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

 
NCT01603641 
 
Study ID: 191622-112 
 
Title: BOTOX® Treatment in Pediatric Lower Limb Spasticity: Open-label Study 
 
Protocol Amendment 3 Date: 28 January 2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Approval Date: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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Title Page 
ALLERGAN – CONFIDENTIAL 
The following contains confidential, proprietary information  
which is the property of Allergan 
STUDY TITLE 
BOTOX® Treatment in Pediatric Lower Limb Spasticity:  Open-label Study 
 
Protocol Number:   
191622-112 Amendment 3 
EudraCT Number: 
2012-000084-24 
Phase: 
3 
Name of Investigational Product: 
BOTOX® (botulinum toxin type A) purified 
neurotoxin complex (US Adopted Name is 
onabotulinumtoxinA) 
Sponsor: 
 
Allergan (North 
America) 
2525 Dupont Drive 
Irvine, California USA
92612 
+1-714-246-4500 
+1-800-347-4500 
Allergan Ltd. 
1st Floor, Marlow 
International, 
The Parkway, Marlow 
Buckinghamshire 
SL7 1YL United Kingdom 
Tel: +44 (0) 1628 494444 
Fax: +44 (0) 1628 494449 
Emergency Telephone Number(s): 
Refer to the Study Contacts Page. 
 
 
   
 
 
 
  
  
 

 
 
Approval Date: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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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: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
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: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
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 ................................................................................. 20 
1.1 
Pediatric Spasticity ................................................................................................. 20 
1.2 
Management of Spasticity in Children ................................................................... 21 
1.3 
BOTOX for Management of Pediatric Spasticity .................................................. 22 
1.3.1 
Use of BOTOX in Pediatric Lower Limb Spasticity ............................ 22 
1.4 
Dose Justification ................................................................................................... 23 
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................................................................................................... 30 
4.5 
Permissible and Prohibited Medications/Treatments ............................................. 34 
4.5.1 
Permissible Medications/Treatments..................................................... 34 
4.5.2 
Prohibited Medications/Treatments....................................................... 36 
4.5.3 
Special Diet or Activities ....................................................................... 37 
5. 
Study Treatments ............................................................................................................. 37 
5.1 
Study Treatments and Formulations ...................................................................... 37 
5.2 
Methods for Blinding ............................................................................................. 37 
5.3 
Method for Assignment to Treatment Groups ........................................................ 37 
5.4 
Treatment Regimen and Dosing ............................................................................. 38 
5.4.1 
Treatment Cycle 1 for De Novo Patients ............................................... 38 

 
 
Approval Date: 
 
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Allergan Confidential 
Protocol 191622-112 Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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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 ............................................... 41 
5.4.5 
Retreatment Visits ................................................................................. 41 
5.5 
Storage of Study Medications/Treatments ............................................................. 42 
5.6 
Preparation of Study Medications/Treatments ....................................................... 42 
5.7 
Treatment Administration ...................................................................................... 42 
6. 
Response Measures and Summary of Data Collection Methods ..................................... 43 
6.1 
Efficacy Measures .................................................................................................. 43 
6.1.1 
Primary Efficacy Measure ..................................................................... 43 
6.1.2 
Safety Measures .................................................................................... 43 
6.2 
Examination Procedures, Tests, Equipment, and Techniques ................................ 43 
6.3 
Other Study Supplies ............................................................................................. 44 
6.4 
Summary of Methods of Data Collection .............................................................. 44 
7. 
Statistical Procedures ....................................................................................................... 45 
7.1 
Analysis Populations .............................................................................................. 45 
7.2 
Collection and Derivation of Primary and Secondary Efficacy Assessments ........ 45 
7.2.1 
Efficacy Variables .................................................................................. 46 
7.2.2 
Primary Efficacy Variable(s) ................................................................. 46 
7.3 
Hypothesis and Methods of Analysis ..................................................................... 46 
7.3.1 
Efficacy Analyses .................................................................................. 46 
7.3.2 
Safety Analyses ..................................................................................... 47 
7.4 
Subgroup Analyses ................................................................................................. 48 
7.5 
Sample Size Calculation ........................................................................................ 48 
7.6 
Interim Analyses..................................................................................................... 48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Approval Date: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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8.4 
Instructions for the Patients .................................................................................... 58 
8.5 
Unscheduled Visits ................................................................................................. 58 
8.6 
Compliance with Protocol ...................................................................................... 58 
8.7 
Early Discontinuation of Patients .......................................................................... 58 
8.8 
Withdrawal Criteria ................................................................................................ 59 
8.9 
Study Termination .................................................................................................. 59 
9. 
Adverse Events ................................................................................................................ 59 
9.1 
Definitions .............................................................................................................. 59 
9.1.1 
Adverse Event ....................................................................................... 59 
9.1.2 
Serious Adverse Event .......................................................................... 60 
9.1.3 
Severity .................................................................................................. 60 
9.1.4 
Relationship to Study Drug or Study Procedure ................................... 61 
9.2 
Procedures for Reporting Adverse Events ............................................................. 61 
9.3 
Procedures for Reporting a Serious Adverse Event ............................................... 61 
10.  Administrative Items ....................................................................................................... 62 
10.1  Protection of Human Subjects ................................................................................ 62 
10.1.1 
Compliance with Informed Consent Regulations (US 21 CFR Part 50) 
and Relevant Country Regulations ........................................................ 62 
10.1.2 
Compliance With IRB or IEC Regulations ........................................... 62 
10.1.3 
Compliance With Good Clinical Practice ............................................. 63 
10.1.4 
Compliance With Electronic Records; Electronic Signatures Regulations 
(US 21 CFR Part 11) ............................................................................. 63 
10.2  Changes to the Protocol ......................................................................................... 63 
10.3  Patient Confidentiality ........................................................................................... 63 
10.3.1 
Patient Privacy ....................................................................................... 63 
10.4  Documentation ....................................................................................................... 64 
10.4.1 
Source Documents ................................................................................. 64 
10.4.2 
Case Report Form Completion .............................................................. 65 
10.4.3 
Study Summary ..................................................................................... 65 
10.4.4 
Retention of Documentation ................................................................. 65 

