of any serotype for any condition within 3 months prior to the day 1 visit (de novo 
patients only)  
 
 
 
 
 
 
• 
History of surgical intervention of the study upper limb within 12 months prior to the day 1 visit (de novo 
patients only) or planned surgical intervention of any limb(s) during the study 
 
 

 
 
Approval Date: 
 
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Response Measures 
Safety measures: 
• 
Adverse events 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
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 all treated patients who have at least 1 MAS-B 
score recorded after day 1. 
Safety variables such as the incidence of adverse events
 
 
   
 
 
 
Sample Size Calculation:   
Approximately 213 patients will be enrolled.  The sample size was determined empirically.  

 
 
 
 
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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 

 
 
Approval Date: 
 
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conditions (Hawamdeh et al, 2007).  All of these conditions are associated with significant 
morbidity and mortality and present an unmet medical need with limited treatment options. 
A less prevalent type of disorder associated with pediatric spasticity is stroke.  Information 
on the prevalence of childhood post-stroke spasticity in the 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).  

 
 
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Major drawbacks of systemic anti-spastic therapy include the lack of specificity of targeting 
muscle groups and CNS side effects such as drowsiness, constipation, and cognitive 
impairment.  Local pharmacologic treatments include phenol or alcohol injections for 
specific chemolysis of targeted nerves.  The main risks of phenol are its potential to cause 
irreversible damage to the nerve and nearby structures, as well as reduce sensation and cause 
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 

 
 
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been considerable experience worldwide since the early 1990s with the use of BOTOX in the 
treatment of spasticity associated with cerebral palsy. 
1.3.1 
Use of BOTOX in Pediatric Lower Limb Spasticity 
Allergan has completed 5 trials with BOTOX for the treatment of lower limb spasticity in 
children with cerebral palsy.  These studies have demonstrated an acceptable safety profile of 
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 Pediatric 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 

 
 
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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 
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 of BOTOX treatment in pediatric 
cerebral palsy patients with upper limb spasticity. 

 
 
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The doses selected for this study are supported by Allergan clinical trial experience, clinical 
expert advice, published literature including consensus guidelines for botulinum toxin type A 
treatment of pediatric spasticity, and nonclinical toxicology data.  The pharmacodynamic 
effect of BOTOX is influenced by adjunctive procedures or therapies, such as casting, PT or 
OT, and other pharmacologic treatments.  In addition, in response to the neuromuscular 
blockade of the agonist muscles, the corresponding antagonist muscles could become 
overactive and necessitate the change of dose or the selection of muscles to be injected in 
subsequent treatment cycles.   
In clinical practice, the total dose of BOTOX required for management of the impaired limb 
depends on a variety of factors, including goals of treatment as defined by the patient/family 
and physician, number of muscles to be injected, degree of increased muscle tone, desired 
degree of muscle relaxation to be achieved, and size/dimensions of the muscle(s).  Allergan 
has consulted with clinical experts in the field of pediatric spasticity who have recommended 
doses ranging from 3 to 8 U/kg in a single upper limb as doses within this range are likely to 
be efficacious in reducing spasticity and would allow for individualization of the treatment 
paradigm based on individual patient presentation.   
The doses in this study are supported by the dose ranges described in the published literature.  
All of the randomized, controlled studies in upper limb pediatric spasticity published to date 
utilized 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 do 
not commonly require treatment and are not eligible for injection in the present study.  In a 
study conducted by Pieber et al (2011) doses up to 12 U/kg were used but the dosing details 
are not provided in the publication. 
The doses in the present study are further supported by 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, were 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 

 
 
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multiple muscles of 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 proposed 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 maximum doses 
(U/kg) in the current study.  The international consensus statement published in 2010 
recommended 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 (Fehlings et al, 2010). 
The doses selected for this study are 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.   
In addition to the upper limb injection, this study also allows for injection of affected muscles 
of the lower limb at doses up to 8 U/kg (not to exceed 300 U) if only the lower limb is 
injected or at doses up to 10 U/kg (not to exceed 340 U) if both upper and lower limbs, or 
both lower limbs only in triplegic patients, are injected in treatment cycles 2 through 5 to 
optimize individual treatment.  Based on the consensus guidelines, the maximum total body 
dose of 10 U/kg is an acceptable dose for multilevel treatment. 
Based on the above dose considerations, repeated doses of at least 6 U/kg (maximum 8 U/kg, 
not to exceed 300 U) for the upper limb and up to 8 U/kg (maximum 300 U) for the lower 
limb(s) (not to exceed a maximum total body dose of 10 U/kg or 340 U for upper and lower 
limbs combined or for both lower limbs only in triplegic patients) are considered to be 
appropriate. 
2. 
Study Objectives and Clinical Hypotheses  
2.1 
Study Objectives 
To evaluate the long-term safety of repeated doses of BOTOX for the treatment of pediatric 
upper limb spasticity.   

