Clinical trial NCT03861936
Conditions: Masseter Muscle Prominence
Sponsor: Allergan
Start date: 2019-05-16; Completion date: 2020-07-02
Enrollment: 150 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Based on the results of the Phase 2 Study 191622-130 \[NCT02010775\], the current Phase 2b study is designed to further evaluate the safety and efficacy of BOTOX® for the treatment of Masseter Muscle Prominence (MMP) in adults.

Detailed description:

Arms: arm 1: OnabotulinumtoxinA (botulinum toxin Type A; BOTOX®) 72 units (U) total dose administered intramuscularly to the bilateral masseter muscles on Day 1. arm 2: OnabotulinumtoxinA (botulinum toxin Type A; BOTOX®) 48U total dose administered intramuscularly to the bilateral masseter muscles on Day 1. arm 3: Placebo (Normal saline) administered intramuscularly to the bilateral masseter muscles on Day 1.
Interventions: intervention 1: OnabotulinumtoxinA intervention 2: Normal saline
Intervention descriptions: intervention 1: OnabotulinumtoxinA (botulinum toxin Type A;BOTOX®) administered intramuscularly to the bilateral masseter muscles on Day 1. intervention 2: Normal saline (placebo) administered intramuscularly to the bilateral masseter muscles on Day 1.

Protocol documents:
Prot_000.pdf: 
 
   
 
 
 
         NCT03861936 
 
Study ID: 1789-202-008 
 
 
Title: BOTOX® (onabotulinumtoxinA) Treatment of Masseter Muscle 
Prominence: A Phase 2b, Multicenter, Randomized, Double-Blind, Multi-
Dose, Placebo-Controlled Study 
 
                             Protocol Date: February 12, 2019 


 
 
Approval Date: 
 
12-Feb-2019
 
 
Protocol 1789-202-008 
BOTOX 
 
 
Title Page 
Protocol Title: BOTOX® (onabotulinumtoxinA) Treatment of Masseter Muscle Prominence: 
A Phase 2b, Multicenter, Randomized, Double-Blind, Multi-Dose, Placebo-Controlled Study 
Protocol Number: 1789-202-008 
Product: OnabotulinumtoxinA 
Brief Protocol Title: BOTOX Treatment of Masseter Muscle Prominence 
Development Phase: 2b 
Sponsor Name and Legal Registered Address:  
Allergan Sales LLC  
5 Giralda Farms 
Madison, NJ 07940 
USA 
Regulatory Agency Identifying Number: IND 133,035 
Emergency Telephone Number 
 
 
Refer to the study contacts page 
SAE Reporting Fax Number/Email: 
 
 
Business Unit  
Email 
Phone 
Fax 
Allergan 
 
Not applicable 
 
 
Sponsor Signatory: 
  
Associate Vice President and Section Head 
Medical Aesthetics 
Refer to the final page of this protocol for electronic signature and date of approval. 
 
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Table of Contents 
Title Page ........................................................................................................................................1 
Table of Contents ...........................................................................................................................2 
List of Tables ..................................................................................................................................5 
List of Figures .................................................................................................................................5 
1. 
Protocol Summary ..........................................................................................................6 
1.1. 
Synopsis ............................................................................................................................6 
1.2. 
Schema ..............................................................................................................................9 
1.3. 
 
2. 
Introduction ...................................................................................................................13 
2.1. 
Study Rationale ...............................................................................................................13 
2.2. 
Background .....................................................................................................................14 
2.3. 
Benefit/Risk Assessment ................................................................................................15 
3. 
Objectives and Endpoints ............................................................................................17 
4. 
Study Design ..................................................................................................................18 
4.1. 
Overall Design ................................................................................................................18 
4.2. 
Scientific Rationale for Study Design ............................................................................18 
4.3. 
Justification for Dose ......................................................................................................20 
4.4. 
End of Study Definition ..................................................................................................21 
5. 
Study Population ...........................................................................................................22 
5.1. 
Inclusion Criteria ............................................................................................................22 
5.2. 
Exclusion Criteria ...........................................................................................................23 
5.3. 
Lifestyle Considerations .................................................................................................25 
5.4. 
Screen Failures ................................................................................................................25 
6. 
Study Intervention ........................................................................................................26 
6.1. 
Study Interventions Administered ..................................................................................26 
6.1.1. 
Other Study Supplies ......................................................................................................29 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................29 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................30 
6.4. 
Study Intervention Compliance ......................................................................................31 
6.5. 
Concomitant Therapy .....................................................................................................31 
6.5.1. 
 