 
 
Approval Date: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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10.5  Labeling, Packaging, and Return or Disposal of Study Medications/Treatments . 66 
10.5.1 
Labeling/Packaging ............................................................................... 66 
10.5.2 
Clinical Supply Inventory ..................................................................... 66 
10.5.3 
Return or Disposal of Study Medications/Treatments and/or Supplies 66 
10.6  Monitoring by the Sponsor .................................................................................... 66 
10.7  Handling of Biological Specimens......................................................................... 67 
10.8  Publications ............................................................................................................ 67 
10.9  Coordinating Investigator ...................................................................................... 67 
11.  References ........................................................................................................................ 67 
12.  Attachments ..................................................................................................................... 71 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.2  Package Insert/Summary of Product Characteristics ............................................. 82 
12.3  Glossary of Abbreviations ...................................................................................... 83 
12.4  Protocol Amendment 1 Summary .......................................................................... 85 
12.5  Protocol Amendment 2 Summary .......................................................................... 87 
12.6  Protocol Amendment 3 Summary .......................................................................... 93 
 

 
 
Approval Date: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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Approval Date: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
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, 
onabotulinumtoxinA)  
Phase:  3 
Study Objectives:  To evaluate the long-term safety of repeated doses of BOTOX for the treatment of pediatric 
lower limb spasticity 
Clinical Hypothesis:  Repeated doses of BOTOX (up to 8 U/kg in the lower limb alone, up to 10 U/kg in a 
combination of both lower limbs, or up to 10 U/kg in a combination of upper and lower limbs) have an 
acceptable safety profile for treating pediatric lower limb spasticity (with or without treatment in the upper 
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 191622-111) 
are to receive a total of 8 U/kg (not to exceed 300 U) either in a single affected lower limb or divided 
between both study limbs (referred to as the study lower limb or study lower limbs). 
Rollover patients (who participated in Allergan Study 191622-111) during the first treatment cycle 
may receive up to a maximum of 8 U/kg (not to exceed 300 U) in the same lower limb that was treated 
in Study 191622-111 (referred to as the study lower limb).  Patients with clinically significant upper 
limb spasticity may be eligible to receive BOTOX treatment in an affected upper limb up to a 
maximum of 8 U/kg (not to exceed 300 U).  The combined lower and upper 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 a single lower limb or a single 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 diplegic 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 4 U/kg in the 
study lower limb(s) 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. 
 
 
 
 
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Approval Date: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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Study Population Characteristics 
Patients who successfully completed Study 191622-111 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 191622-111 cannot be enrolled in this study.  
Additionally, de novo patients (who did not participate in Study 191622-111) who meet inclusion 
criteria and do not meet the exclusion criteria may be enrolled in this study. 
Number of Patients:   
Approximately 350 patients will be enrolled.  
Condition/Disease:   
Medically stable monoplegic, hemiplegic, or diplegic pediatric patients with cerebral palsy who have 
dynamic muscle contracture of the ankle plantar flexors associated with equinus foot position 
Key Inclusion Criteria:   
Rollover patients:  
• 
Eligible patients who successfully completed Allergan Study 191622-111 without major protocol 
deviations (eg, noncompliance to protocol-required procedures) and who, in the investigator’s 
clinical judgment, did not experience an adverse event that may indicate an unacceptable safety 
risk for additional BOTOX treatments 
• 
Stable medical condition in the investigator’s opinion 
• 
Written informed consent has been obtained from parent/legally authorized representative 
• 
Written minor assent has been obtained in accordance with local laws and institutional review 
board (IRB)/independent ethics committee (IEC) requirements 
• 
Written documentation has been obtained in accordance with the relevant country and local 
privacy requirements, where applicable (eg, Written Authorization for Use and Release of Health 
and Research Study Information for United States [US] sites and written Data Protection consent 
for European Union [EU] sites) 
• 
Negative urine pregnancy test at day 1 visit (for females of childbearing potential, defined as 
females post menarche) 
De novo patients: 
 
 
• 
Minimum weight of 10 kg at the screening and day 1 visits 
• 
Monoplegic, hemiplegic, or diplegic patients with cerebral palsy with dynamic muscle contracture 
(spasticity confirmed by Hypertonia Assessment Tool [HAT]) of the ankle plantar flexors.  
Equinovarus and equinovalgus deformities are acceptable. 
 
 
 
 
 
 
 
 

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

 
 
Approval Date: 
 
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• 
History of surgical intervention of the lower leg (the knee and below of the study limb[s]) within 
12 months prior to the day 1 visit (de novo patients only) or planned surgical intervention of any 
limb(s) during the study 
 
  
 
 
 
 
 
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. 
 
  
Safety variables such as the incidence of adverse events, 
 
 
 

 
 
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Sample Size Calculation:  
Approximately 350 patients will be enrolled.  The sample size was determined empirically. 
 