 
 
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2.2 
Clinical Hypothesis 
Repeated doses of BOTOX (up to 8 U/kg in the upper limb alone and up to 10 U/kg in a 
combination of upper and lower limbs) have an acceptable safety profile for treating pediatric 
upper limb spasticity (with or without treatment in the lower limb). 
3. 
Study Design 
This is a multicenter, open-label study evaluating the safety of repeated treatments of 
BOTOX in pediatric upper limb spasticity.  Patients who successfully completed Allergan 
Study 191622-101 without major protocol deviations (eg, noncompliance to protocol-
required procedures) may be eligible for enrollment in this study (rollover patients) if they 
meet the inclusion criteria and do not meet the exclusion criteria. 
Additionally, de novo patients (who did not participate in Allergan Study 191622-101) who 
meet the inclusion criteria and do not meet the exclusion criteria may be enrolled in this 
study.  Depending on the number of rollover patients from Study 191622-101 and the dropout 
rate for the present study, enrollment of de novo patients may be limited. 
The study duration will be approximately 60 weeks.  The total number of clinic visits will 
depend on the number and timing of treatments received by the patient.  There will be a total 
of approximately 12 clinic visits for de novo patients, approximately 11 clinic visits for 
rollover patients who transitioned from Study 191622-101, and up to 5 telephone follow-up 
visits for all patients.  Qualified rollover patients do not have to be re-screened for the current 
study; the exit visit from Study 191622-101 becomes the day 1 visit for this study after the 
patient signs the Study 191622-105 informed consent and assent (as applicable).  These visits 
allow up to 5 treatment cycles with 12 weeks between treatments.   
The timing of study visits and treatments is shown in Figure 1 and Figure 2.  See Section 5.4 
for a detailed description of the treatment regimen and Section 8 for a detailed description of 
the study visits.  For this study, visits based on day 1 are referred to by “study week” and 
visits based on treatment are referred to by “treatment cycle week.” 
If the patient does not meet the retreatment criteria during the 12-week window, he or she 
may be treated any time up to study week 48 (the last opportunity for retreatment) but should 
be evaluated at least every 6 weeks (calculated from the latest treatment visit date) until he or 
she meets the retreatment criteria or until study week 48.  The exit visit will be study week 48 

 
 
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unless the patient receives treatment after study week 36, in which case the exit visit will be 
12 weeks after the last treatment. 
 

 
 
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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 adverse events data 
throughout the entire duration of the study to ensure the safety of the study participants.  The 
SDRC may elect to review additional safety parameters (eg, laboratory data), or change the 
frequency of their review meetings depending upon emerging safety findings or changes in 
patient enrollment rates.   
For additional details regarding SDRC membership, standard operational procedures, 
frequency of review meetings, and other details, please refer to the SDRC charter. 
4. 
Study Population and Entry Criteria 
4.1 
Number of Patients  
Approximately 213 patients will be enrolled.   
4.2 
Study Population Characteristics 
Medically stable monoplegic, hemiplegic, or triplegic children with upper limb spasticity 
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. 
Patients who successfully completed Allergan Study 191622-101 without major protocol 
deviations (eg, noncompliance to protocol-required procedures) and have not experienced an 
adverse event that, in the investigator’s opinion, may indicate an unacceptable safety risk for 
additional BOTOX treatments may be eligible for enrollment in this study.  Patients who 
became pregnant during Study 191622-101 cannot be enrolled in this study.  
Additionally, de novo patients (who did not participate in Study 191622-101) who meet the 
inclusion criteria and do not meet the exclusion criteria may be enrolled in this study. 

 
 
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4.3 
Inclusion Criteria 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following are inclusion criteria for de novo patients: 
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 
 
 
 
 

 
 
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4.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study for both rollover 
patients and de novo patients unless otherwise specified: 
 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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11. Uncontrolled epilepsy 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
17. Botulinum toxin therapy of any serotype for any condition within 3 months prior to the 
day 1 visit (de novo patients only) 
 
 
 

 
 
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20. History of surgical intervention of the study upper limb within 12 months prior to the 
day 1 visit (de novo patients only) or planned surgical intervention of any limb(s) during 
the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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4.5 
Permissible and Prohibited Medications/Treatments 
4.5.1 
Permissible Medications/Treatments 
Concomitant anti-spastic medications or muscle relaxants will be permitted during the study.  
Patients who are already on concomitant anti-spastic medications or muscle relaxants 
(eg, benzodiazepines, baclofen [oral or pump], scopolamine [oral or patch], tizanidine, 
vigabatrin, or dantrolene) at the time of the day 1 visit will be encouraged to remain on a 
stable dose and regimen during the study; however, dose adjustments to their concomitant 
anti-spastic medications or muscle relaxants will be allowed as clinically indicated.  Initiation 
and adjustment of anti-epileptics will be permitted during the study.  If patient already has an 
intrathecal baclofen pump implanted, intrathecal baclofen therapy is permitted for both de 
novo and rollover patients during the study at the investigator’s discretion. 
Patients will also be permitted to use soft splints, casts and dynamic splints (UltraFlex®, 
DynaSplint®), and constraint therapy 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 (including OT and PT) considered necessary for the patient’s welfare may be given 
at the discretion of the investigator.  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.   

