BOTOX® Treatment of Masseter Muscle Hypertrophy
Phase: PHASE2
Conditions: Masseter Muscle Hypertrophy
Sponsor: Allergan

NCT02010775 
 
Study ID: 191622‐130 
 
Title: BOTOX® TREATMENT OF MASSETER MUSCLE HYPERTROPHY 
 
Protocol Amendment 1 Date: 28‐Feb‐2014 
 
 
 

 
 
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Title Page 
ALLERGAN – CONFIDENTIAL 
The following contains confidential, proprietary information 
that is the property of Allergan 
 
BOTOX® TREATMENT OF MASSETER MUSCLE HYPERTROPHY 
Protocol Number:   
191622-130 
Phase: 
2 
Name of Investigational Product: 
BOTOX® (botulinum toxin type A) purified neurotoxin complex 
Sponsor: 
Allergan (North America) 
2525 Dupont Drive 
Irvine, California USA 
92612 
 
 
Emergency Telephone Numbers: 
Refer to Study Contacts Page 
Serious Adverse Event Reporting Fax 
Numbers: 
 
Allergan Medical Safety Physician 
Contact Information: 
 
 
 
 
Allergan Signatory: 
 
Refer to the final page of this protocol for electronic signature and 
date of approval. 
 
The following information can be found on the 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/IEC. 

 
 
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INVESTIGATOR SIGNATURE PAGE 
INVESTIGATOR: 
 
 
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. 
• ensure that all persons assisting with the trial are adequately informed about the protocol, 
the investigational product, and their trial-related duties and functions. 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 
 

 
 
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Table of Contents 
Table of Contents ...................................................................................................................... 3 
List of Tables ............................................................................................................................. 6 
List of Figures ........................................................................................................................... 6 
Protocol Summary .................................................................................................................... 7 
1 
Background and Clinical Rationale ................................................................................. 13 
1.1 
Rationale for Dose Selection and Population......................................................... 14 
1.2 
Rationale for Efficacy Assessments ....................................................................... 14 
1.3 
Rationale for Safety Assessments, CT Imaging, and Dental Examination ............ 15 
2 
Study Objectives and Clinical Hypotheses ...................................................................... 16 
2.1 
Study Objectives .................................................................................................... 16 
2.2 
Clinical Hypotheses ............................................................................................... 16 
3 
Study Design .................................................................................................................... 16 
3.1 
Data Review Committee (DRC) ............................................................................ 18 
4 
Study Population and Entry Criteria ................................................................................ 18 
4.1 
Number of Subjects ................................................................................................ 18 
4.2 
Study Population Characteristics ........................................................................... 18 
4.3 
Inclusion Criteria .................................................................................................... 18 
4.4 
Exclusion Criteria................................................................................................... 19 
4.5 
Permissible and Prohibited Medications/Treatments ............................................. 21 
4.5.1  Permissible Medications/Treatments ......................................................... 21 
4.5.1.1 
Definition of Women of (Non-)Childbearing Potential and/or 
Acceptable Contraceptive Methods ........................................... 21 
4.5.2  Prohibited Medications/Treatments ........................................................... 22 
5 
Study Treatments ............................................................................................................. 22 
5.1 
Study Treatments and Formulations ....................................................................... 22 
5.2 
Control Treatments ................................................................................................. 23 
5.3 
Methods for Masking/Blinding .............................................................................. 23 
5.4 
Treatment Allocation Ratio and Stratification........................................................ 23 
5.5 
Method for Assignment to Treatment Groups/Randomization .............................. 24 
5.6 
Treatment Regimen and Dosing ............................................................................. 24 
5.7 
Storage of Study Treatment .................................................................................... 25 

 
 
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5.8 
Preparation of Study Medications/Treatments ....................................................... 25 
 
 
5.10  Retreatment ............................................................................................................ 27 
6 
Response Measures and Summary of Data Collection Methods ..................................... 28 
6.1 
Efficacy Measures .................................................................................................. 28 
6.2 
Primary Efficacy Measure ...................................................................................... 28 
6.3 
Secondary Efficacy Measure .................................................................................. 28 
 
 
 
 
 
 
6.5 
Other Study Supplies .............................................................................................. 29 
6.6 
Summary of Methods of Data Collection .............................................................. 30 
7 
Statistical Procedures ....................................................................................................... 30 
7.1 
Analysis Populations .............................................................................................. 30 
7.2 
Collection and Derivation of Primary and Secondary Efficacy Assessments ........ 31 
7.2.1  Primary Efficacy Variable .......................................................................... 31 
7.2.2  Secondary Efficacy Variable ...................................................................... 31 
7.3 
Hypothesis and Methods of Analysis ..................................................................... 32 
7.3.1  Primary Efficacy Analyses ......................................................................... 32 
7.3.2  Secondary Efficacy Analyses ..................................................................... 32 
 
 
 
 
7.4 
Subgroup Analyses ................................................................................................. 37 
7.5 
Sample Size Calculation ........................................................................................ 37 
7.6 
Interim Analyses..................................................................................................... 37 
7.7 
Final Analyses ........................................................................................................ 38 
8 
Study Visit Schedule and Procedures .............................................................................. 39 
8.1 
Subject Entry Procedures ....................................................................................... 39 
8.1.1  Overview of Entry Procedures ................................................................... 39 
8.1.2  Informed Consent and Subject Privacy ...................................................... 39 
8.2 
Washout Intervals/Run-in ....................................................................................... 39 
8.3 
Procedures for Final Study Entry ........................................................................... 39 
8.4 
Visits and Associated Procedures ........................................................................... 40 
8.5 
Instructions for the Subjects ................................................................................... 40 

 
 
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8.6 
Unscheduled Visits ................................................................................................. 40 
8.7 
Compliance with Protocol ...................................................................................... 41 
8.8 
Early Discontinuation of Subjects .......................................................................... 41 
8.9 
Withdrawal Criteria ................................................................................................ 41 
8.10  Study Termination .................................................................................................. 41 
9 
Adverse Events ................................................................................................................ 41 
9.1 
Definitions .............................................................................................................. 42 
9.1.1  Adverse Event ............................................................................................ 42 
9.1.2  Serious Adverse Event ............................................................................... 42 
9.1.3  Severity ...................................................................................................... 43 
9.1.4  Relationship to Study Drug or Study Procedure ........................................ 43 
9.2 
Procedures for Reporting Adverse Events ............................................................. 43 
9.3 
Procedures for Reporting a Serious Adverse Event ............................................... 44 
9.4 
Procedures for Unmasking of Study Medication ................................................... 45 
10  Administrative Items ....................................................................................................... 45 
10.1  Protection of Human Subjects ................................................................................ 45 
10.1.1  Compliance with Informed Consent Regulations (US 21 CFR Part 50) and 
Relevant Country Regulations ................................................................... 45 
10.1.2  Compliance With IRB or IEC Regulations ................................................ 45 
10.1.3  Compliance With Good Clinical Practice .................................................. 46 
10.1.4  Compliance With Electronic Records; Electronic Signatures Regulations 
(US 21 CFR Part 11) .................................................................................. 46 
10.2  Changes to the Protocol ......................................................................................... 46 
10.3  Subject Confidentiality .......................................................................................... 46 
10.3.1  Subject Privacy .......................................................................................... 46 
10.4  Documentation ....................................................................................................... 47 
10.4.1  Source Documents ..................................................................................... 47 
10.4.2  Case Report Form Completion................................................................... 48 
10.4.3  Study Summary .......................................................................................... 48 
10.4.4  Retention of Documentation ...................................................................... 48 
10.5  Labeling, Packaging, and Return or Disposal of Study Medications/Treatments .. 49 
10.5.1  Labeling/Packaging .................................................................................... 49 
10.5.2  Clinical Supply Inventory .......................................................................... 49 
10.5.3  Return or Disposal of Study Medications/Treatments and/or Supplies ..... 49 
10.6  Monitoring by the Sponsor .................................................................................... 49 

 
 
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10.7  Publications ............................................................................................................ 50 
11  References ........................................................................................................................ 50 
12  Attachments ..................................................................................................................... 53 
12.1  Examination Procedures, Tests, Equipment, and Techniques ................................ 53 
12.1.1  Masseter Muscle Prominence Scale (MMPS)............................................ 53 
12.1.2  Lower Facial Volume Measurement .......................................................... 55 
 
 
 
 
 
 
 
 
 
12.2  Glossary of Abbreviations ...................................................................................... 80 
12.3  Protocol Amendment Summary ............................................................................. 81 
 
List of Tables 
 
 
Table 2 
Dose Escalation by Cohort .............................................................................. 17 
Table 3 
Injection Volume by Cohort ............................................................................ 25 
 