 
 
 
Approval Date: 
 
28-Jan-2014
Allergan Confidential 
 
Protocol 191622-112 Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
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Approval Date: 
 
28-Jan-2014
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28-Jan-2014
Allergan Confidential 
 
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Allergan Confidential 
 
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Approval Date: 
 
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1. 
Background and Clinical Rationale 
1.1 
Pediatric Spasticity 
Spasticity is classically defined as a disorder of the sensorimotor system characterized by a 
velocity-dependent increase in muscle tone with exaggerated tendon jerks, resulting from 
hyperexcitability of the stretch reflex (Lance, 1980).  The most common cause of focal 
spasticity in children is cerebral palsy.  Cerebral palsy is a disorder caused by a 
non-progressive insult of the central nervous system (CNS) that occurs prenatally, perinatally, 
or during the first 2 years of life and can result in functional motor impairment, irregular 
movement, and abnormal posture.  The increase in the muscle-stretch reflex causes muscle 
contraction of abnormal strength and duration.  Spastic muscles show “velocity-dependent” 
resistance to passive movement and exaggerated tendon jerks (Lance, 1980). 
The patterns of spasticity depend on the areas of the developing brain that are damaged.  In 
patients with hemiplegic spasticity, one half of the body (1 arm and 1 leg) is affected with 
spasticity.  Approximately 25% of children with cerebral palsy present with hemiplegic 
spasticity in which the upper limb is usually more affected than the lower limb 
(Stanley et al, 2000).  Spastic diplegia, presented in about 13% to 30% of patients with 
cerebral palsy, is characterized by spasticity of both legs with relative sparing of the arms 
(Odding et al, 2006; Stanley et al, 2000).  Although the arms are less affected, they may still 
show abnormal reflexes and reduced dexterity.  Spastic triplegia is characterized by spasticity 
affecting both lower extremities and 1 arm is usually affected more severely than the other.  
Spastic quadriplegia affects all 4 limbs and is the most severe but least common form of 
spastic cerebral palsy, affecting approximately 20% of patients.  Since both cerebral 
hemispheres are affected, intellectual impairment is common.  Patients with quadriplegia 
may also have severe dysarthria, dysphagia, and other comorbidities such as epilepsy and 
blindness.  Spasticity and abnormal muscle tone contribute both to impairment of function 
and reduced longitudinal muscle growth in children with cerebral palsy (Dunne et al, 1995).   
Cerebral palsy is the most common etiology associated with pediatric spasticity with a 
prevalence rate of approximately 2.5 in 1000 live births, a number that has increased from 
1.5 in 1000 live births 40 years ago (Odding et al, 2006) and is considered to be the most 
severe childhood physical disability (Beckung and Hagberg, 2002).  Essentially all patients 
with cerebral palsy have impaired motor function with spasticity affecting as many as 90%.  
Other less prevalent types of disorders associated with pediatric spasticity include 
posttraumatic brain or spinal cord injury, multiple sclerosis, and other neurodegenerative 

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

 
 
Approval Date: 
 
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dysesthesias and neuropathic pain (Gracies et al, 1997).  Intrathecal baclofen is reserved for 
patients with disabling general spasticity that is unresponsive to conservative 
pharmacotherapy (Koman et al, 2004). 
Orthopedic procedures such as contracture release, tendon lengthening, and tendon transfer 
can reduce spasticity symptoms that may result in improved access for hygiene and brace 
(orthotic) tolerability.  These surgical procedures may also result in pain reduction, as well as 
reduction in bone deformity (osteotomy).  However, many forms of surgery are best delayed 
until tendons and joints have grown to a reasonable proportion of their adult size since it is 
more difficult to predict the outcome of surgery in younger children.  Surgical procedures 
have been reported as delayed due to the ability of botulinum toxin (type A) therapy to 
minimize fixed muscle shortening and soft tissue and skeletal deformation and reduce pain 
associated with spasticity (Molenaers et al, 2006). 
Neurosurgical procedures include selective dorsal rhizotomy and selective peripheral 
neurotomy (Chambers, 1997; Steinbok, 2006).  Selective dorsal rhizotomy is used to treat 
severe spasticity of the lower extremities that interferes with mobility or positioning.  It is 
usually most effective in a small number of select diplegic or quadriplegic children with 
cerebral palsy who are expected to be independent ambulators.  In children with underlying 
muscle weakness, rhizotomy can worsen rather than improve function. 
1.3 
BOTOX for Management of Pediatric Spasticity 
Botulinum neurotoxin type A (BoNT-A) blocks neuromuscular conduction by binding to 
receptor sites on motor nerve terminals, entering the nerve terminals, and inhibiting the 
release of acetylcholine.  When injected intramuscularly at therapeutic doses, BoNT-A 
produces localized chemical denervation of the muscle, resulting in focal muscle weakness.  
This muscle weakness is reversible through nerve ending recovery over a period of 3 or more 
months.  Relaxation of rigid muscles by BoNT-A allows a child to participate in PT or OT, 
which encourages the use of both targeted and antagonistic muscles with goals of muscle 
stretching, strengthening, improved motor control, and acquisition of new skills.  There has 
been considerable experience worldwide since the early 1990s with the use of BOTOX in the 
treatment of spasticity associated with cerebral palsy. 
1.3.1 
Use of BOTOX in Pediatric Lower Limb Spasticity 
Allergan has completed 5 trials with BOTOX for the treatment of lower limb spasticity in 
children with cerebral palsy.  These studies have demonstrated an acceptable safety profile of 
BOTOX at the dose ranges evaluated for this patient population.  Study OCUL-118-8051, a 

 
 