 
 
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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 their 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 representatives 
regarding the importance of maintaining their agreed-upon method of contraception.  A urine 
pregnancy test is required prior to each study treatment for female patients of childbearing 
potential. 
If a female patient of childbearing potential becomes pregnant during the study, the 
investigator will notify Allergan immediately after the pregnancy is confirmed and the patient 
will be exited from the study after appropriate safety follow-up.  The investigator will 
(1) notify the patient’s physician that the patient was being treated with BOTOX and 
(2) follow the progress of the pregnancy.  The investigator must document the outcome of the 
pregnancy and provide a copy of the documentation to Allergan. 
4.5.2 
Prohibited Medications/Treatments 
Patients should not be permitted to initiate the following therapy during the study: 
• Anti-spastic medications or muscle relaxants (eg, benzodiazepines, vigabatrin, 
baclofen [oral or pump], scopolamine [oral or patch], tizanidine, or dantrolene) 
Patients who enter the study on any of the above concomitant medications should remain on 
a stable dose throughout the study to the extent possible unless judged by the investigator to 
be clinically inappropriate. 
In addition, the following treatments or therapy are not permitted during the study: 
• Botulinum toxin therapy of any serotype (outside of the study treatment)  
• Phenol or alcohol injection to the study upper limb 

 
 
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• Planned surgery in any limb(s) 
Co-administration of aminoglycosides or other agents that could interfere with 
neuromuscular transmission (eg, curare-like agents) should only be used with caution as the 
effects of toxin theoretically could be potentiated. 
The decision to administer a prohibited medication/treatment is to be 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  
OT/PT is an important element of the treatment approach in pediatric patients with spasticity.  
While no study-specific OT/PT will be required, patients should follow 
investigator’s/therapist’s recommendations regarding appropriate OT/PT.  OT/PT should 
remain consistent, to the extent possible, throughout the entire duration of the study. 
5. 
Study Treatments  
5.1 
Study Treatments and Formulations 
The study treatment will be BOTOX.  BOTOX 
 contains 100 U 
of Clostridium botulinum toxin type A, 0.5 mg of albumin (human), and 0.9 mg of sodium 
chloride in a sterile, vacuum-dried form without preservative.  The study medication will be 
reconstituted with 2 mL of 0.9% sodium chloride (preservative-free). 
5.2 
Methods for Blinding 
This is an open-label study, and therefore no blinding of the study medication is required. 
5.3 
Method for Assignment to Treatment Groups 
At the screening visit, after the de novo patient and/or legally authorized representative has 
signed the informed consent and minor assent (as applicable), the site will call the interactive 
voice response system (IVRS) or log on to the interactive web response system (IWRS) to 
obtain the patient number that will serve as the patient identification number on all study 
documents.  At the study day 1 visit for both de novo and rollover patients, the site will 
access the IVRS/IWRS to enroll the patient.  Rollover patients transitioning from Allergan 

 
 
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Study 191622-101 will maintain the same patient number that was assigned in that prior 
study.   
Study medication will be labeled with medication kit numbers.  At day 1 and at all 
retreatment visits when the patient qualifies for retreatment, sites will call the IVRS or log 
onto the IWRS to obtain specific study medication kit numbers for each 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 with the study source documents. 
5.4 
Treatment Regimen and Dosing 
Each patient may receive up to 5 treatments during the course of study.  Treatment cycle 1 for 
de novo patients requires identification and injection to the principal muscle group identified 
in the study upper limb.  All other treatments for both rollover and de novo patients allow 
injections to upper limb only, lower limb(s) only, or a combination of upper and lower limbs.  
If a patient meets the retreatment criteria, including no indication of an unacceptable safety 
risk, and it is considered to be clinically appropriate by the investigator, the patient should 
receive at least 6 U/kg in the study upper limb every 12 to 14 weeks, with the total dose not 
to exceed the maximum specified for each treatment cycle. 
5.4.1 
Treatment Cycle 1 for De Novo Patients 
Each de novo patient will have either the elbow flexors or the wrist flexors designated as the 
principal muscle group for analysis purposes.  
 