6.5.2. 
 
6.5.3. 
 
6.6. 
Dose Modification ..........................................................................................................33 
6.7. 
Intervention After the End of the Study ..........................................................................33 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................33 
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7.1. 
Discontinuation of Study Intervention ............................................................................34 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................34 
7.3. 
Lost to Follow Up ...........................................................................................................34 
8.
Study Assessments and Procedures.............................................................................36 
8.1. 
Efficacy Assessments .....................................................................................................36 
8.1.1. 
Primary Efficacy Assessment .........................................................................................36 
8.1.2. 
Secondary Efficacy Assessments ....................................................................................37 
8.1.3. 
Other/Exploratory Efficacy Assessments .......................................................................38 
8.1.4. 
Additional Assessments ..................................................................................................39 
8.2. 
Safety Assessments .........................................................................................................40 
8.2.1. 
Vital Signs .......................................................................................................................40 
8.2.2. 
Height and Weight ..........................................................................................................40 
8.2.3. 
Pregnancy Testing ...........................................................................................................40 
8.2.4. 
Oral Examination ............................................................................................................40 
8.2.5. 
Screening for TMJD .......................................................................................................41 
8.3. 
Adverse Events and Serious Adverse Events .................................................................41 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information ................................................................................41 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse 
Events ..............................................................................................................................42 
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ...........................................42 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ..................................42 
8.3.5. 
Pregnancy ........................................................................................................................43 
8.3.6. 
Protocol-Specific Adverse Events ..................................................................................43 
8.3.7. 
Adverse Events of Special Interest .................................................................................43 
8.3.8. 
Medication Errors ...........................................................................................................43 
8.4. 
Treatment of Overdose ...................................................................................................44 
8.5. 
Pharmacokinetics ............................................................................................................44 
8.6. 
Pharmacodynamics .........................................................................................................44 
8.7. 
Genetics ..........................................................................................................................44 
8.8. 
Biomarkers and Other Assessments ...............................................................................44 
8.9. 
Health Economics ...........................................................................................................44 
9.
Statistical Considerations .............................................................................................45 
9.1. 
Statistical Hypotheses .....................................................................................................45 
9.2. 
Sample Size Determination ............................................................................................45 
9.3. 
Populations for Analyses ................................................................................................45 
9.4. 
Statistical Analyses .........................................................................................................45 
9.4.1. 
Efficacy Analyses ...........................................................................................................46 
9.4.2. 
Safety Analyses ...............................................................................................................47 
9.4.3. 
Other Analyses ................................................................................................................48 
9.5. 
Interim Analyses .............................................................................................................48 
10.
Supporting Documentation and Operational Considerations ..................................49 
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10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................49 
10.1.1. Regulatory and Ethical Considerations ...........................................................................49 
10.1.2. Financial Disclosure ........................................................................................................49 
10.1.3. Informed Consent Process ..............................................................................................50 
10.1.4. Data Protection................................................................................................................50 
10.1.5. Posting Clinical Study Data ............................................................................................50 
10.1.6. Data Quality Assurance ..................................................................................................50 
10.1.7. Source Documents ..........................................................................................................51 
10.1.8. Study and Site Closure ....................................................................................................51 
10.1.9. Publication Policy ...........................................................................................................52 
10.1.10. Compliance with Protocol...............................................................................................52 
10.2. 
Appendix 2: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................53 
10.3. 
Appendix 3: Abbreviations .............................................................................................58 
10.4. 
Appendix 4: Standard Discontinuation Criteria..............................................................60 
10.5. 
Appendix 5: Study Tabular Summary ............................................................................62 
10.6. 
Appendix 6: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................64 
10.7. 
Appendix 7: Efficacy Measures ......................................................................................67 
10.7.1. Masseter Muscle Prominence Scale – Investigator Assessment .....................................67 
10.7.2. Lower Facial Volume Measurement ...............................................................................69 
10.7.3. Facial Width Measurement .............................................................................................70 
10.7.4. Mandibular Facial Angle Measurement ..........................................................................72 
10.8. 
Appendix 8: Example Patient Reported Outcomes 
Questionnaires, Descriptions, and Instructions...............................................................73 
10.8.1. Masseter Muscle Prominence Scale – Participant (MMPS-P) .......................................73 
10.8.2. Masseter Muscle Prominence Participant Self-Assessment of 
Change (PSAC) ...............................................................................................................75 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11. 
References ......................................................................................................................88 
 