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placebo-controlled study, included 145 patients (72 BOTOX; 73 placebo) with equinus foot 
deformity who were 2 to 14 years old.  Patients received injections of BOTOX (4 to 8 U/kg; 
note that BOTOX doses throughout this protocol are expressed per body weight) or placebo.  
The proportion of responders based on gait pattern score was significantly greater (p ≤ 0.05) 
in the BOTOX group compared to the placebo group at weeks 2, 8, and 12.   
Study OCUL-119-8051, an open-label multiple-treatment extension of Study 
OCUL-118-8051, included 207 patients who received injections of BOTOX at 4 U/kg.  For 
the first 2 years of the study the proportion of responders ranged from 39% to 64%.   
Study OCUL-120-8051, a placebo-controlled study, included 35 ambulatory patients with 
equinus foot deformity (17 BOTOX; 18 placebo) who were 2 to 14 years old.  Patients 
randomized to BOTOX received 4 U/kg in the affected limb.  The proportion of responders 
based on gait pattern score was significantly greater (p ≤ 0.05) in the BOTOX group 
compared to the placebo group at weeks 8 and 12.  Twenty-five of the 35 patients entered a 
2-year, multiple-treatment open-label follow-up study (BTOX-121-8051).   
The fifth study (191622-021), a placebo-controlled study, included 149 patients with equinus 
foot deformity (73 BOTOX; 76 placebo) who were 2 to 8 years old.  Patients randomized to 
BOTOX received 4 U/kg in each affected limb (up to a maximum of 8 U/kg).  No significant 
differences in the proportion of responders based on the gait pattern score were observed 
between the 2 treatment groups.  
1.4 
Dose Justification 
The purpose of this study is to further investigate the safety of BOTOX treatment in pediatric 
patients with cerebral palsy who have dynamic muscle contracture of the ankle plantar 
flexors associated with equinus foot position. 
The maximum lower limb dose in a single limb selected for this study corresponds to the 
maximum dose group (8 U/kg) from the efficacy Study 191622-111.  This dose is supported 
by Allergan clinical trial experience in pediatric lower limb spasticity, clinical expert advice, 
published literature including consensus guidelines for botulinum toxin type A treatment of 
pediatric spasticity, and nonclinical toxicology data. 
The doses for lower limb treatment used in the present study are supported by the dose 
ranges described in the consensus guidelines and published literature.  The European 
consensus paper (Heinen et al, 2010) recommended a dose range of 1 to 20 U/kg with a 
maximum total dose of 400 U, regardless of location of injection.  The American Academy of 

 
 
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Neurology also concluded that botulinum toxin doses ranging from 2 to 30 U/kg for 
treatment of the upper and lower limbs are effective and generally safe (Delgado et al, 2010).  
The 2010 International Consensus Paper for botulinum toxin treatment in lower limb 
spasticity for children with cerebral palsy recommends a dose range of 16 to 20 U/kg for 
patients with Gross Motor Function Classification System – Expanded and Revised 
(GMFCS-E&R) level I to IV without risk factors (Love et al, 2010).  The higher dose ranges 
were based on studies allowing injections to multiple muscles (multi-level injections) across 
upper and lower extremities (Heinen et al, 2006; Molenaers et al, 2009).   
Doses recommended for individual muscles are 3 to 6 U/kg for gastrocnemius, 2 to 3 U/kg 
for soleus, and 1 to 2 U/kg for tibialis posterior (Russman et al, 2008).  In published double-
blind studies in pediatric patients with lower limb spasticity, a dose of 2 to 8 U/kg was most 
commonly used for the gastrocnemius muscles.  The maximum dose ranged from 200 to 
600 U for both legs.  Doses used in Study 191622-111 and the present study are consistent 
with the range of doses recommended by the consensus documents and reflect current 
clinical practice. 
In addition, the safety of 10 U/kg for combined treatment of the lower limb and upper limb or 
both lower limbs in this study is also supported by the no-observable-adverse-effect levels 
(NOAELs) established in BOTOX toxicology studies.  In single and repeated-dose studies in 
rats, 10 and 16 U/kg were defined as NOAELs, respectively.  In monkeys, the single-dose 
intramuscular NOAEL was determined to be 16 U/kg when administered into the 
gastrocnemius muscle.  In repeated-dose toxicity studies in monkeys involving multiple 
injection sites that more closely mimic clinical use, the NOAEL was 8, 12, or 16 U/kg for 2, 
4, or 6 injection sites, respectively. 
Based on the above dose considerations, doses of up to 8 U/kg (maximum 300 U) for one 
lower limb, up to 10 U/kg (maximum 340 U) for both lower limbs, and up to 8 U/kg 
(maximum 300 U) for the upper limb (not to exceed a maximum total body dose of 10 U/kg 
or 340 U for upper and lower limbs combined) 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 
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2.2 
Clinical Hypothesis 
Repeated doses of BOTOX (up to 8 U/kg in the lower limb alone, up to 10 U/kg in a 
combination of both lower limbs, or up to 10 U/kg in a combination of upper and lower 
limbs) have an acceptable safety profile for treating pediatric lower limb spasticity (with or 
without treatment in the upper limb). 
3. 
Study Design 
This is a multicenter, open-label study evaluating the safety of repeated treatments of 
BOTOX in dynamic muscle contracture in pediatric patients with lower limb spasticity due 
to cerebral palsy.  Patients who successfully completed Allergan Study 191622-111 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 191622-111) who 
meet inclusion criteria and do not meet the exclusion criteria may be enrolled in this study.  
Depending on the number of rollover patients from Study 191622-111 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 191622-111, 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 191622-111 becomes the day 1 visit for this study after the 
patient signs the Study 191622-112 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- to 14-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 

 
 