 
 
 
 
During the first treatment cycle, de novo patients are to receive at least 6 U/kg of BOTOX in 
the study upper limb and all muscles in the principal muscle group must be injected.  That is, 
if elbow is designated as the principal muscle group, biceps, brachialis and brachioradialis 
must be injected; if wrist is designated as the principal muscle group, flexor carpi ulnaris and 
flexor carpi radialis must be injected. 

 
 
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  The total dose 
injected during this cycle should be no more than 8 U/kg (not to exceed 300 U) in the upper 
limb only or in a combination of upper and lower limbs. 
5.4.2 
Treatment Cycle 1 for Rollover Patients  
Patients transitioning from Study 191622-101 will be allowed to receive injections in the 
upper limb, the lower limb(s), or a combination of upper and lower limbs in all cycles, 
including treatment cycle 1.  
 
 
 
5.4.3 
Treatment Cycles 2 Through 5 for All Patients (Rollover and 
De Novo)  
For treatment cycles 2 through 5, the maximum dose for treatment only in the study upper 
limb remains the same as for treatment cycle 1; the maximum dose for combined upper and 
lower limbs or for both lower limbs only for triplegic patients can be increased to 10 U/kg 
(not to exceed 340 U).  Dose limitations by the number of limbs affected are as follows:  
• up to 8 U/kg (not to exceed 300 U) for each treatment session if administered only to 
the study upper limb or only to 1 lower limb,  
• up to 10 U/kg (not to exceed 340 U) if administered to a combination of upper and 
lower limbs, or 
• up to 10 U/kg (not to exceed 340 U) if administered to both lower limbs only (for 
triplegic patients only). 
The dose for each muscle and the total dose will be determined by the investigator.   
 

 
 
 
 
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5.4.4 
Treatment Regimen/Dosage Adjustment 
For all patients enrolled, the dose should be calculated based on patient’s body weight in 
kilograms measured on the day of each treatment/retreatment visit.  For purposes of dose 
calculation only, the patient’s weight will be rounded to the nearest whole kilogram.  If the 
dose by body weight (U/kg x body weight) exceeds the per-muscle dose, the total maximum 
dose for the study upper limb or for the lower limb(s), or the total body maximum units, then 
the maximum dose (“not to exceed” units) should be used.  The dose for each injection site 
should not exceed 50 U. 
5.4.4.1 
Retreatment Criteria  
Patients may be retreated if they meet all of the following criteria on the day of retreatment 
prior to the injection:   
a. 
 
 
b. At least 12 weeks since the last study treatment of BOTOX 
c. Did not experience the following since previous treatment: 
• adverse events of compromised respiratory function, aspiration, difficulty 
swallowing, or clinically significant excessive salivation.  Patients who have 
experienced these adverse events must not receive any further study treatments. 
• an adverse event or excessive weakness that, based on the investigator’s clinical 
judgment, indicates an unacceptable safety risk for additional BOTOX treatments.  
Patients may be re-evaluated for retreatment once the adverse event or muscle 
weakness is resolved.   
• 
 
 
 
d. A negative urine pregnancy test for female patients of childbearing potential 

 
 
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5.5 
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. 
 
 
 
 
5.6 
Preparation of Study Medications/Treatments 
BOTOX (100 U vial) will be reconstituted with 2 mL of preservative-free saline.   
5.7 
Treatment Administration 
Muscle localization techniques such as e-stimulation, sonography, and/or electromyography 
(EMG) are recommended for this study.  The study medication may be administered in 
conjunction with appropriate anesthesia according to each investigator’s standard practice.  
Patients who are planning to undergo general anesthesia should be carefully examined by the 
investigator to ensure that they are suitable candidates for general anesthesia. 

 
 
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6. 
Response Measures and Summary of Data Collection Methods 
6.1 
Efficacy Measures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.1 
Primary Efficacy Measure 
No primary efficacy measure is identified. 
6.2 
Safety Measures 
• Adverse events 
 
  
 
  
 
 
 
 
 
 
 
 
 
6.3 
Examination Procedures, Tests, Equipment, and Techniques  
The procedures are described in Attachment 12.1.   

 
 
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6.4 
Other Study Supplies 
The following study supplies will be provided by Allergan or the vendor contracted by 
Allergan: 
• 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  
• Calibrated temperature recorder for monitoring refrigerator temperatures  
• Syringe labels 
• Goniometer 
• Kilogram-only weight scale for selected sites (weight should be measured and 
collected in kilograms only) 
The study sites will be responsible for providing the following supplies/equipment: 
• Needles and syringes for study drug reconstitution and injection 
• Sterile saline (0.9% without preservative) for study drug reconstitution 
• Surgical gloves for study drug reconstitution 
• 
 
 
• Access to a computer with internet connection (high-speed connection for eCRF 
completion)  
• Standard 12-lead ECG 
• Weight scale with height measure (if not supplied by Allergan) 
• Centrifuge for processing lab samples 
• Ultrasound and/or e-stimulation or EMG device for muscle localization techniques, if 
applicable 
6.5 
Summary of Methods of Data Collection 
An IVRS/IWRS will be used to assign patient numbers for de novo patients and to 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.  