List of Figures 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Protocol Summary 
Study Compound:  BOTOX® (Botulinum Toxin Type A) purified neurotoxin complex (referred to in this 
protocol as BOTOX) 
Phase:  2 
Study Objective:  to evaluate the safety and efficacy of a range of doses of BOTOX for the treatment of 
subjects with bilateral masseter muscle hypertrophy (MMH) 
Clinical Hypotheses:  BOTOX treatment of MMH has an acceptable safety profile and is more effective than 
placebo, as demonstrated by a change in lower facial volume 
Study Design 
Structure:  multicenter, randomized, double-blind, placebo-controlled, up to 2-treatment, dose-escalation study 
Duration:  12 months following randomization 
Study Treatment Groups:  BOTOX 
Controls:  placebo (saline) 
Dosage/Dose Regimen:  BOTOX or placebo will be administered intramuscularly to the bilateral masseter 
muscles (6 total injections, 3 injections/masseter).  The initial BOTOX total dose will be 24 U (12 U/masseter) 
and the maximum BOTOX total dose will be 96 U (48 U/masseter).  The planned dose escalation is as follows: 
Cohort 
Total Dose 
Target Sample Size 
Target Total 
Subjects/Cohort 
1 
24 U 
40 
50 
placebo 
10 
2 
48 U 
40 
50 
placebo 
10 
3 
72 U 
40 
50 
placebo 
10 
4 
96 U 
40 
50 
placebo 
10 
 
Each cohort will be enrolled over an approximately 2-week period.  The next cohort will be enrolled following 
a planned independent Data Review Committee (DRC) meeting and Allergan’s written notification to proceed. 
For each cohort, the DRC including Allergan nonstudy team members and non-Allergan nonstudy clinicians 
will meet to review safety and efficacy data through day 90.  The DRC will assess if the data support study 
retreatment of the current cohort and/or advancement to the next cohort. 
Subjects who meet the following retreatment criteria at the day 180 visit will receive a second treatment: 
• 
Allergan written notification allowing retreatment of the current cohort 
• 
subject has marked (grade 4) or very marked (grade 5) bilateral masseter muscle hypertrophy, as assessed 
by the investigator using the Masseter Muscle Prominence Scale (MMPS) 
• 
females of childbearing potential must have a negative urine pregnancy test prior to treatment 
The second treatment is only allowed at the day 180 visit.  Subjects will receive the same treatment as they 
received at the day 1 visit. 
Randomization/Stratification:  After completion of all baseline procedures, subjects will be randomized and 
enrolled in cohorts of approximately 50 subjects each.  Within each cohort, subjects will be randomized 4:1 to 
BOTOX (N = approximately 40) or placebo (N = approximately 10).  Stratification will be by baseline (day 1) 
MMPS grade. 

 
 
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Study Population Characteristics 
Number of Subjects:  Based on 4 planned cohorts, approximately 200 subjects will be enrolled at approximately 
4 to 12 investigational sites.  The actual number of subjects in the study will be determined by the number of 
cohorts and number of subjects entering each cohort.  Approximately 70% of the enrolled population in each 
cohort will be Asian, and subjects of Asian race will be further grouped by self-identified ethnicity (Chinese, 
Japanese, Korean, or other). 
Condition/Disease:  adult subjects with marked (grade 4) or very marked (grade 5) MMH, as determined by the 
investigator using the MMPS 
Key Inclusion Criteria: 
• 
adult male or female, 18 (or older if legal age of adulthood is > 18 as per local regulations) to 50 years of 
age, inclusive, at the time of consent 
• 
subject has marked (grade 4) or very marked (grade 5) bilateral MMH (identical grades for left and right 
masseter), as determined at screening and confirmed on day 1 by the investigator using the MMPS 
Key Exclusion Criteria: 
• 
any medical condition that may put the subject at increased medical risk with exposure to BOTOX 
including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or any 
other condition that might interfere with neuromuscular function 
• 
prior botulinum toxin treatment of any serotype  
o 
to the masseter muscle or lower face at any time or  
o 
to any other part of the body within the 6 months prior to study day 1 
 
 
• 
history of dental or surgical procedure for lower facial shaping or masseter muscle reduction 
 
 
 
 
• 
history of or current temporomandibular joint disorder (TMJD) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Response Measures 
Efficacy: 
Primary 
• 
lower facial volume (cm3) calculated from VECTRA M3 digital photography system 
 
3D image models 
Secondary 
• 
investigator’s assessment of MMH using the MMPS (5 grades:  1 = minimal, 2 = mild, 3 = moderate, 
4 = marked, 5 = very marked) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Statistical Methods and Types of Analyses: 
Three analysis populations will be used: 
• 
The modified intent-to-treat (mITT) population will consist of all randomized subjects who received study 
treatment and had at least 1 follow-up visit.  The analysis will be based on the actual treatment subjects 
received. 
• 
The per-protocol (PP) population will consist of randomized subjects who have no significant deviations 
from the protocol.  Key criteria will be determined prior to database lock. 
• 
The safety population will consist of all subjects who are treated with at least 1 injection of study treatment. 
Day 1 will be considered as baseline for all measures except for the dental examination and CT imaging, for 
which the screening visit will be considered baseline.  The primary efficacy variable will be lower facial volume 
at day 90.  The change from baseline in lower facial volume will be analyzed by analysis of variance (ANOVA) 
with treatment and baseline MMPS grade as factors to assess the response between each BOTOX dose 
compared with placebo. 
For analysis of the mITT population, the last observation carried forward (LOCF) method will be used to 
impute missing values.  For analysis of the PP population, observed data without imputation will be used. 

 
 
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For each cohort, there will be a database snapshot with key data through the day 90 visit, for the purpose of the 
DRC assessment.  There will be a final database lock with all study data after all subjects have completed the 
study (final cohort day 360).  Subjects’ treatment assignment will remain blinded for all site personnel, study 
subjects, and Allergan personnel directly involved with ongoing operational activities of the clinical study, until 
completion of the final database lock. 
Data will be summarized with descriptive statistics, frequency tables, and data listings.  Categorical variables 
will be analyzed using Fisher’s exact tests, Pearson’s chi-square tests, or Cochran-Mantel-Haenszel (CMH) 
tests as appropriate.  Continuous variables will be analyzed using t-test, analysis of covariance (ANCOVA), or 
corresponding nonparametric methods. 
Sample Size Calculation: 
The sample size used in this study is determined empirically.  For each cohort, approximately 40 subjects will 
be randomized to BOTOX and approximately 10 subjects will be randomized to placebo.  Assuming the 
VECTRA lower facial volume is a normal distribution and the effect size is 1, a 1-sided test with 
0.10 significance level will have 93% power to detect a statistically significant change in the BOTOX group 
compared with the placebo group.  The commercial software nQuery version 6.01 procedure MTT0U-1 was 
used for the power calculation. 

 
 
 
 
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1 
Background and Clinical Rationale 
Botulinum toxin type A purified neurotoxin (BOTOX®) has been used for therapeutic and 
cosmetic purposes for over 2 decades and is 1 of the most common noninvasive aesthetic 
products in clinical use.  When BOTOX is injected into a muscle, it interferes with 
neuromuscular transmission, producing temporary chemical denervation resulting in 
localized relaxation of the muscle and reduction in muscle activity.  When injected into a 
hypertrophic masseter muscle, the effect of BOTOX has been observed as a reduction in the 
size of the muscle, perceived as lower facial shaping or slimming.  This is the first Allergan-
sponsored study of BOTOX for the treatment of masseter muscle hypertrophy (MMH), and 
worldwide there is no neuromodulator currently approved for treatment of this indication. 
MMH may be unilateral or bilateral, and it may be idiopathic or occur in association with 
conditions such as bruxism, occlusal and muscular imbalances, temporomandibular joint 
disorder (TMJD), or excessive chewing habits (Aydil et al, 2012; Choe et al, 2005; 
Mischkowski et al, 2005).  Aesthetically, MMH may appear as a wide, square, or trapezoidal 
lower face shape that is deemed undesirable, particularly in Asian countries.  Individuals may 
seek surgical or nonsurgical alteration of prominent masseter muscles and/or mandibles to 
decrease a bulky or square-appearing lower face (Ahn et al, 2004; Liew and Dart, 2008). 
The medical literature documenting the use of botulinum toxins, including BOTOX, for 
treatment of MMH dates back to 1994 (Moore and Wood, 1994; Smyth, 1994).  Published 
cases characterize the patient population (Asian and non-Asian), injection techniques 
utilized, clinical results achieved, and adverse events (Ahn et al, 2004; Aydil et al, 2012; 
Choe et al, 2005; Liew and Dart, 2008).  Due to the inherent risks associated with surgical 
intervention, the aesthetic procedure of treating the masseter muscle with botulinum toxin 
has gained popularity among physicians and patients. 
In the medical literature, most side effects associated with BOTOX treatment of MMH have 
been local and expected, based on the well-established safety profile of BOTOX and the 
muscles injected.  Adverse events reported in the medical literature include pain, discomfort, 
or muscle ache at the sites of injection; masticatory difficulties; speech disturbances; and 
cosmetic complaints related to the masseter and/or adjacent facial muscles.  Typically, these 
events have been reported within 2 weeks posttreatment, were mild to moderate in severity, 
and resolved within 1 to 3 months.  For further details regarding the safety of BOTOX 
treatment of MMH, including a comprehensive summary of the published literature reporting 
treatment in > 350 patients, please refer to the Investigator’s Brochure. 