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study week 48 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 350 patients will be enrolled.   
4.2 
Study Population Characteristics 
The study population is medically stable monoplegic, hemiplegic, or diplegic pediatric 
patients with cerebral palsy who have dynamic muscle contracture of the ankle plantar 
flexors associated with equinus foot position. 
Patients who successfully completed Allergan Study 191622-111 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 191622-111 cannot be enrolled in this study.  
Additionally, de novo patients (who did not participate in Study 191622-111) who meet 
inclusion criteria and do not meet 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 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: 
 
 

 
 
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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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13. Uncontrolled epilepsy 
 
 
 
  
 
 
 
  
 
 
 
   
 
 
 
 
  
 
 
 
  
 
 
 
 
 
   
19. 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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22. History of surgical intervention of the lower leg (the knee and below of the study 
limb[s]) within 12 months prior to the day1 visit (de novo patients only) or planned 
surgical intervention of any limb(s) during the study 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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, oral baclofen, scopolamine [oral or patch], tizanidine, vigabatrin, or 

 
 
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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®) 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. 
For females of childbearing potential who may participate in the study, the following 
methods of contraception, if properly used, are generally considered reliable:  oral 
contraceptives, patch contraceptives, injection contraceptives, implantable contraceptives, 
male condom with intravaginal spermicide, diaphragm or cervical cap with spermicide, 
vaginal contraceptive ring, intrauterine device, surgical sterilization (bilateral tubal ligation 
or removal of both ovaries), vasectomized partner, or sexual abstinence. 
The investigator and each patient (and/or her legally authorized representative) will 
determine the appropriate method of contraception for the patient during the participation in 
the study.  The method of contraception must be documented in the patient’s medical record 

 
 
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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 lower limb 
• 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 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. 

 
 
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4.5.3 
Special Diet or Activities 
PT/OT is an important element of the treatment approach in pediatric patients with spasticity.  
While no study-specific PT/OT will be required, patients should follow 
investigator’s/therapist’s recommendations regarding appropriate PT/OT.  PT/OT 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.  
 
 
 
 
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 
Study 191622-111 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 where the patient qualifies for reinjection, 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. 

 
 
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5.4 
Treatment Regimen and Dosing 
Each patient may receive up to 5 treatments during the course of study.  The dose for each 
muscle and total dose will be calculated.  
 
  
 
 
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 4 U/kg in the study lower limb(s) 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 
During the first treatment cycle, de novo patients are to receive a total of 8 U/kg (not to 
exceed 300 U) either in a single study lower limb or divided between both study lower limbs 
only for diplegic patients.  
5.4.2 
Treatment Cycle 1 for Rollover Patients  
Patients transitioning from Study 191622-111 will be allowed to receive injections in the 
upper limb, the lower limb, 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 a single lower 
limb or 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 diplegic 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 
one lower limb or only to one upper limb or 

 
 
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• up to 10 U/kg (not to exceed 340 U) if administered to both lower limbs for diplegic 
patients or  
• up to 10 U/kg (not to exceed 340 U) if administered to a combination of upper and 
lower limbs 
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, 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 lower limb(s) or upper limb, 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 reinjected if they meet all of the following criteria on the day of retreatment 
prior to the injection:   
 
 
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 
Muscles localization techniques such as e-stimulation, sonography, and/or electromyography 
(EMG) are recommended for this study.  Motor endplate targeting injection techniques are 
recommended (Van Campenhout and Molenaers, 2011). 
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 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
6.1.1 
Primary Efficacy Measure 
No primary efficacy measure is identified. 
 
 
• 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Examination Procedures, Tests, Equipment, and Techniques  
The procedures are described in Attachment 12.1.   

 
 
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6.4 
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 

 
 
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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.  Blood samples for 
immunogenicity tests will be shipped by the central laboratory, analyzed by a specialty 
laboratory using validated assays, and the data will be transferred to Allergan or enter to the 
eCRF. 
7. 
Statistical Procedures 
The database lock will occur when all patients have completed the study and all data except 
immunogenicity data have been cleaned.  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, applicable changes from baseline to 

 
 
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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 191622-111, an additional set 
of variables using the original baseline values in the previous study will also derived.  In 
addition, the time interval from the injection in Study 191622-111 to the first injection in this 
study will be derived. 
 
  
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
7.2.2 
Primary Efficacy Variable(s) 
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.  
 
 
 
 
 
 
 
 
 
 
 
   
 
   
 

 
 
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7.4 
Subgroup Analyses 
The safety analyses for all adverse events will be presented by age, previous exposure to 
botulinum toxin, and type of anesthesia, if appropriate.   
7.5 
Sample Size Calculation 
Approximately 350 patients will be enrolled.  The sample size was determined empirically 
rather than by sample size calculation. 
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.   
8.5 
Unscheduled Visits 
Unscheduled visits can be performed and at the discretion of the investigator eg, for safety 
concerns or for retreatment evaluation (if time since the last study treatment has been at least 
12 weeks).  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 post baseline 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.  