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List of Tables 
Table 1–1 
Schedule of Visits and Procedures .................................................................... 11 
Table 6–1 
Study Interventions Administered ..................................................................... 26 
Table 6–2 
Injection Volume ............................................................................................... 29 
Table 10-1 
Highly Effective and Acceptable Contraceptive Methods ................................ 65 
 
List of Figures 
Figure 1-1 
Study Schema ...................................................................................................... 9 
Figure 6-1 
Schematic of Injection Area .............................................................................. 28 
Figure 10-1 
Lower Facial Volume Measurement ................................................................. 69 
Figure 10-2 
Standardized Target AOI from a 3D Facial Shape Model ................................ 70 
Figure 10-3 
Lower Facial Width Measurement .................................................................... 71 
Figure 10-4 
Mandibular Facial Angle Measurement ............................................................ 72 
 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: BOTOX® (onabotulinumtoxinA) Treatment of Masseter Muscle Prominence: 
A Phase 2b, Multicenter, Randomized, Double-Blind, Multi-Dose, Placebo-Controlled Study 
Protocol Number: 1789-202-008 
Brief Title: BOTOX Treatment of Masseter Muscle Prominence 
Study Phase: 2b 
Study Rationale: 
The masseter muscle is 1 of 4 muscles used for mastication. Prominence of the masseter muscle 
can appear as a widened lower face, which is an aesthetic concern for individuals who prefer a 
narrower lower face shape. When BOTOX is injected into a masseter muscle, BOTOX treatment 
has been observed to reduce the size of the muscle (Moore 1994), producing an effect perceived 
as lower facial shaping or slimming (Wu 2010). 
Study 191622-130 was the first Allergan-sponsored study of BOTOX for the treatment of 
masseter muscle prominence (MMP). This was a 12-month, multicenter, double-blind, 
randomized, placebo-controlled, dose-escalation, Phase 2 study in which BOTOX treatment of 
MMP was shown to be safe at doses ranging from 24 U (12 U/masseter) to 96 U 
(48 U/masseter). Participants were adults < 50 years with body mass index ≤ 30 kg/m2 and who 
had marked to very marked MMP, assessed by the investigator using the Masseter Muscle 
Prominence Scale (MMPS). For the primary and key secondary endpoints (at Day 90), 
statistically significant positive efficacy results were demonstrated for all 4 BOTOX doses, with 
a dose-dependent trend favoring the higher 3 doses (48 U, 72 U, and 96 U), which produced 
statistically significant changes in MMP compared with placebo. There were no safety trends or 
patterns identified with a dose increase, although facial paresis (including reports of weak or 
altered smile) was reported in the highest dose group (96 U) as a local effect.  
Based on the results of the Phase 2 Study 191622-130, the current Phase 2b study is designed to 
further evaluate the safety and efficacy of BOTOX 48 U and 72 U for the treatment of MMP in 
adults. 
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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
• 
To compare the efficacy of 
BOTOX with placebo in 
participants with bilateral 
MMP 
• 
Proportion of responders who achieve MMPS Grade ≤ 3 at Day 90, per 
investigator assessments of MMP using the MMPS (5 severity grades: 
1 = minimal, 2 = mild, 3 = moderate, 4 = marked, 5 = very marked) 
• 
To compare the safety of 
BOTOX with placebo in 
participants with MMP 
• 
Incidence of adverse events (AEs) and change from baseline in vital signs 
Secondary 
 