 
 
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This study is designed to evaluate the safety and efficacy of different doses of BOTOX for 
the treatment of MMH, to identify potential effects on associated structures (mandible and 
teeth), and to assist in the design of future clinical studies. 
1.1 
Rationale for Dose Selection and Population 
A review of the medical literature of BOTOX treatment of MMH found the mean dose was 
approximately 36 units (U) per masseter (range:  10 U to 100 U/masseter) administered into 
1 to 6 injection sites/masseter (refer to the Investigator’s Brochure).  In the present study, the 
initial dose (24 U, 12 U/masseter) will be tested to characterize the lowest threshold of 
potential treatment effect, whereas other planned doses (48 U, 72 U, and 96 U) are 
representative of total doses typical for treatment of hypertrophic masseter muscles.  Subjects 
treated in this study are required to have marked or very marked bilateral MMH (grade 4 or 5 
using Allergan’s Masseter Muscle Prominence Scale [MMPS]; see Attachment 12.1.1) and 
will represent a variety of ethnicities, predominantly Asian. 
1.2 
Rationale for Efficacy Assessments 
In the medical literature, various imaging methods have been used to assess effects of 
botulinum toxin on masseter muscle size and lower facial shape (refer to the Investigator’s 
Brochure).  Technologies used to measure quantitative changes in masseter muscle volume 
have included ultrasound, computed tomography (CT), and magnetic resonance imaging 
(MRI).  Photographic technologies developed to provide 3-dimensional (3D) quantitative 
analysis of facial morphology include image subtraction technique, moire topography, liquid 
crystal scanning, light luminance scanning, laser scanning, stereo-lithography, and passive 
stereophotogrammetry (Adriaens, 2012; Kim et al, 2005; Tzou and Frey, 2011), which all 
measure change to the lower facial contour.  Previous studies reported peak efficacy of 
botulinum toxin treatment of MMH at 3 months (Hong et al, 2005; Kim et al, 2003; 
Kim et al, 2007; Park et al, 2003), therefore, day 90 is the primary timepoint in the present 
study. 
In the present study, the VECTRA M3 3D Stereophotogrammetry system 
 
 and CT imaging will be used to quantify the 
effect of BOTOX by lower facial volume (Attachment 12.1.2) and masseter muscle volume 
(Attachment 12.1.3), respectively.  The VECTRA system has previously been validated for 
use in the facial region (de Menezes, 2010), and data from this study will be used to validate 
its use in the defined lower facial area encompassing the masseter muscle.  In addition, the 
lower facial width (Attachment 12.1.4) and mandibular facial angle (Attachment 12.1.5) will 

 
 
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be calculated using 2-dimensional (2D) images projected from the VECTRA M3 3D image 
models. 
Allergan developed the MMPS, a clinician’s assessment tool for evaluation of masseter 
muscle prominence associated with MMH (see Attachment 12.1.1).  The MMPS is to be used 
by trained clinicians to evaluate and grade the hypertrophy of the masseter muscle on the left 
and right sides of the face.  The MMPS is a static measurement encompassing both visual 
and palpable examination of the masseter muscle both at rest and at jaw-clench state.  The 
MMPS showed substantial inter- and intra-rater reliability in the nontreatment scale 
validation Study 191622-128, confirming its acceptability for use in the present study. 
A reduction in masseter muscle volume may be perceived by subjects as a change in their 
lower facial shape at rest:  specifically, narrowing of their lower facial width and change in 
their lower facial angle from a bulky trapezoidal or square toward a slimmer ovoid shape.  
Allergan developed the Lower Facial Shape Classification (LFSC; see Attachment 12.1.6), an 
assessment tool to be used by trained clinicians and subjects to assess a subject’s lower facial 
shape.  The LFSC to be piloted in the current study has not been tested for reliability. 
1.3 
Rationale for Safety Assessments, CT Imaging, and Dental 
Examination 
Safety assessments include attention to potential local and systemic effects of BOTOX 
treatment of MMH.  Local adverse events (eg, pain, discomfort, and muscle ache at sites of 
injection) have been reported within the first 2 weeks posttreatment; therefore, a telephone 
follow-up visit is scheduled approximately 14 days following the day 1 and day 180 
treatments.  Because the masseter muscle is 1 of the primary muscles of mastication, 
masticatory difficulties (eg, transient masseter muscle fatigue after vigorous chewing and 
weakness on chewing) have been reported.  Temporary speech disturbances have also been 
reported.  In general, these adverse events have been reported as mild and resolved without 
treatment. 
In the literature, nonclinical studies have reported on mandibular bone and dental changes 
following BOTOX treatment of the masseter muscle in animal models (Navarrete et al, 2013; 
Rafferty et al, 2012; Tsai and Huang, 2008; Tsai et al, 2010).  However, differences in the 
structure and function of the mandible and dentition in animals contribute to difficulty 
interpreting the relevance to humans (refer to the Investigator’s Brochure).  One clinical 
study of botulinum toxin (Dysport®) injected in the masseter muscles of 10 women showed 
no changes in mandibular cortex thickness, mandibular bone thickness, and mandibular 

 
 
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volume on CT at 3 months (Chang et al, 2011).  It is unknown whether BOTOX treatment of 
MMH may impact characteristics of the mandible and/or dentition in subjects.  The medical 
literature does not indicate any clinically relevant change to these craniofacial structures 
adjacent to the masseter muscle.  Therefore, Allergan has developed exploratory CT 
measures to determine whether any potential safety and/or efficacy signals may be detected 
that are not currently reported in the medical literature. 
The present study includes CT and dental examinations developed by Allergan with input 
from consultants and specifically designed to identify potential effects of BOTOX treatment 
of MMH on the mandible and teeth.  The CT scan captured by a CT technologist will be 
transferred to a central reader, who will review it to assess for changes in lower facial shape 
(masseter muscle volume, bigonial width, mandibular flare angle, and gonial angle) as well 
as relevant indicators of change in bone structure (mandibular condylar head shape, 
mandibular condylar cortical surface, mandibular condylar head, mandibular condylar 
position, glenoid fossa/eminence, and cortical thickness under the insertion point of the 
masseter muscle at the mandibular ramus).  The dental examination will be conducted by a 
dentist to assess for any potential changes in dentition, occlusion, and overall oral health 
(Attachment 12.1.7).  Both CT and dental measures will be taken at screening (considered as 
baseline), day 90, and at study exit (day 360 or study discontinuation). 
In summary, the data obtained from this study will be used to develop a better understanding 
of the safety and efficacy of different dose regimens of BOTOX for the treatment of MMH. 
2 
Study Objectives and Clinical Hypotheses 
2.1 
Study Objectives 
The study objective is to evaluate the safety and efficacy of a range of doses of BOTOX for 
the treatment of subjects with bilateral MMH. 
2.2 
Clinical Hypotheses 
BOTOX treatment of MMH has an acceptable safety profile and is more effective than 
placebo, as demonstrated by change in lower facial volume. 
3 
Study Design 
This is a multicenter, randomized, placebo-controlled, up to 2-treatment, dose-escalation 
study to assess a range of doses of BOTOX for the treatment of MMH.  Up to 16 scheduled 

 
 
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visits are planned:  screening (day -56 to day -1), day 1 (randomization/treatment), day 14 
(telephone followup), monthly (days 30, 60, 90, 120, 150, 180 [possible retreatment]), and 
day 194 (telephone followup, only for subjects retreated at day 180), monthly (days 210, 240, 
270, 300, and 330), and study exit (day 360). 
After completion of all baseline study procedures and re-verification that the subjects meet 
all inclusion and exclusion criteria, subjects will be randomized and enrolled in cohorts of 
approximately 50 subjects each.  Within each cohort, subjects will be randomized 4:1 to 
BOTOX (N = approximately 40) or placebo (N = approximately 10).  Stratification will be 
by baseline (day 1) MMPS grade.  Approximately 70% of the enrolled population in each 
cohort will be Asian, and subjects of Asian race will be further grouped by self-identified 
ethnicity (Chinese, Japanese, Korean, or other).  Each cohort will be enrolled over 
approximately a 2-week period.  When at least 50 subjects have been enrolled, randomization 
will be halted to allow observation of the cohort through the day 90 visit.  The next cohort 
will be enrolled following a planned independent Data Review Committee (DRC) meeting 
(see Section 3.1) and Allergan’s written notification to proceed. 
On day 1, subjects will receive a single treatment of either BOTOX or placebo administered 
bilaterally to the masseter muscles as 3 injections/masseter in the area of maximal muscle 
bulge.  The initial BOTOX total dose will be 24 U (12 U/masseter) and the maximum total 
dose will be 96 U (48 U/masseter).  Table 2 shows the planned dose-escalation scheme. 
Table 2 
Dose Escalation by Cohort 
Cohort 
Total Dose 
Target Sample Size 
Target Total 
Subjects/Cohort 
1 
24 U 
40 
50 
placebo 
10 
2 
48 U 
40 
50 
placebo 
10 
3 
72 U 
40 
50 
placebo 
10 
4 
96 U 
40 
50 
placebo 
10 
 
Based on the DRC assessment and provisions for retreatment, subjects who meet the 
retreatment criteria (see Section 5.10) at the day 180 visit may receive a second study 
treatment.  The second treatment is only allowed at the day 180 visit, and the same dose as 
day 1 will be administered. 