 
 
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For patients ≥ 6 years of age at day 1, the C-SSRS will be conducted 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 lock will occur when all patients have completed the study.  A detailed analysis 
plan will be generated prior to the database lock.  All planned analyses will be performed 
after the database is locked. 
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.  
 
 
  
7.2 
Collection and Derivation of Primary and Secondary Efficacy 
Assessments 
 
 
 
 
 
 
 
 
  The applicable scores, and applicable changes from baseline to 
each follow-up office visit, as well as any applicable response status at each follow-up office 
visit, will be derived.  For rollover patients from Allergan Study 191622-101, an additional 
set of variables using the original baseline values in the previous study will also be derived.  
In addition, the time interval from the injection in Study 191622-101 to the first injection in 
this study will be derived.   

 
 
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7.2.1 
Efficacy Variables  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2.2 
Primary Efficacy Variable 
No primary efficacy variable is identified. 
7.3 
Hypothesis and Methods of Analysis 
There will be no hypothesis testing unless otherwise specified. 
 
 
 
 
 
 
 
 
   
 
 
 
 
 

 
 
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7.3.2 
Safety Analyses 
Safety variables including the incidence of adverse events, 
 
 
 
 
 
  
The incidence of adverse events will be tabulated by primary system organ class and the 
preferred term overall and for each treatment cycle.  
 
 
 
 
 
 
 
 
 
   
 
7.4 
Subgroup Analyses 
The analyses of adverse events will be presented by previous exposure to botulinum toxin, 
type of anesthesia, and age group, if appropriate. 
7.5 
Sample Size Calculation 
Approximately 213 patients will be enrolled.  The sample size was determined empirically 
rather than by sample size calculation. 

 
 
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7.6 
Interim Analyses 
Periodic safety summaries will be provided to the SDRC for review.  In addition, periodic 
safety and efficacy data summaries may be generated for the purpose of study monitoring.  
An interim safety analysis may be performed for regulatory filing, if needed. 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
   
 
  
 
 

 
 
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.  

 
 
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.  

 
 
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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.   

 
 
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8.5 
Unscheduled Visits 
Unscheduled visits can be performed at the discretion of the investigator, eg, for safety 
concerns or for retreatment evaluation (if at least 12 weeks since the last study treatment).  If 
the patient is eligible and receives study treatment, this visit becomes a treatment visit.  
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 postbaseline visit, patients/caregivers will be questioned on concomitant medication 
use and procedures or test 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.  Notification of early 
patient discontinuation from the study and the reason for discontinuation will be made to 
Allergan and be clearly documented on the appropriate eCRF.  Patients who wish to 
discontinue future treatments should be asked to consider returning for the study exit visit.  
The last visit for the patient will be considered the study exit visit.  Procedures identified in 
Table 1 and Table 2 for the exit/early termination visit will be performed if the study exit visit 
occurs earlier than study week 48.   
8.8 
Withdrawal Criteria 
Patients will be withdrawn from the study if they: 
• develop a medically significant hypersensitivity reaction to the study drug such as 
angioedema or anaphylaxis, or 
• become pregnant during the study 
Patients will continue to be followed up for safety until the issue is resolved or the condition 
is stabilized.  Please see Section 4.5.1.1 for follow-up for patients who become pregnant 
during the study. 

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

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

 
 
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9.3 
Procedures for Reporting a Serious Adverse Event 
Any serious adverse event occurring during the study period (beginning with informed 
consent) and for at least 28 days after the last dose of study drug must be immediately 
reported no later than 24 hours after learning of a serious adverse event.  Serious adverse 
events must be reported to Allergan or its designee as listed on the Allergan Study Contacts 
Page and recorded on the serious adverse event form.  All patients with a serious adverse 
event must be followed 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. 
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 (US 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 

 
 
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IRB/IEC of a protocol amendment, except where necessary to eliminate immediate hazards 
to study patients, or when the changes involve only logistical or administrative aspects of the 
study (eg, change in monitors, change of telephone numbers). 
10.3 
Patient Confidentiality 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
patient’s name will not be disclosed in these documents.  The patient’s name may be 
disclosed to the Sponsor of the study, Allergan, or the governing health authorities or the 
FDA if they inspect the study records.  Appropriate precautions will be taken to maintain 
confidentiality of medical records and personal information. 
10.3.1 
Patient Privacy 
Written authorization (US sites only), data protection consent (European sites only), and 
other documentation in accordance with the relevant country and local privacy requirements 
(where applicable) is to be obtained from each patient prior to enrollment into the study, 
and/or from the patient’s legally authorized representative in accordance with the applicable 
privacy requirements (eg, the Health Insurance Portability and Accountability Act Standards 
for Privacy of Individually Identifiable Health Information (“HIPAA”), European Union Data 
Protection Directive 95/46/EC [“EU Directive”]). 
In accordance with HIPAA requirements, additional purposes of this study include the 
following:   
• to publish anonymous patient data from the study; and 
• to create and maintain a data repository 
10.4 
Documentation 
10.4.1 
Source Documents 
Source documents may include a patient’s medical records, hospital charts, clinic charts, the 
investigator’s patient study files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and electrocardiograms.  The investigator’s copy of the case report forms 
serves as part of the investigator’s record of a patient’s study-related data.   