• 
To compare the efficacy of 
BOTOX with placebo in 
participants with MMP 
based on multiple clinical 
efficacy assessments 
• 
Proportion of responders who achieve Masseter Muscle Prominence Scale – 
Participant (MMPS-P) Grade ≤ 3 at Day 90, per participant assessments of 
MMP using the MMPS-P (5 severity grades: 1 = not at all pronounced, 
2 = mildly pronounced, 3 = moderately pronounced, 4 = pronounced, 
5 = very pronounced) 
• 
Proportion of responders who achieve ≥ 2-grade improvement from 
baseline at Day 90, per investigator using the MMPS  
• 
Proportion of responders who achieve ≥ 2-grade improvement from 
baseline at Day 90, per participant using the MMPS-P 
• 
Proportion of responders who achieve Participant Self-Assessment of 
Change (PSAC) Grade ≥ 2 (at least moderately improved from baseline) at 
Day 90, per participant using the PSAC 
• 
Change from baseline in lower facial volume (cm3) at Day 90, calculated 
from standardized images 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Overall Study Design: 
This is a 6-month, multicenter study consisting of a single treatment period. The study is a 
double-blind, randomized, placebo-controlled, single-treatment design, which will assess the 
safety and efficacy of BOTOX treatment for MMP. Up to 8 scheduled visits are planned: 
screening (Day -14 to Day -1), baseline (Day 1), follow-up (Days 30, 60, 90, 120, 150), and 
study exit (Day 180). 
Number of Participants: 
Approximately 150 participants will be randomized in a 1:1:1 ratio yielding approximately 
50 participants in each of the BOTOX 48 U and 72 U groups and 50 in the placebo group.  
Number of Sites: 
Approximately 15 sites in the US 
Intervention Groups and Study Duration: 
On Day 1, participants will be randomized in a 1:1:1 ratio to receive a single treatment of 
BOTOX 48 U, BOTOX 72 U, or placebo. Randomization will be stratified at each investigator 
site by the participant’s baseline MMPS Grade (4 or 5). After verification that the participants 
meet all inclusion and exclusion criteria and completion of all baseline study procedures, 
participants will be randomized and enrolled.  
Treatments will be administered intramuscularly to the bilateral masseter muscles as 
 