 
 
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3.1 
Data Review Committee (DRC) 
For each cohort, the DRC, made up of identified Allergan nonstudy team members and non-
Allergan nonstudy clinicians specializing in dentistry, radiology, and/or oral and 
maxillofacial surgery, will meet to review cumulative safety and efficacy data through 
day 90.  The DRC will assess if the data support retreatment of the current cohort and/or 
study advancement to the next cohort. 
All DRC members will be independent from the study team.  Details of the DRC 
membership, data review procedures, timing of review, and communication between the 
DRC and other parties are detailed in the study DRC Charter. 
4 
Study Population and Entry Criteria 
4.1 
Number of Subjects 
Based on the proposed doses, it is anticipated that approximately 200 subjects will be 
enrolled in the 4 planned cohorts.  The actual number of subjects entering the study will be 
determined by the number of cohorts conducted and the number of subjects enrolled within 
each cohort. 
Subjects will be enrolled at approximately 4 to 12 investigational sites. 
4.2 
Study Population Characteristics 
The study population will be adult subjects with marked (grade 4) or very marked (grade 5) 
MMH, as determined by the investigator using the MMPS, and who meet eligibility criteria 
for this protocol as specified in Sections 4.3 and 4.4.  Approximately 70% of the enrolled 
population in each cohort will be Asian, and subjects of Asian race will be further grouped by 
self-identified ethnicity (Chinese, Japanese, Korean, or other). 
4.3 
Inclusion Criteria 
The following are requirements for entry into the study: 
1. adult male or female, 18 (or older if legal age of adulthood is > 18 as per local 
regulations) to 50 years of age, inclusive, at the time of consent 
2. Written informed consent has been obtained. 

 
 
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3. Written documentation has been obtained in accordance with the relevant country 
and local privacy requirements, where applicable. 
4. Subject has marked (grade 4) or very marked (grade 5) bilateral MMH (identical 
grades for left and right masseter), as determined at screening and confirmed on 
day 1 by the investigator using the MMPS. 
4.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
 
2. any medical condition that may put the subject at increased medical risk with 
exposure to BOTOX including diagnosed myasthenia gravis, Eaton-Lambert 
syndrome, amyotrophic lateral sclerosis, or any other condition that might interfere 
with neuromuscular function 
3. prior botulinum toxin treatment of any serotype  
a. to the masseter muscle or lower face at any time, or  
b. to any other part of the body within the 6 months prior to study day 1 
 
 
 
 
 
 
7. history of or current TMJD 
 
 
 
 
 

 
 
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4.5 
Permissible and Prohibited Medications/Treatments 
4.5.1 
Permissible Medications/Treatments 
Therapy considered necessary for the subject’s welfare may be given at the discretion of the 
investigator.  The subject’s usual facial and orthodontic regimen (eg, topical treatments and 
night guard usage) should remain consistent throughout the study.  If the permissibility of a 
specific medication/treatment is in question, please contact Allergan. 
If concurrent medications may have an effect on study outcomes, these medications should 
be administered in dosages that remain constant throughout the course of the trial. 
4.5.1.1 
Definition of Women of (Non-)Childbearing Potential and/or 
Acceptable Contraceptive Methods 
Women of non-childbearing potential are considered as those who are postmenopausal (at 
least 12 consecutive months without menstruation) or those who have had a hysterectomy or 
bilateral oophorectomy.  For women 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, male condom 
with intravaginal spermicide, diaphragm or cervical cap with spermicide, vaginal 
contraceptive ring, intrauterine device, surgical sterilization, vasectomized partner, or sexual 
abstinence. 
Contraceptive methods using Chinese traditional medicine or other herbal remedies are not 
considered acceptable methods of contraception in this study. 
The investigator and each subject will determine the appropriate method of contraception for 
the subject during the participation in the study.  At each visit, the investigator should discuss 
compliance with contraceptive use with females of childbearing potential. 

 
 
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If a female becomes pregnant during the study, the investigator will notify Allergan 
immediately after the pregnancy is confirmed.  The investigator will (1) notify the subject’s 
physician that the subject was being treated with an investigational drug, 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. 
If a pregnancy is confirmed after the subject has received study treatment, the subject may 
choose to exit the study after appropriate safety followup or to remain in the study for all 
safety and efficacy follow-up assessments through the end-of-study visit.  However, CT will 
not be performed and a second study treatment will not be administered for any pregnant 
subject or on any subject of childbearing potential who does not demonstrate a negative urine 
pregnancy test immediately before each CT or prior to retreatment. 
4.5.2 
Prohibited Medications/Treatments 
The decision to administer a prohibited medication/treatment is done with the safety of the 
study participant as the primary consideration.  When possible, Allergan should be notified 
before the prohibited medication/treatment is administered. 
Prohibited treatments and procedures include, but are not limited to: 
• facial surgery that could affect lower facial shape/appearance 
• facial shaping procedures including use of fat-reducing injectables or skin-tightening 
laser treatments; implantation of a prosthetic device or autologous fat transplantation; use 
of temporary, semi-permanent, or permanent filler product in the face 
• elective dental extractions, braces, implants, or reconstructive surgery 
• treatment with botulinum toxin of any serotype for any indication 
Co-administration of aminoglycosides or agents that could interfere with neuromuscular 
transmission (eg, curare-like agents) or muscle relaxants should be used with caution as the 
effects of the toxin, theoretically, could be potentiated. 
5 
Study Treatments 
5.1 
Study Treatments and Formulations 
BOTOX (botulinum toxin type A) purified neurotoxin complex 
 
 
 

 
 
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5.2 
Control Treatments 
BOTOX placebo 
 
 
 
5.3 
Methods for Masking/Blinding 
All study treatments will be provided in identical vials and cartons to maintain blinding of 
the study. 
At each study site, a designated staff member will serve as the drug reconstitutor (DR).  This 
person will be responsible for study treatment preparation. 
The DR will prepare the vial of study treatment as described in Sections 5.6 and 5.8.  Once 
the study treatment vial is reconstituted, the DR will draw the required volume into an 
appropriately sized syringe and label the syringe with the subject’s number.  The DR will 
then provide the filled syringes to the investigator, who will inject the subject according to 
the study treatment administration instructions in Section 5.9. 
For each cohort, the injection volume and treatment administration will be identical whether 
the subject is assigned to the BOTOX or the placebo group. 
5.4 
Treatment Allocation Ratio and Stratification 
Subjects will be randomly allocated to BOTOX or placebo using the automated interactive 
voice response system (IVRS) or the interactive web response system (IWRS). 
Subjects will be stratified by baseline (day 1) MMPS grade (4 or 5). 

 
 
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5.5 
Method for Assignment to Treatment Groups/Randomization 
At the screening visit, after the subject signs informed consent, the site will call the IVRS or 
log on to the IWRS to obtain a subject number and coded initials that will serve as the subject 
identification number on all study documents. 
The IVRS/IWRS will be used to manage the randomization and assignment of subjects into 
1 of the 2 treatment groups for each cohort based on a central randomization schedule 
prepared by Allergan Biostatistics prior to day 1.  The randomization will occur after all 
baseline procedures have been completed and the investigator has re-verified that the subject 
has met all inclusion and exclusion criteria.  Randomization will be stratified by the subject’s 
baseline (day 1) MMPS grade (4 or 5), as assessed by the investigator. 
Study treatment will be labeled with kit numbers.  The IVRS/IWRS will provide the site with 
the specific kit number for each randomized subject at the time of randomization (day 1).  
The IVRS/IWRS will also issue the specific kit number for each subject who qualifies for 
retreatment on day 180.  Sites will dispense study treatment according to the IVRS/IWRS 
instructions.  Sites will receive the IVRS/IWRS confirmation notifications for each 
transaction that will be maintained with the study source documents. 
5.6 
Treatment Regimen and Dosing 
A range of doses from 24 U (12 U/masseter) up to 96 U (48 U/masseter) will be studied in 
escalating dose cohorts.  For each cohort, all subjects will receive 1 treatment of BOTOX or 
placebo on day 1.  The same dose will be injected intramuscularly into the left and right 
masseter muscles.  A total of 6 injections will be made (3 injections/masseter) into the area of 
maximal masseter muscle prominence at clench (mouth closed and teeth clenched). 
 