 
 
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The following information should be entered into the patient’s medical record: 
• Patient’s name 
• Patient’s contact information 
• The date that the patient entered the study, patient number, and medication kit number 
• The study title and/or the protocol number of the study and the name of Allergan 
• A statement that informed consent and/or assent, if applicable was obtained 
(including the date).  A statement that written authorization (US sites only), data 
protection consent (EU sites only), or other country and local subject privacy required 
documentation for this study has been obtained (including the date). 
• A statement that patient meets all the inclusion criteria and does not meet any of the 
exclusion criteria.  If a patient does not qualify for the study, a screen failure reason 
should be noted. 
• Dates of all patient visits 
• Medical and surgical history  
• Documentation of results of all procedures conducted during the course of the trial 
including the dose determination process and reason(s) why patient did not meet 
retreatment criteria.  
 
• The results of laboratory tests performed by the site (eg, results of hematology, serum 
chemistry, HbA1c, and urine pregnancy tests) 
• All concurrent medications (list all prescription, non-prescription and herbal 
medications being taken 3 months prior to or at the time of enrollment).  At each 
subsequent visit, changes to the list of medications and concurrent procedures should 
be recorded. 
• Occurrence and status of any adverse events 
• The date the patient exited the study, and a notation as to whether the patient 
completed the study or reason for discontinuation 
10.4.2 
Case Report Form Completion 
The investigator is responsible for ensuring that data are properly recorded in each patient's 
eCRF and related documents.  An investigator who has signed the protocol signature page 
should personally sign for the eCRFs (as indicated in the 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 
 
 
  
 
 

 
 
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10.5.2 
Clinical Supply Inventory 
The investigator must keep an accurate accounting of the number of investigational units 
received from Allergan, dispensed to the patients, and the number of units returned to 
Allergan or Allergan designee during and at the completion of the study.  A detailed 
inventory must be completed for the study medication.  The study medication must be 
reconstituted and administered only by appropriately qualified persons to patients in the 
study.  The medication is to be used in accordance with the protocol under the direct 
supervision of an investigator. 
10.5.3 
Return or Disposal of Study Medications/Treatments and/or 
Supplies 
All clinical study medications/treatments and/or supplies will be returned to Allergan or 
Allergan designee for destruction. 
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, and hematology 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.   

 
 
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10.8 
Publications 
Allergan as the sponsor, has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and 
Allergan personnel.  Authorship will be established prior to the writing of the manuscript.  As 
this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Allergan.   
10.9 
Coordinating Investigator 
A signatory Coordinating Investigator will be designated prior to the writing of the Clinical 
Study Report. 
11. 
References  
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:S121-128. 
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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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. 
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. 
Gracies JM, Elovic E, McGuire J, Simpson D.  Traditional pharmacological treatments for 
spasticity.  Part 1:  Local treatments.  Muscle Nerve Suppl. 1997;7:S61-S91. 
Hawamdeh ZM, Ibrahim AI, Al-Qudah AA.  Long-term effect of botulinum toxin (A) in the 
management of calf spasticity in children with diplegic cerebral palsy.  Eura Medicophys. 
2007;43:311-318. 
Heinen F, Desloovere K, Schroeder AS, Berweck S, Borggraefe I, van Campenhout A, et al.  
The updated European Consensus 2009 on the use of botulinum toxin for children with 
cerebral palsy.  Eur J Paediatr Neurol. 2010;14:45-66. 
Heinen F, Schroeder AS, Fietzek U, Berweck S.  When it comes to botulinum toxin, children 
and adults are not the same: multimuscle option for children with cerebral palsy.  Mov 
Disord. 2006;21:2029-2030. 
Hoare BJ, Wallen MA, Imms C, Villanueva E, Rawicki HB, Carey L.  Botulinum toxin A as 
an adjunct to treatment in the management of the upper limb in children with spastic cerebral 
palsy (UPDATE).  Cochrane Database Syst Rev. 2010;(1):CD003469. 