 
 
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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. 
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 

 
 
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medicinal (investigational) product.  In addition, during the screening period, adverse events 
will be assessed regardless of the administration of a pharmaceutical product.   
Adverse events will be assessed and documented, as appropriate, throughout the study (ie, 
after informed consent has been obtained).  At each visit, the investigator will begin by 
querying for adverse events by asking each patient/caregiver a general, non-directed question 
such as “How have you been feeling since the last visit?”  Directed questioning and 
examination will then be done as appropriate.  All reported adverse events will be 
documented on the appropriate eCRF.   
9.1.2 
Serious Adverse Event 
A serious adverse event is any adverse event occurring at any dose that results in any of the 
following outcomes:  death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a 
congenital anomaly/birth defect.  Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  (See Section 9.3 for procedures for reporting a serious adverse event.) 
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 
 

 
 
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9.1.4 
Relationship to Study Drug or Study Procedure 
A determination will be made of the relationship (if any) between an adverse event and the 
study drug or study procedure, as applicable.  A causal relationship is present if a 
determination is made that there is a reasonable possibility that the adverse event may have 
been caused by the drug or study procedure.   
9.2 
Procedures for Reporting Adverse Events 
Any adverse event must be recorded on the appropriate eCRF. 
All adverse events that are drug-related and unexpected (not listed as treatment-related in the 
current Investigator’s Brochure) must be reported to the governing IRB/IEC as required by 
the IRB/IEC, local regulations, and the governing health authorities.  Any adverse event that 
is marked “ongoing” at the exit visit must be followed-up as appropriate. 
9.3 
Procedures for Reporting a Serious Adverse Event 
Any serious adverse event occurring during the study period (beginning with informed 
consent) and for at least 28 days after the last dose of study drug must be immediately 
reported no later than 24 hours after learning of a serious adverse event.  Serious adverse 
events must be reported to Allergan or its designee as listed on the Allergan Study Contacts 
Page and recorded on the serious adverse event form.  All patients with a serious adverse 
event must be followed and the outcomes reported.  The investigator must supply Allergan 
and the IRB/IEC with any additional requested information (eg, autopsy reports and terminal 
medical reports).  
In the event of a serious adverse event, the investigator must: 
1. Notify Allergan immediately by fax or email using the serious adverse event form 
(contact details can be found on page 1 of the serious adverse event form); phone 
numbers and relevant Allergan personnel contacts are also on the front page of 
protocol. 
2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of 
the patient. 

 
 
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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. 
10.1 
Protection of Human Subjects 
10.1.1 
Compliance with Informed Consent Regulations (US 21 CFR 
Part 50) and Relevant Country Regulations 
Written informed consent is to be obtained from each patient prior to enrollment into the 
study, and/or from the patient’s legally authorized representative.  If the patient is under the 
legal age of consent, the consent form must be signed by the legally authorized representative 
in accordance with the relevant country and local regulatory requirements. 
Written parental/legally authorized representative informed consent in addition to a separate 
written minor consent and/or assent (in accordance with any applicable state and local 
laws/regulations) are required for each minor study patient prior to study enrollment or any 
study-related procedures in the study. 
10.1.2 
Compliance With IRB or IEC Regulations 
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) 
or applicable IEC regulations.  The investigator must obtain approval from a properly 
constituted IRB/IEC prior to initiating the study and re-approval or review at least annually.  
Allergan is to be notified immediately if the responsible IRB/IEC has been disqualified or if 
proceedings leading to disqualification have begun.  Copies of all IRB/IEC correspondence 
with the investigator should be provided to Allergan. 

 
 
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10.1.3 
Compliance With Good Clinical Practice 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines.  
10.1.4 
Compliance With Electronic Records; Electronic Signatures 
Regulations (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 
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: 

 
 
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•  to publish anonymous patient data from the study; and  
•  to create and maintain a data repository 
10.4 
Documentation 
10.4.1 
Source Documents 
Source documents may include a patient’s medical records, hospital charts, clinic charts, the 
investigator’s patient study files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and electrocardiograms.  The investigator’s copy of the case report forms 
serves as part of the investigator’s record of a patient’s study-related data.   
The following information should be entered into the patient’s medical record: 
• Patient’s name 
• Patient’s contact information 
• The date that the patient entered the study, patient number, and medication kit number 
• The study title and/or the protocol number of the study and the name of Allergan 
• A statement that informed consent and/or assent, if applicable was obtained 
(including the date).  A statement that written authorization (US sites only), data 
protection consent (EU sites only), or other country and local subject patient privacy 
required documentation for this study has been obtained (including the date). 
• A statement that patient meets all the inclusion criteria and does not meet any of the 
exclusion criteria.  If a patient does not qualify for the study, a screen failure reason 
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.  
  
• For sites performing the Edinburgh Visual Gait score, the videotape 

 
 
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• The results of laboratory tests performed by the site (eg, results of hematology, serum 
chemistry, HbA1c, urine pregnancy, and immunogenicity tests) 
• All concurrent medications (list all prescription, non-prescription and herbal 
medications being taken 3 months prior to or at the time of enrollment).  At each 
subsequent visit, changes to the list of medications and concurrent procedures should 
be recorded. 
• Occurrence and status of any adverse events 
• The date the patient exited the study, and a notation as to whether the patient 
completed the study or reason for discontinuation 
10.4.2 
Case Report Form Completion 
The investigator is responsible for ensuring that data are properly recorded in each patient’s 
eCRF and related documents.  An investigator who has signed the protocol signature page 
should personally sign for the eCRFs (as indicated in the eCRFs) to ensure that the 
observations and findings are recorded in the eCRFs correctly and completely.  The eCRFs 
are to be completed in a timely manner. 
10.4.3 
Study Summary 
An investigator’s summary will be provided to Allergan within a short time after the 
completion of the study, or as designated by Allergan.  A summary is also to be provided to 
the responsible IRB/IEC. 
10.4.4 
Retention of Documentation 
All study-related correspondence, patient records, consent forms, patient privacy 
documentation, records of the distribution and use of all investigational products, and 
electronic copies of eCRFs must be maintained on file. 
For countries falling within the scope of the ICH guidelines, the Allergan-specific essential 
documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or if needed by Allergan. 