 
 

 
 
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Table 3 
Injection Volume by Cohort 
Cohort 
Total Dose 
Dose / 
Masseter 
Total Injection Volume (mL) 
Volume Per Injection (mL) 
1 
24 U 
12 U 
0.6 
0.1 
placebo 
placebo 
2 
48 U 
24 U 
1.2 
0.2 
placebo 
placebo 
3 
72 U 
36 U 
1.8 
0.3 
placebo 
placebo 
4 
96 U 
48 U 
2.4 
0.4 
placebo 
placebo 
 
Based on meeting retreatment criteria described in Section 5.10, subjects may receive a 
second treatment (same as that of day 1 [BOTOX or placebo]) administered in the same 
manner. 
5.7 
Storage of Study Treatment 
Study treatment must be stored in a secure area and administered only to subjects entered into 
the clinical study, at no cost to the subject, in accordance with the conditions specified in this 
protocol. 
Lyophilized vials of study medication must be stored immediately upon receipt within the 
temperature range referenced in the Study Manual until used.  Refer to the Study Manual for 
more detailed instructions. 
5.8 
Preparation of Study Medications/Treatments 
At each study site, a designated staff member will serve as the DR.  This person will be 
responsible for study treatment preparation. 
 
 
Detailed instructions on reconstitution and syringe preparation are provided in the Study 
Manual. 

 
 
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5.9 
Treatment Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 

 
 
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5.10 
Retreatment 
After treatment on day 1, subjects will receive a second treatment based on meeting the 
following criteria at the day 180 visit: 
• Allergan decision and written notification to study sites allowing a second treatment 
• Subject has presence of bilateral masseter muscle hypertrophy of at least marked 
(grade 4), as measured by the investigator using the MMPS. 
• Females of childbearing potential must have a negative urine pregnancy test prior to 
treatment. 

 
 
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The second treatment is only allowed at the day 180 visit.  Retreatment is prepared and 
administered in the same manner as described in Sections 5.1 to 5.9.  Subjects will receive 
the same treatment at day 180 as they received at day 1. 
6 
Response Measures and Summary of Data Collection Methods 
6.1 
Efficacy Measures 
6.2 
Primary Efficacy Measure 
• lower facial volume (cm3) calculated from VECTRA M3 digital photography system 3D 
image models 
(see Attachment 12.1.2) 
6.3 
Secondary Efficacy Measure 
• investigator’s assessment of MMH using the MMPS (5 grades:  1 = minimal, 2 = mild, 
3 = moderate, 4 = marked, 5 = very marked; see Attachment 12.1.1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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6.5 
Other Study Supplies 
The following will be provided by Allergan: 
• temperature recording device for monitoring refrigerator’s temperature 
. will provide the photography system for the dental photographs to 
the dentists and the VECTRA M3 digital photography system and corresponding equipment. 
The following will be provided by the site: 
• cotton pads and makeup remover 
• alcohol wipes 
• medical gloves 
• urine pregnancy test kits with minimum sensitivity of 25 IU/mL 
• sterile surgical marker pens 
• appropriately sized sterile needles and syringes for study treatment reconstitution and 
injection 

 
 
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• sterile saline (0.9% without preservative) 
• refrigerator to store study treatment kits according to the Study Manual 
• covered container for discarded medical waste materials (sharps box) 
• internet connection (high-speed connection for electronic case report form completion) 
6.6 
Summary of Methods of Data Collection 
This protocol will use electronic case report forms (eCRFs) using remote electronic data 
capture (EDC) through a qualified third party vendor.  The data will be entered on the eCRFs 
on an ongoing basis throughout the study. 
7 
Statistical Procedures 
A detailed statistical analysis plan will be generated and finalized prior to the first cohort 
day 90 database snapshot. 
For each cohort, there will be a database snapshot with key data through the day 90 visit, for 
the purpose of the DRC.  There will be a final database lock with all study data after all 
subjects have completed the study (final cohort day 360).  Subjects’ treatment assignment 
will remain blinded for all site personnel, study subjects, and Allergan personnel directly 
involved with ongoing operational activities of the clinical study, until completion of the final 
database lock. 
7.1 
Analysis Populations 
All efficacy analyses will be performed on the modified intent-to-treat (mITT) population as 
treated, consisting of all randomized subjects who received study treatment and had at least 
1 follow-up visit.  A per-protocol (PP) analysis will also be performed on the primary 
endpoint.  The PP population will be defined prior to database lock.  Criteria used as a 
guideline in determining the exclusion of subjects or data from the PP analysis include 
violation of key inclusion and exclusion criteria, taking prohibited medication, and receiving 
the incorrect treatment. 
The safety analyses will be based on the safety population, which will include all subjects 
who receive at least 1 injection of treatment.  All safety analyses will be performed with 
subjects analyzed by their actual treatment or regimen received on day 1. 

 
 
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7.2 
Collection and Derivation of Primary and Secondary Efficacy 
Assessments 
Efficacy results for all study visits will be summarized based on time since injection.  Visit 
windows for all timepoints will be described in the statistical analysis plan. 
Pairwise comparisons will be done between each BOTOX group and the placebo group.  A 
pairwise comparison will also be done between a BOTOX group and the next higher dose 
BOTOX group.  For interim analyses, subjects in the placebo group(s) from previous 
cohort(s) will be pooled with the placebo group from the current cohort for analysis if the 
results for the placebo groups are combinable.  For final analysis, all subjects who received 
placebo will be pooled together as a total placebo group if the results for the placebo groups 
are combinable.  Details will be specified in the Analysis Plan. 
The primary efficacy variable will be the lower facial volume at day 90.  The change from 
baseline in lower facial volume will be analyzed by analysis of variance (ANOVA) with 
treatment and baseline (day 1) MMPS grade as factors to assess the response between 
groups. 
For analysis of the mITT population, the last observation carried forward (LOCF) method 
will be used to impute missing values.  For analysis of the PP population, observed data 
without imputation will be used. 
7.2.1 
Primary Efficacy Variable 
The primary efficacy variable, change from baseline in lower facial volume (cm3), is 
calculated from VECTRA M3 digital photography system 3D image models 
 
 
7.2.2 
Secondary Efficacy Variable 
The secondary efficacy variable is the investigator’s assessment of MMH using the MMPS 
(1 = minimal, 2 = mild, 3 = moderate, 4 = marked, 5 = very marked). 

 
 
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7.3 
Hypothesis and Methods of Analysis 
7.3.1 
Primary Efficacy Analyses 
Descriptive statistics for change from baseline in lower facial volume for each study visit 
(sample size, mean, standard deviation, median, minimum, and maximum) will be provided 
by treatment regimen for all scheduled visits. 
The primary efficacy analysis will be based on the mITT population.  Day 90 is the primary 
timepoint. 
The following set of hypotheses will be used to compare the BOTOX groups with placebo: 
• Null hypothesis:  BOTOX and placebo are equally effective in changing lower facial 
volume at day 90. 
• Alternative hypothesis:  BOTOX and placebo are not equally effective in changing lower 
facial volume at day 90. 
The change from baseline in lower facial volume at each visit will be analyzed using an 
ANOVA model with treatment and baseline (day 1) MMPS grade as factors.  In addition, 2-
sided 95% confidence intervals for the treatment differences will be provided. 
Analysis will be performed for the PP population and also based on observed data (ie, strictly 
data that falls within the visit windows) for the mITT population. 
7.3.2 
Secondary Efficacy Analyses 
The proportion of responders will be analyzed with a responder defined as subjects who 
achieve an MMPS grade of ≤ 3.  The proportion of responders will be analyzed using 
Cochran-Mantel-Haenszel (CMH) tests stratified by baseline (day 1) MMPS grade. 
 