 
 
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Jethwa A, Jonathan M, Macarthur C, Knights S, Fehlings T, Fehlings D.  Development of the 
Hypertonia Assessment Tool (HAT): a discriminative tool for hypertonia in children.  Dev 
Med Child Neurol. 2010;52:e83-e87.  
Keidan I, Shahar E, Barzilay Z, Passwell J, Brand N.  Predictors of outcome of stroke in 
infants and children based on clinical data and radiologic correlates.  Acta Paediatr. 
1994;83:762-765. 
Koman IA, Smith BP, Evans P, Williams R, Richardson R, Rushing J.  Placebo-controlled, 
double-blind, randomized clinical trial evaluating the effect of botulinum toxin A on upper 
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.   
Lance JW.  Symposium synopsis.  In:  Feldmann RG, Young RR, Koella WP, eds.  Spasticity 
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 
Neurol. 2006;48:533-539. 
Love SC, Valentine JP, Blair EM, Price CJ, Cole JH, Chauvel PJ.  The effect of botulinum 
toxin type A on the functional ability of the child with spastic hemiplegia: a randomized 
controlled trial.  Eur J Neurol. 2001;8(Suppl 5):50-58. 
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.  
Dev Med Child Neurol. 2006;48:170-175. 
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. 

 
 
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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 Klin 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. 
2007;119:e1149-e1158. 
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. 
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. 
von Baeyer CL, Spagrud LJ.  Systematic review of observational (behavioral) measures of 
pain for children and adolescents aged 3 to 18 years.  Pain. 2007;127:140-150.  

 
 
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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  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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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 
 
 
 
BoNT-A 
botulinum neurotoxin type A 
BOTOX® 
botulinum toxin type A purified neurotoxin complex (US Adopted 
Name, onabotulinumtoxinA) 
CFR 
Code of Federal Regulations (US) 
 
 
CNS 
central nervous system 
 
 
D 
day 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMG 
electromyography 
EU 
European Union 
 
 
 
GCP 
Good Clinical Practices 
 
 
 
 
 
 
HbA1c 
glycosylated hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act Standards for 
Privacy of Individually Identifiable Health Information 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
MACS 
Manual Ability Classification System 
 
 
 
 
 
NA 
not applicable 
No. 
number 
NOAEL 
No-observable-adverse-effect level 

 
 
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OT 
occupational therapy 
PT 
physical therapy 
QUEST 
Quality of Upper Extremity Skills Test 
 
 
 
 
 
 
Scrn 
screening 
SDRC 
Safety Data Review Committee 
Tx 
treatment 
U 
unit, corresponding to the median lethal dose (LD50) in mice 
US 
United States 
V1 
slow velocity 
V3 
fast velocity 
Wk 
week 
 

 
 
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12.4 
Protocol Amendment 1 Summary 
Title:  BOTOX® Treatment in Pediatric Upper Limb Spasticity:  Open-label Study 
Protocol 191622-105, Amendment 1 
Date of Amendment:  30 March 2012 
Amendment Summary 
This summary includes changes made to Protocol 191622-105 (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 
 
 
 
 
 
 
 
 
 
8.3.1, 
 
 
 
 
 
 
 
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. 

 
 
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Section(s) 
Revision 
Rationale 
 
 
 
 
 
 
 

 
 
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12.5 
Protocol Amendment 2 Summary 
Title:  BOTOX® Treatment in Pediatric Upper Limb Spasticity:  Open-label Study 
Protocol 191622-105, Amendment 2 
Date of Amendment:  7 December 2012 
Amendment Summary 
This summary includes changes made to Protocol 191622-105 Amendment 1 (e-signature 
date 02 April 2012) to provide clarifications 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.  Underlining is used to identify wording that 
has been added and strikethrough for wording that has been deleted.  Minor editorial and 
document formatting revisions have not been summarized. 
Section(s) 
Revision 
Rationale 
Summary 
Changes corresponding to those 
identified below in the body were 
made to the Summary section. 
For consistency within the 
protocol 
 
 
 
 
 
 
1.4, Dose Justification  
5.4, Treatment Regimen 
and Dosing 
Table 3 
Added wording for a combination 
of only both lower limbs for 
triplegic patients  
Allows a dose up to 
10 U/kg and not to exceed 
340 U to be injected 
during treatment cycles 2 
to 5 when only both lower 
limbs are treated. 
3, Study Design 
Replaced details regarding dosing 
with a cross reference to 
Section 5.4, Treatment Regimen 
and Dosing 
To consolidate dosing 
information in a clearly 
designated section. 