 
 
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In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation. 
Allergan requires that it be notified in writing if the investigator wishes to relinquish 
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of 
ownership to a suitably qualified, responsible person. 
10.5 
Labeling, Packaging, and Return or Disposal of Study 
Medications/Treatments 
 
 
  
 
 
10.5.2 
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 

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

 
 
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Butler C, Darrah J.  Effects of neurodevelopmental treatment (NDT) for cerebral palsy:  an 
AADPDM evidence report.  Dev Med Child Neurol. 2001;43:778-790. 
Chambers HG.  The surgical treatment of spasticity.  Muscle Nerve Suppl. 1997;6:S121-128. 
Cobeljic G, Bumbasirevic M, Lesic A, Bajin Z.  The management of spastic equinus in 
cerebral palsy. Orthop Trauma 2009;23:201-209. 
Delgado MR, Hirtz D, Aisen M, Ashwal S, Fehlings DL, McLaughlin J, et al.  Practice 
parameter:  pharmacologic treatment of spasticity in children and adolescents with cerebral 
palsy (an evidence-based review).  Neurology. 2010;74:336-343. 
Detrembleur C, Lejeune TM, Renders A, Van Den Bergh PY.  Botulinum toxin and short-
term electrical stimulation in the treatment of equinus in cerebral palsy.  Mov Disord. 
2002;17:162-169. 
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. 
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. 

 
 
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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.  
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, Novak I, Kentish M, Desloovere K, Heinen F, Molenaers G, et al.  Botulinum toxin 
assessment, intervention, and after-care for lower limb spasticity in children with cerebral 
palsy: international consensus statement.  Eur J Neurol. 2010;17(Suppl 2):9-37. 
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. 
Molenaers G, Desloovere K, Fabry G, de Cock P.  The effects of quantitative gait assessment 
and botulinum toxin A on musculoskeletal surgery in children with cerebral palsy.  J Bone 
Joint Surg. 2006;88:161-170. 
Molenaers G, Schörkhuber V, Fagard K, Van Campenhout A, De Cat J, Pauwels P, et al.  
Long-term use of botulinum toxin type A in children with cerebral palsy: treatment 
consistency.  Eur J Paediatr Neurol. 2009;13:421-429. 
Odding E, Roebroeck ME, Stam HJ.  The epidemiology of cerebral palsy: incidence, 
impairments and risk factors.  Disabil Rehabil. 2006;28:183-191. 
O’Flaherty S, Waugh MC.  Pharmacologic management of the spastic and dystonic upper 
limb in children with cerebral palsy.  Hand Clin. 2003;19:585-589. 
Palisano R, Rosenbaum P, Bartlett D, Livingston M.  GMFCS – E&R: Gross motor function 
classification system expanded and revised.  2007. Available from: 
http://motorgrowth.canchild.ca/en/GMFCS/resources/GMFCS-ER.pdf. 

 
 
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Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al.  The 
Columbia- Suicide Severity Rating Scale (C-SSRS):  Initial validity and internal consistency 
findings from three multi-site studies with adolescents and adults.  Am J Psychiatry.  
2011;168:1266-1277. 
Read HS, Hazlewood ME, Hillman SJ, Prescott RJ, Robb JE.  Edinburgh Visual Gait Score 
for use in cerebral palsy.  J Pediatr Orthopaed.  2003;23:296-301. 
Rodda J, Graham HK.  Classification of gait patterns in spastic hemiplegia and spastic 
diplegia: a basis for a management algorithm.  Eur J Neurol. 2001;8 (Suppl. 5):98-108. 
Russman BS, Tilton AH, Gormley Jr ME.  Cerebral palsy:  a rational approach to a treatment 
protocol and the role of botulinum toxin in treatment.  In:  Brashear A, Mayer NH, eds.  
Spasticity and other forms of muscle overactivity in the upper motor neuron syndrome.  
Etiology, evaluation, management and the role of botulinum toxin.  New York, New York:  
WeMove; 2008:  Chapter 12. 
Scheinberg A, Hall K, Lam LT, O’Flaherty S.  Oral baclofen in children with cerebral palsy:  
A double-blind cross-over pilot study.  J Paediatr Child Health. 2006;42:715-720. 
Stanley F, Blair E, Alberman E.  Cerebral Palsy: epidemiology and causal pathways.  Clinics 
in Developmental Medicine, No 151. London, England: Mac Keith Press; 2000:3-15. 
Steinbok P.  Selection of treatment modalities in children with spastic cerebral palsy.  
Neurosurg Focus. 2006;21:1-8. 
Van Campenhout A, Molenaers G.  Localization of the motor endplate zone in human 
skeletal muscles of the lower limb: anatomical guidelines for injection with botulinum toxin.  
Dev Med Child Neurol. 2011;53(2):108-119. 
von Baeyer CL, Spagrud LJ.  Systematic review of observational (behavioral) measures of 
pain for children and adolescents aged 3 to 18 years.  Pain. 2007;127:140-150.  
Wallen M, Waugh M-C, O’Flaherty S.  Functional outcomes of intramuscular botulinum 
toxin type A and occupational therapy in the upper limbs of children with cerebral palsy:  
a randomized controlled trial.  Arch Phys Med Rehab. 2007;88:1-10. 
 
 

 
 
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12. 
Attachments 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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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. 