 
 
 
 
 
 

 
 
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7.4 
Subgroup Analyses 
Subgroup analyses of the primary efficacy variable will be provided by subgroups of race 
(Asian and non-Asian), gender, age (18 to 35 years and 36 to 50 years), and baseline (day 1) 
MMPS grade (4 and 5). 
7.5 
Sample Size Calculation 
The sample size used in this study is determined empirically. 
For each cohort, 40 subjects will be randomized to BOTOX, and 10 subjects will be 
randomized to placebo.  Assuming the VECTRA lower facial volume is a normal distribution 
and the effect size is 1, a 1-sided test with 0.10 significance level will have 93% power to 
detect a statistically significant change in the BOTOX group compared with the placebo 
group.  The commercial software nQuery version 6.01 procedure MTT0U-1 was used for the 
power calculation. 
7.6 
Interim Analyses 
An interim database lock may be performed to support a regulatory filing, if needed.  The 
treatment assignments will be unblinded to selected individuals for interim analyses.  
Unblinded data will be disseminated only to Allergan personnel who are directly involved in 
submission-related activities.  These data will remain blinded for all Allergan personnel who 
are directly involved with the ongoing operational activities of the clinical study, all subjects, 

 
 
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and all site personnel until the final database lock.  Further details regarding an interim 
analysis will be provided in the analysis plan. 
7.7 
Final Analyses 
A final database lock will be performed following the last subject’s completion of the 
day 360 (study exit or early discontinuation) visit.  All study data, from every subject and 
every visit, will be included in this final analysis. 

 
 
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8 
Study Visit Schedule and Procedures 
Please see Table 1 for a schematic of the schedule of visits and procedures. 
8.1 
Subject Entry Procedures  
8.1.1 
Overview of Entry Procedures 
Prospective subjects as defined by the criteria in Sections 4.3 and 4.4 (inclusion and 
exclusion criteria, respectively) will be considered for entry into this study. 
8.1.2 
Informed Consent and Subject Privacy 
The study will be discussed with the subject, and a subject wishing to participate must give 
informed consent prior to any study-related procedures or change in treatment.  The subject 
must also give authorization and other written documentation in accordance with the relevant 
country and local privacy requirements (where applicable) prior to any study-related 
procedures or change in treatment. 
Each subject that provides informed consent will be assigned a subject number that will be 
used on subject documentation throughout the study. 
8.2 
Washout Intervals/Run-in 
Subjects taking prohibited medications, agents that could interfere with neuromuscular 
transmission, or muscle relaxants must undergo a washout of the medication(s) for at least 
28 days prior to entering the study.  If washout is required for the purposes of this study then 
the subject must sign the informed consent before the washout is commenced. 
For subjects who have undergone facial shaping procedures (eg, use of fat-reducing 
injectables or skin-tightening laser treatments; implantation of a prosthetic device or 
autologous fat transplantation; use of temporary, semi-permanent, or permanent filler product 
in the face) prior to screening, the procedure must have occurred at least 6 months prior to 
entering the study. 
8.3 
Procedures for Final Study Entry 
A subject is considered to have enrolled in the study upon randomization to treatment on 
day 1 after completion of all pre-treatment and randomization procedures and after the 
investigator re-verifies the subject has met all the inclusion and exclusion criteria for study 

 
 
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entry.  Some inclusion and exclusion criteria will require verification by the dentist, 
radiologist, or CT technologist.  Prior to day 1, 
. must approve each 
subject’s VECTRA photos; 1 retake will be allowed before day 1 if the photos are not 
acceptable. 
See Section 5.5 for the method for assignment to treatment groups/randomization. 
8.4 
Visits and Associated Procedures 
Training 
The investigator performing MMPS and LFSC assessments will be trained on the appropriate 
use of the MMPS and LFSC prior to screening study subjects.  Documentation of 
investigator training will be maintained in the study center regulatory binder with a copy sent 
to Allergan. 
On day 1, enrolled subjects will view a training presentation on how to use the LFSC to 
assess their own lower facial shape.  Each subject will choose the lower facial shape grade 
that best matches the contour of the lower portion of his/her face (1, 2, 3, or 4). 
Screening, Treatment, and Follow-up Visits 
For a summary of the procedures to be performed at scheduled visits, see Table 1 (Schedule 
of Visits and Procedures). 
Evaluations should be performed by the same evaluator throughout the study whenever 
possible.  If it is not possible to use the same evaluator to follow the subject, then evaluations 
should overlap (examine the subject together and discuss findings) for at least 1 visit. 
8.5 
Instructions for the Subjects 
Once their VECTRA photos have been approved by 
., subjects will be 
instructed to maintain their baseline weight (remain within 10% of baseline) and, for males, 
maintain a clean-shaven lower face for study visits. 
8.6 
Unscheduled Visits 
Unscheduled visits can be performed if safety concerns arise and at the discretion of the 
investigator.  If a subject is seen for an unscheduled visit, an assessment and record of 

 
 
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adverse events should be completed.  Additional evaluations should be performed, as 
necessary, and the appropriate case report forms should be completed. 
8.7 
Compliance with Protocol 
Enrolled subjects should be able to attend all clinic visits for treatment administration and 
followup. 
8.8 
Early Discontinuation of Subjects 
Subjects may voluntarily withdraw from the study at any time.  Notification of early subject 
discontinuation from the study and the reason for discontinuation will be made to Allergan 
and will be clearly documented on the appropriate case report form.  All day 360/study exit 
procedures should be performed (Table 1), including an exit CT scan, unless the investigator 
proposes a medical reason to waive the exit CT scan. 
8.9 
Withdrawal Criteria 
Subjects should be discontinued from the study if any of the following criteria are met. 
• Subject develops (or has an exacerbation of) any medical condition that, in the opinion of 
the investigator, would put the subject at an unacceptable medical risk or compromises 
the subject’s ability to participate in the study. 
• Subject is unable/unwilling to comply with study procedures. 
Where possible, the decision to withdraw a subject from the study should be discussed with 
Allergan. 
8.10 
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 case report 
form.  If adverse events occur, the first concern will be the safety of the study participants.  

 
 
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9.1 
Definitions 
9.1.1 
Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.  In addition, during the screening period, adverse events 
will be assessed regardless of the administration of a pharmaceutical product. 
Note:  Adverse events must be collected once informed consent has been obtained, regardless 
of whether or not the subject has been administered study drug. 
Progression of treatment indication including new or worsening of anticipated clinical signs 
or symptoms, which are collected as clinical efficacy variables and assessed as unequivocally 
associated with the disease progression and/or lack of efficacy, should NOT be reported as 
adverse events unless the disease progression is greater than anticipated in the natural course 
of the disease. 
Adverse events will be assessed, documented, and recorded in the case report forms 
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 subject 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 case report form. 
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 
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Allergan considers all cancer adverse events as serious adverse events.  In addition, Allergan 
considers any abortion (spontaneous or nonspontaneous) as a serious adverse event. 
Pre-planned surgeries or procedures for pre-existing, known medical conditions for which a 
subject requires hospitalization is not reportable as a serious adverse event. 
Any pre-planned surgery or procedure should be clearly documented in the site source 
documents by the medically qualified investigator at the time of the subject’s entry into the 
study.  If it has not been documented at the time of the subject’s entry into the study, then it 
should be documented as a serious adverse event and reported to Allergan. 
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 that 
cannot be graded. 
 
9.1.4 
Relationship to Study Drug or Study Procedure 
A determination will be made of the relationship (if any) between an adverse event and the 
study drug or study procedure, as applicable.  A causal relationship is present if a 
determination is made that there is a reasonable possibility that the adverse event may have 
been caused by the drug or study procedure. 
9.2 
Procedures for Reporting Adverse Events 
Any adverse event must be recorded on the appropriate case report form. 
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 Institutional Review 
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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 but no later than 24 hours after learning of a serious adverse event.  Serious adverse 
events must be reported to Allergan as listed on the Allergan Study Contacts Sheet and 
recorded on the serious adverse event form.  All subjects with a serious adverse event must 
be followed up and the outcomes reported.  The investigator must supply Allergan and the 
IRB/IEC with any additional requested information (eg, autopsy reports and discharge 
summaries).  
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 Study Contacts 
Page. 
2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and followup of 
the subject. 
3. Provide Allergan with a complete, written description of the adverse event(s) on 
the serious adverse event form describing the event chronologically, including any 
treatment given (eg, medications administered, procedures performed) for the 
adverse event(s).  Summarize relevant clinical information about the event:  signs, 
symptoms, diagnosis, clinical course and relevant clinical laboratory tests, etc.  
Include any additional or alternative explanation(s) for the causality 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. 