 
 
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Section(s) 
Revision 
Rationale 
4.4, Exclusion Criteria 
Changed #21 regarding history of 
fracture in the study upper limb 
within 12 months from “prior to the 
screening visit” to “prior to the 
day 1 visit.” 
For consistency with other 
criteria 
4.5.2, Prohibited 
Medications/Treatments 
Added to the wording that requires 
a patient to remain on a stable dose 
of anti-spastic medications: to the 
extent possible unless judged by the 
investigator to be clinically 
inappropriate.  
For clarification 
5.3, Method for 
Assignment to Treatment 
Groups 
Added At the study day 1 visit for 
both de novo and rollover, the site 
will access the IVRS/IWRS to 
enroll the patient; 
For clarification 
5.4, Treatment Regimen 
and Dosing 
At the beginning of 5.4, replaced 
similar wording that was in 5.4.2 
and 5.4.3 with:  If a patient meets 
the retreatment criteria, including 
no indication of an unacceptable 
safety risk, and it is considered to 
be clinically appropriate by the 
investigator, the patient should 
receive at least 6 U/kg in the study 
upper limb every 12 to 14 weeks, 
with the total dose not to exceed the 
maximum specified for each 
treatment cycle.  
For clarification 
5.4.3, Treatment Cycles 2 
Through 5 for All 
Patients (Rollover and 
De Novo) 
Revised description of dose 
limitations  
For clarification 

 
 
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Section(s) 
Revision 
Rationale 
 
 
 
 
 
 
5.4.4, Treatment 
Regimen/Dosage 
Adjustment 
Added For purposes of dose 
calculation, the patient’s weight 
will be rounded to the nearest 
whole kilogram.   
For clarification 
5.4.4.1, Retreatment 
Criteria 
 
Revised to “Patients should may be 
retreated” if they meet the 
retreatment criteria. 
For clarification 
5.4.5, Retreatment Visits 
Deleted sentence regarding dose 
(because that is specified in 
Section 5.4.3).  Revised the last 
sentence to “…determine if the 
patient will be eligible for 
retreatment and if the above-
mentioned dosing regimens are 
clinically appropriate for the patient 
or dose reduction relative to the last 
injection received is required. 
For clarification 
6.4, Other Study Supplies For the calibrated temperature 
recorder, deleted mention of freezer 
temperatures. 
Only refrigerator monitors 
are needed and will be 
supplied. 
 
In addition to ultrasound and/or 
e-stimulation, added EMG device 
for muscle localization, if 
applicable 
For clarification 
 
 
 
 
 

 
 
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Section(s) 
Revision 
Rationale 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
8.8, Withdrawal Criteria 
 
Added that patients will be 
withdrawn from the study if they 
develop a medically significant 
hypersensitivity reaction to the 
study drug such as angioedema or 
anaphylaxis, or if a patient becomes 
pregnant during the study. 
For clarification 
 
 
 
 
 
 

 
 
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Section(s) 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 

 
 
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12.6 
Protocol Amendment 3 Summary 
Title:  BOTOX® Treatment in Pediatric Upper Limb Spasticity:  Open-label Study 
Protocol 191622-105, Amendment 3 
Date of Amendment:  January 2014 
Amendment Summary 
This summary includes changes made to Protocol 191622-105 Amendment 2 (e-signature 
date 11 December 2012).  
 
 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.1 
Changed “members” to “participants” and 
removed “or investigator” from the examples 
given of ad hoc SDRC participants 
Clarification 
 
 
 
 
 
 
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 27 to exclude 
patients with significant suicidality from 
treatment 
To avoid confounding the 
safety data 

 
 
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Section(s) 
Revision 
Rationale 
 
 
  
 
 
4.5.1 
Added a sentence on use of anti-epileptics  
Clarification that anti-
epileptics are permissible 
during the study 
5.4.4.1 
Amended bullet (c) of the retreatment criteria 
To specify that patients who 
experience certain adverse 
events will not receive 
further study treatments 
5.4.5 
Revised paragraph regarding retreatment for 
patients with adverse events of compromised 
respiratory function, aspiration, difficulty 
swallowing, or clinically significant excessive 
salivation  
To specify that patients who 
experience these adverse 
events will not receive 
further study treatments 
6.4 
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 
 
 
 
 
 
  
  
 
 
 
 
9.3 
Updated serious adverse event language 
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 
 
 
 
 
 
12.1.13; 12.1.14 
Amended “investigator” to “physician 
investigator” 
Clarification 
 

 
 
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12.7 
Protocol Amendment 4 Summary 
Title:  BOTOX® Treatment in Pediatric Upper Limb Spasticity:  Double-blind Study 
Protocol 191622-105, Amendment 4 
Date of Amendment:  July 2016 
Amendment Summary 
This summary includes changes made to Protocol 191622-105 Amendment 3 (January 2014).  
This protocol was amended to decrease the sample size. 
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 enroll in 
study was decreased from 350 to 213 
Based on decreased number 
of completers from DBPC 
study due to adjusted 
treatment differences from 
upper limb studies. 
Protocol Summary; 
7.5 (sample size 
calculation) 
Number of patients was revised from 350 to 
213.  
Based on decreased number 
of completers from DBPC 
study