 
 
Approval Date: 
 
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12.3 
Glossary of Abbreviations  
Term/Abbreviation 
Definition 
AFO 
ankle foot orthosis 
 
 
 
BoNT-A 
botulinum neurotoxin type A 
BOTOX® 
Botulinum Toxin Type A Purified Neurotoxin Complex (US 
adopted name onabotulinumtoxinA), referred to as BOTOX 
CFR 
Code of Federal Regulations (US) 
 
 
CNS 
central nervous system 
 
 
D 
day 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
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 
ITT 
intent-to-treat 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
 
 
 
 
 
NA 
not applicable 
No. 
number 

 
 
Approval Date: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
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NOAEL 
No-observable-adverse-effect level 
OT 
occupational therapy 
PT 
physical therapy 
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 
 

 
 
Approval Date: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
85 
 
 
 
12.4 
Protocol Amendment 1 Summary 
Title:  BOTOX® Treatment in Pediatric Lower Limb Spasticity:  Open-label Study 
Protocol 191622-112, Amendment 1 
Date of Amendment:  30 March 2012 
Amendment Summary 
This summary includes changes made to Protocol 191622-112 (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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.7, Handling 
of Biological 
Specimens 
Revised approximate volume of 
blood collection for hematology 
and chemistry regardless of 
weight from 5 to 7 mL and total 
for children 15 kg and above 
from 12 to 14 mL. 
Based on the revised central laboratory 
(Covance) requirements. 

 
 
Approval Date: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
86 
 
 
 
Section(s) 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Approval Date: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
87 
 
 
 
12.5 
Protocol Amendment 2 Summary 
Title:  BOTOX® Treatment in Pediatric Lower Limb Spasticity:  Open-label Study 
Protocol 191622-112, Amendment 2 
Date of Amendment:  29 November 2012 
Amendment Summary 
This summary includes changes made to Protocol 191622-112 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 
Tables 1 and 2, Schedules 
 
 
 
 
 
 
1.4, Dose Justification 
2.2, Clinical Hypothesis 
5.4, Treatment Regimen 
and Dosing 
Table 3 
Added wording for a combination 
of both lower limbs for diplegic 
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 both lower 
limbs are treated 

 
 
Approval Date: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
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88 
 
 
 
Section(s) 
Revision 
Rationale 
1.4, Dose Justification 
Second paragraph: 
The maximum lower limb dose in a 
single limb doses selected for in 
this study corresponds to the 
maximum high dose group (8 U/kg) 
from the efficacy Study 191622-
111.  This dose is These doses are 
supported by Allergan clinical trial 
experience in pediatric lower limb 
spasticity, clinical expert advice, 
published literature including 
consensus guidelines for botulinum 
toxin type A treatment of pediatric 
spasticity, and nonclinical 
toxicology data. 
For clarification 
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 
4.4, Exclusion Criteria 
Changed #23 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 

 
 
Approval Date: 
 
28-Jan-2014
Allergan Confidential 
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Section(s) 
Revision 
Rationale 
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 4 U/kg in the study 
lower limb(s) every 12 to 14 weeks, 
with the total dose not to exceed the 
maximum specified for each 
treatment cycle.  
For clarification 
5.4.1, Treatment Cycle 1 
for De Novo Patients 
Specified that a total of 8 U/kg is to 
be injected either in the single study 
lower limb or divided between both 
study lower limbs only for diplegic 
patients. 
For clarification 
5.4.3, Treatment Cycles 2 
Through 5 for All 
Patients (Rollover and 
de novo) 
Revised description of dose 
limitations  
For clarification 
Table 3 
Revised title to be more specific 
(Maximum Per-muscle, Per-limb, 
and Total Body Dose), added row 
for total maximum dose for both 
lower limbs, and added footnote to 
indicate that only 1 upper limb is to 
be injected. 
For clarification 
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 
reinjected” if they meet the 
retreatment criteria. 
For clarification 

 
 
Approval Date: 
 
28-Jan-2014
Allergan Confidential 
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Section(s) 
Revision 
Rationale 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Approval Date: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
91 
 
 
 
Section(s) 
Revision 
Rationale 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.7, Early 
Discontinuation of 
Patients 
Revised study week 42 to study 
week 48. 
Correction  
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 
 
 
 
 

 
 
Approval Date: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
92 
 
 
 
Section(s) 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Approval Date: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
93 
 
 
 
12.6 
Protocol Amendment 3 Summary 
Title:  BOTOX® Treatment in Pediatric Lower Limb Spasticity:  Open-label Study 
Protocol 191622-112, Amendment 3 
Date of Amendment:  January 2014 
Amendment Summary 
This summary includes changes made to Protocol 191622-112 Amendment 2 (e-signature 
date 28 November 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 13a regarding 
seizure frequency for exclusion 
Clarification 
 
Modified Exclusion Criterion 14 regarding 
vulnerable respiratory state 
Clarification 
 
Added Exclusion Criterion 29 to exclude 
patients with significant suicidality from 
treatment 
To avoid confounding the 
safety data 

 
 
Approval Date: 
 
28-Jan-2014
Allergan Confidential 
Protocol 191622-112 Amendment 3 
BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 
 
 
 
94 
 
 
 
Section(s) 
Revision 
Rationale 
Protocol Summary; 
 
 
 
 
 
 
 
Added a sentence on use of anti-epileptics  
Clarification that anti-
epileptics are permissible 
during the study 
5.4.1.1 
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 
Removed:  “Non-frost-free -20°C freezer for 
storage of serum neutralizing antibody 
samples” 
Correction 
 
Added bullet that Allergan will supply a 
kilogram-only weight scale for selected sites, 
and that the site will supply it only if it is not 
already supplied by Allergan 
To ensure that patient’s 
weight is collected in 
kilograms only 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
9.3 
Updated serious adverse event language 
Per new Allergan protocol 
template 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Approval Date: 
 
28-Jan-2014
ALLERGAN 
 
 
 
 
 
 
 
 
 
            
 
           
 
            
 
           
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
Protocol 191622-112 Amd 3