 
 
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9.4 
Procedures for Unmasking of Study Medication 
When necessary for the safety and proper treatment of the subject, the investigator can 
unmask the subject’s treatment assignment to determine which treatment has been assigned 
and institute appropriate follow-up care.  When possible, the sponsor (Allergan Medical 
Safety Physician) should be notified prior to unmasking study medication.  The investigator 
should inform the sponsor (Allergan Medical Safety Physician) of the unmasking if there is 
no notification prior to the unmasking. 
The treatment assignment for the subject can be determined by designated site personnel 
calling into the IVRS or IWRS system via password protected access.  The reason for 
breaking the code must be recorded in the subject’s source documents. 
10 
Administrative Items 
This protocol is to be conducted in accordance with the applicable Good Clinical Practice 
(GCP) regulations and guidelines, eg, the International Conference on Harmonisation (ICH) 
Guideline on GCP. 
10.1 
Protection of Human Subjects 
10.1.1 
Compliance with Informed Consent Regulations (US 21 CFR 
Part 50) and Relevant Country Regulations 
Written informed consent is to be obtained from each subject prior to any study-related 
activities or procedures in the study, and/or from the subject's legally authorized 
representative.  If the subject 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. 
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 subjects, or when the changes involve only logistical or administrative aspects of the 
study (eg, change in monitors or change of telephone numbers). 
10.3 
Subject 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 
subject’s name will not be disclosed in these documents.  The subject's name may be 
disclosed to the Sponsor of the study, Allergan, or the governing health authorities or the US 
Food and Drug Administration (FDA) if they inspect the study records.  Appropriate 
precautions will be taken to maintain confidentiality of medical records and personal 
information. 
10.3.1 
Subject Privacy 
Personal information protection authorization, privacy documentation, and other 
documentation in accordance with the relevant country and local privacy requirements 
(where applicable) are to be obtained from each subject prior to enrollment into the study, 
and/or from the subject's legally authorized representative in accordance with the applicable 
privacy requirements (eg, the Personal Information Protection and Electronic Documents Act 
[PIPEDA]). 

 
 
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In accordance with local personal information protection authorization or privacy 
documentation requirements, additional purposes of this study include publishing anonymous 
subject data from the study. 
10.4 
Documentation 
10.4.1 
Source Documents 
Source documents may include a subject's medical records, hospital charts, clinic charts, the 
investigator's subject study files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and electrocardiograms.  The investigator's copy of the eCRFs serves as part 
of the investigator's record of a subject's study-related data. 
The following information should be entered into the subject's medical record: 
• subject’s name 
• subject’s initials (coded) 
• subject’s age 
• subject number 
• subject’s contact information 
• the date that the subject entered the study, subject number, and subject randomization (or 
medication kit) number 
• the study title and/or the protocol number of the study and the name of Allergan 
• a statement that informed consent, local personal information protection authorization or 
privacy documentation, or other country and local subject privacy required 
documentation for this study has been obtained (including the dates) 
• dates of all subject visits 
• all concurrent medications (List all prescription and non-prescription medications being 
taken at the time of enrollment.  At each subsequent visit, changes to the list of 
medications should be recorded.) 
• occurrence and status of any adverse events 

 
 
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• the date the subject exited the study, and a notation as to whether the subject completed 
the study or reason for discontinuation 
• results of urine pregnancy tests 
• key study variables 
10.4.2 
Case Report Form Completion 
The investigator is responsible for ensuring that data are properly recorded on each subject's 
eCRFs and related documents.  An investigator who has signed the protocol signature page 
should personally sign the eCRFs (as indicated in the eCRF) to ensure that the observations 
and findings are recorded on the eCRFs correctly and completely.  The eCRFs are to be 
completed in a timely manner at the completion of the study, or as otherwise specified by 
Allergan. 
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, subject records, consent forms, subject privacy 
documentation, records of the distribution and use of all investigational products, and copies 
of eCRFs should be maintained on file. 
For countries falling within the scope of the ICH guidelines, 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 if required by the applicable regulatory requirement(s) 
or if needed by Allergan. 
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation. 

 
 
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Allergan requires that it be notified in writing if the investigator wishes to relinquish 
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of 
ownership to a suitably qualified, responsible person. 
10.5 
Labeling, Packaging, and Return or Disposal of Study 
Medications/Treatments 
10.5.1 
Labeling/Packaging 
The investigational materials will be packaged and labeled in identically appearing vials.  
The study treatment will be identified as an investigational compound.  The study number 
and kit number will be identified on the unit label. 
10.5.2 
Clinical Supply Inventory 
The investigator must keep an accurate accounting of the number of investigational units 
received from Allergan, dispensed to the subjects, the number of units returned to the 
investigator by the subject, and the number of units returned to Allergan during and at the 
completion of the study.  A detailed inventory must be completed for the study medication.  
The study medication must be dispensed only by an appropriately qualified person to 
subjects in the study.  The medication is to be used in accordance with the protocol by 
subjects who are under the direct supervision of an investigator.  A unit is defined as a study 
medication vial. 
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 investigators and appropriate staff at mutually convenient times to discuss 
study-related data and questions. 
10.7 
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. 
11 
References 
Adriaens J, van Loon B, Ingels KJ, Berge SJ, Maal TJ.  Three-dimensional 
stereophotogrammetric method of quantifying the effect of botulinum toxin type A injections 
on masseter hypertrophy.  Plast Reconstr Surg.  2012;130(2):376e-378e. 
Ahn J, Horn C, Blitzer A.  Botulinum toxin for masseter reduction in Asian patients.  Arch 
Facial Plast Surg.  2004;6(3):188-191. 
Aydil B, Basaran B, Unsaler S, Suoglu Y.  The use of botulinum toxin type A in masseteric 
muscle hypertrophy:  long-term effects and lasting improvement.  Kulak Burun Boggaz Ihtis 
Derg (Journal of Ear, Nose and Throat).  2012;22(5):249-253. [English translation from 
Turkish] 
Chang CS, Bergeron L, Yu CC, Chen PKT, Chen YR.  Mandible changes evaluated by 
computed tomography following botulinum toxin A injections in square-faced patients.  
Aesth Plast Surg.  2011;35:452-455. 
Choe SW, Cho WI, Lee CK, Seo SJ.  Effects of botulinum toxin type A on contouring of the 
lower face.  Dermatol Surg.  2005;31(5):502-508. 
de Menezes M, Rosati R, Ferrario VF, Sforza C.  Accuracy and reproducibility of a 
3-dimensional stereophotogrammetric imaging system.  J Oral Maxillofac Surg.  
2010;68:2129-2135. 
Hong HS, Kang SC, Kim C-Y, Kim ST.  Long-term evaluation of the effect of botulinum 
toxin A injection in patients with masseteric hypertrophy.  Korean J Oral Med.  
2005;30(1):121-129. 

 
 
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Kim HJ, Yum K-W, Lee S-S, Heo M-S, Seo K.  Effects of botulinum toxin type A on bilateral 
masseteric hypertrophy evaluated with computed tomographic measurement.  Dermatol Surg.  
2003;29:484-489. 
Kim J-H, Shin JH, Kim ST, Kim C-Y.  Effects of two different units of botulinum toxin type 
A evaluated by computed tomography and electromyographic measurement of human 
masseter muscle.  Plast Reconstr Surg.  2007;119(2):711-717. 
Kim N-H, Chung J-H, Park R-H, Park J-B.  The use of botulinum toxin type A in aesthetic 
mandibular contouring.  Plast Reconstr Surg.  2005;115(3):919-930. 
Liew S, Dart A.  Nonsurgical reshaping of the lower face.  Aesthet Surg J.  2008;28(3):251-
257. 
Mischkowski RA, Siessegger M, Lazar F, Zoller JE.  [Chemodenervation with botulinum 
toxin in masseteric hypertrophy].  Mund-, Kiefer-und Gesichtschir.  2005;9(2):101-108. 
Moore AP, Wood GD.  The medical management of masseter hypertrophy with botulinum 
toxin type A.  Br J Oral Maxillofac Surg.  1994;32(1):26-28. 
Navarrete AL, Rafferty KL, Liu ZJ, Ye W, Greenlee GM, Herring SW.  Botulinum neurotoxin 
type A in the masseter muscle:  effects on incisor eruption in rabbits.  Am J Orthod 
Dentofacial Orthop.  2013;143:499-506. 
Park MY, Ahn KY, Jung DS.  Botulinum toxin type A treatment for contouring of the lower 
face.  Dermatol Surg.  2003;29:477-483. 
Rafferty KL, Liu ZJ, Ye W, Navarrete AL, Nguyen TT, Salamati A, et al.  Botulinum toxin in 
masticatory muscles: short- and long-term effects on muscle, bone, and craniofacial function 
in adult rabbits.  Bone.  2012;50:651-662. 
Smyth AG.  Botulinum toxin treatment of bilateral masseteric hypertrophy.  Br J Oral 
Maxillofac Surg.  1994;32(1):29-33. 
Tsai CY, Huang RY.  Growth changes in craniofacial morphology after reducing masticatory 
muscle activity in adult rats.  J Dent Sci.  2008;3:204-211. 
Tsai CY, Huang RY, Lee CM, Hsiao WT, Yang LY.  Morphologic and bony structural changes 
in the mandible after a unilateral injection of botulinum neurotoxin in adult rats.  J Oral 
Maxillofac Surg.  2010;68:1081-1087. 

 
 
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Tzou C-H J, Frey M.  Evolution of 3D surface imaging systems in facial plastic surgery.  
Facial Plast Surg Clin North Am.  2011;19:591-602. 

 
 
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12 
Attachments 
12.1 
Examination Procedures, Tests, Equipment, and Techniques 
12.1.1 
Masseter Muscle Prominence Scale (MMPS) 
Instructions 
Using visual inspection and palpation, you will rate the masseter muscle prominence during 
rest and function, by separately evaluating the right and left side of the subject’s face. 
• Sit directly in front of the subject and inspect the contour of the face in the clenched and 
unclenched state. 
• Define the posterior and anterior border of each masseter, as well as the superior and 
inferior margins. 
• While the subject clenches and relaxes, use your fingers to feel the dimensions and 
surface texture of each masseter. 
• Have the subject repeat the sequence of clenching and relaxing at least twice.  As best as 
possible, distinguish masseter muscle from bone and other non-muscular soft tissue 
(eg, fat). 
• Rate each masseter separately, and record your ratings.  In the presence of discordant 
assessment between rest and clenched states, the subject’s masseter prominence 
assessment noted in the clenched state should factor most significantly in determining the 
overall rating for each side of the face. 
 

 
 
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Rating 
Clinical Evaluation 
Minimal (1) 
AT REST:  With mouth closed and no clenching, surface overlying masseter is 
concave.  There is no contour contributed by masseter muscle.  Masseter is not 
palpable.  
AT CLENCH:  No visible difference in contour compared with when mouth is closed, 
no clenching.  Masseter is minimally palpable and difficult to define. 
Mild (2) 
AT REST:  With mouth closed and no clenching, surface overlying masseter is flat or 
slightly concave.  The contour contributed by masseter muscle may or may not be 
visible.  Masseter is minimally palpable. 
AT CLENCH:  With clenching, minimal difference in lower facial contour compared 
with when mouth is closed, no clenching.  Portion of masseter bulk may be visible and 
palpable. 
Moderate (3) 
AT REST:  With mouth closed and no clenching, surface overlying masseter is flat or 
convex.  The contour contributed by masseter muscle may or may not be visible.  
Masseter is palpable. 
AT CLENCH:  With clenching, the lower face is more convex in contour compared 
with when mouth is closed, no clenching.  Masseter bulk is easily identifiable, 
palpable, and firm. 
Marked (4) 
AT REST:  With mouth closed and no clenching, surface overlying masseter is 
convex.  The masseter muscle, in conjunction with the chin and jawline, creates a 
square lower facial contour.  Masseter is palpable and firm. 
AT CLENCH:  With clenching, the lower face is wider and squarer compared with 
when mouth is closed, no clenching.  Masseter is palpable and firm or hard. 
Very Marked (5) 
AT REST:  With mouth closed and no clenching, surface overlying masseter is 
convex.  The masseter muscle, in conjunction with the chin and jawline, creates a 
trapezoidal lower facial contour.  Masseter is palpable and firm. 
AT CLENCH:  With clenching, the lower face is more trapezoidal compared with 
when mouth is closed, no clenching.  Masseter is palpable and hard. 
 

 
 
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12.1.2 
Lower Facial Volume Measurement 
The lower facial volume measurement (cm3) will be performed by 
 
To measure the difference in volume between two 3D surface models from different 
timepoints (ie, baseline and posttreatment), the models are first registered in 3D space such 
that relative surfaces unrelated to the treatment regions are correspondingly aligned.  The 
analysis region is then defined using a series of anatomical landmarks placed on the baseline 
surface that are then projected mathematically to the posttreatment surface and verified by 
the analysis technician. 
In Figure 2, the green-shaded region represents the defined measurement selection area 
created by the perimeter formed using landmarks (C-F-D-E).  Anatomical landmarks are 
located at:  Lateral canthus (A), Alar recess (B), Earlobe attachment point (C), Prejowl 
sulcus (D), Mandible point (E).  A single interpolated landmark (F) is also used at the 
intersection point of surface lines between points (A)-(D) and (B)-(C). 
The difference in volume is then measured between the select region of the baseline surface 
and the select region of the posttreatment surface.  The lower facial volume is the summed 
volumes for both the left side and the right side of the face, which will be compared between 
each paired baseline/posttreatment timepoint for the study. 
In response to treatment, the region is expected to decrease in volume. 
Figure 2 
Lower Facial Volume Measurement 
 

 
 
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12.2 
Glossary of Abbreviations 
Term/Abbreviation 
Definition 
2D 
2-dimensional 
3D 
3-dimensional 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
CMH 
Cochran-Mantel-Haenszel 
CPAP 
continuous positive airway pressure 
CT 
computed tomography 
DR 
drug reconstitutor 
DRC 
data review committee 
eCRF 
electronic case report form 
EDC 
electronic data capture 
GCP 
Good Clinical Practices 
ICH 
International Conference on Harmonisation 
ID 
identification 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LFSC 
Lower Facial Shape Classification 
LFSQ 
Lower Facial Shape Questionnaire 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMH 
masseter muscle hypertrophy 
MMPS 
Masseter Muscle Prominence Scale 
MRI 
magnetic resonance imaging 
OA 
osteoarthritis 
PP 
per(-)protocol 
ROI 
region of interest 
TMJD 
temporomandibular joint disorder 
US(A) 
United States (of America) 

 
 
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12.3 
Protocol Amendment Summary 
Title:  BOTOX® Treatment of Masseter Muscle Hypertrophy 
Protocol 191622-130 Amendment 1 
Date of Amendment:  February 2014 
Amendment Summary 
This summary includes changes made to Protocol 191622-130 (18 October 2013).  Based on 
input from study dentists and radiologists, this protocol was amended to:  1) revise and 
clarify the CT assessments; and 2) revise and clarify specific measurements and analyses. 
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 
Revision 
Rationale 
Protocol 
Summary; 
Section 3 
Added that approximately 
50 subjects will be enrolled in 
each cohort:  approximately 40 
will receive BOTOX and 
approximately 10 will receive 
placebo 
Clarification 
Protocol 
Summary; 
Table 1; 
Section 3; 
Section 5.5 
Clarified that baseline MMPS 
grade is from day 1 assessment 
and that randomization and 
enrollment will not occur until 
after all baseline procedures are 
performed and the investigator 
has re-verified that subjects meet 
the inclusion and exclusion 
criteria 
Clarification 
 
 
 
 
 
 
 
 
 
Protocol 
Summary; 
Section 4.1 
Updated that “Subjects will be 
enrolled at approximately 4 to 
12 investigational sites” 
To allow for at least 4 investigational 
sites 

 
 
Approval Date: 
 
28-Feb-2014
Allergan Confidential 
Protocol 191622-130 Amendment 1 
 
 
82 
GDD-TA-T-004 v2013.9 
 
Section 
Revision 
Rationale 
Protocol 
Summary; 
Section 4.3 
Added “or older if legal age of 
adulthood is > 18 as per local 
regulations” as minimum age for 
enrollment 
To clarify that the minimum age of 
enrollment is 18 years or older if the 
country-specific legal age of adulthood is 
> 18 years 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol 
Summary; 
Sections 7.2, 
7.3.1 
Changed ANCOVA to ANOVA 
method of analysis of primary 
endpoint, removal of baseline 
value 
Primary measure (based on VECTRA 3D 
images) does not produce a baseline 
value; change will be measured at later 
time points relative to the subject’s own 
baseline image. 
Figure 1 
Updated figure to raise Line A 
Correction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Approval Date: 
 
28-Feb-2014
Allergan Confidential 
Protocol 191622-130 Amendment 1 
 
 
83 
GDD-TA-T-004 v2013.9 
 
Section 
Revision 
Rationale 
 
 
  
 
 
 
 
Section 8.2 
Removed paragraph separation 
between and reordered the first 
2 sentences 
Timing of informed consent in relation to 
washout is relevant to neuromuscular 
agents and muscle relaxants but not to the 
procedures specified for 6 months prior 
to study entry. 
Section 8.8 
and Table 1 
Updated to indicate that if a 
subject discontinues from the 
study early, an exit CT scan 
should be performed, unless the 
investigator proposes a medical 
reason to waive 
To allow for a final CT scan of the 
subject 
Section 
10.4.2 
Removed the statement that 
eCRFs will be maintained in a 
central data repository 
Update 
Section 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Approval Date: 
 
28-Feb-2014
ALLERGAN 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY)/Time (PT) 
Signed by: 
Justification 
  
 
 
            
 
           
 
            
 
           
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
Protocol 191622-130 Amd 1