 
The total study duration is approximately 6 months. 
Data Monitoring Committee: No 
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2. 
Introduction 
BOTOX has been used for therapeutic and aesthetic purposes for 3 decades, with its first 
therapeutic approval (treatment of facial spasmodic disorders) in 1989 and first aesthetic 
approval (treatment of glabellar lines) in 2002. Since the first reports of clinical results with 
botulinum toxin type A treatment of MMH (Moore 1994, Smyth 1994), numerous publications 
in the medical literature suggest BOTOX may be a locally applied, well-tolerated, and 
predictable treatment to improve the appearance of the masseter muscles in the lower face. 
Compared with conservative approaches, BOTOX may produce a relatively rapid, predictable, 
and desired effect of reducing the size and shape of the masseter muscles; compared with 
surgical treatment, BOTOX injections may be less invasive, may lead to fewer side effects and a 
shorter recovery time, and the chemical denervation of the masseter muscle is temporary. 
2.1. 
Study Rationale 
The masseter muscle is 1 of 4 muscles used for mastication. Prominence of the masseter muscle 
can appear as a widened and square lower face shape, which is an aesthetic concern for 
individuals who prefer a narrower and more ovoid lower face shape.  
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 masseter muscle, BOTOX treatment has been 
observed to reduce the size of the muscle (Moore 1994), producing an effect perceived as lower 
facial shaping or slimming (Wu 2010). 
Study 191622-130 was the first Allergan-sponsored study of BOTOX for the treatment of MMP 
as an aesthetic indication. This was a 12-month, multicenter, double-blind, randomized, placebo-
controlled, dose-escalation, Phase 2 study in which BOTOX treatment of MMP was shown to be 
safe at doses ranging from 24 U (12 U/masseter) to 96 U (48 U/masseter). Participants were 
adults < 50 years with BMI ≤ 30 kg/m2 and who had marked to very marked MMP, assessed by 
the investigator using the MMPS. For the primary and key secondary endpoints (at Day 90), 
statistically significant positive efficacy results were demonstrated for all 4 BOTOX doses 
compared with placebo, with a dose-dependent trend favoring the higher 3 doses (48 U, 72 U, 
and 96 U). There were no safety trends or patterns identified with a dose increase, although facial 
paresis (including reports of weak or altered smile) was reported in the highest dose group (96 U) 
as a local effect. For details of dose selection and justification for the current Phase 2b study, see 
Section 4.3. 
Study 191622-130 safety measures included standardized dental and CT exams with the goal to 
identify and characterize BOTOX treatment effects on dentition, masseter muscle volume, and 
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the mandible. Dental exam data yielded no abnormal clinically meaningful posttreatment 
findings for any participant in the study. No safety signal or unexpected new pathological 
development was detected from any exploratory radiologic CT measure. There were no dose-
related trends, AE reports, or abnormal clinically relevant findings on dental examination. 
Based on the results of the Phase 2 Study 191622-130, the current Phase 2b study is designed to 
further evaluate the safety and efficacy of BOTOX 48 U and 72 U for the treatment of MMP in 
adults.  
2.2. 
Background 
The masseter muscle functions to protract and elevate the mandible for mastication. Prominence 
of the masseter muscle can appear as a widened lower face, which is an aesthetic concern for 
individuals who prefer a narrower lower face shape. Individuals who deem this masseter 
prominence as aesthetically undesirable may seek medical treatment to decrease a wide, bulky, 
or square-appearing lower face (Ahn 2004, Chai 2011, Jin 2005, Klein 2014, Liew 2008, 
Morris 2007, Mu 2010, Pu 2009, Shim 2010). 
In medical literature, MMH can be defined as encompassing both functional and aesthetic 
symptoms of an enlarged masseter muscle (Fedorowicz 2013). Allergan’s focus is the aesthetic 
indication; to clarify this, Allergan has shifted from the term MMH used in Study 191622-130 to 
the term MMP for the remainder of the development program. 
MMP may be unilateral or bilateral. It may be idiopathic or may occur in association with 
conditions such as bruxism, occlusal and muscular imbalances, TMJD, or particular chewing 
habits and/or diets (eg, unilateral chewing, chewing gum or hard foods) (Aydil 2012, Choe 2005, 
Mischkowski 2005). The highest incidence of MMP is believed to occur in the second and third 
decades of life, and there is no gender predilection (Smyth 1994). Patients with MMP may also 
have mandibular bony prominence (eg, a prominent mandibular angle) that may contribute to the 
appearance of a wide lower face.  
BOTOX has been used to treat MMP in clinical practice for over 2 decades, predominantly in 
Asian countries where aesthetics favor a slender ovoid facial shape (Ahn 2004, Chang 2016, 
Liew 2008, Moore 1994). There is growing interest in MMP treatment among non-Asian 
populations (Liew 2008) and published reports characterize the patient population (Asian and 
non-Asian), injection techniques utilized, clinical results achieved, and AEs (Ahn 2004, 
Aydil 2012, Choe 2005, Liew 2008, Peng 2017). As a potentially lower-risk alternative to 
surgical intervention, the aesthetic procedure of treating the masseter muscle with botulinum 
toxin has gained popularity among physicians and patients (Ahn 2004, Xie 2014). 
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2.3. 
Benefit/Risk Assessment 
Current treatment options for MMP include conservative (nonsurgical) as well as invasive 
treatment modalities. Conservative treatments include reducing the muscular function and 
activity by behavioral modification, occlusal splints, and/or muscle relaxants (Ahn 2004, 
Aydil 2012, Mischkowski 2005, Rauso 2010, Tartaro 2008, To 2001). These methods have not 
been rigorously studied for this indication and are believed to have limited efficacy. Invasive 
therapies for treating a wide lower face include surgical procedures such as osteotomy, 
ostectomy, and corticectomy to change the shape of the jawline targeting the mandible and/or 
including excision of the masseter (Baek 1989, Chai 2011, Deguchi 1997, Jin 2004, Jin 2005, 
Kim 2001, Kim 2003, Lee 2003, Lee 2006, Mu 2010, Onizuka 1983, Sumiya 2004, Yang 1991), 
and radiofrequency volumetric reduction of the masseter (Park 2007). Risks of surgical reduction 
of the mandible and/or masseter muscle include those of a general anesthetic, pain and 
discomfort, postoperative hemorrhage, edema, hematoma, infection, scarring, injury to the 
alveolar nerve, fracture of the ramus, condyle, or subcondyle mandibular bone structures, 
asymmetric result, and facial nerve damage (Baek 1989, Chai 2011, Choe 2005, Deguchi 1997, 
Jin 2005, Morris 2007, Mu 2010, Pu 2009, Yang 1995). BOTOX for MMP represents a 
potentially lower-risk alternative to surgical intervention and higher efficacious alternative to 
other conservative nonsurgical treatment options. 
In general, data from the completed Phase 2 clinical study of BOTOX treatment of MMP and 
from the medical literature show that BOTOX treatment of MMP has been well tolerated with 
AEs that were primarily local and expected, based on the well-established safety profile of 
BOTOX and the muscles injected. In the Phase 2 Study 191622-130, the most frequently 
reported treatment-related AEs included commonly occurring conditions in the general 
population (eg, headache [2.0%, 3/150]), events associated with the injection procedure (eg, 
injection site pain [3.3%, 5/150]), or events related to local muscle weakness that impact smiling 
or chewing that are consistent with the known BOTOX pharmacological effects following 
injection into the masseter (eg, mastication disorder [5.3%, 8/150] and facial paresis [2.7%, 
4/150; reported verbatim terms: weakness when smiling, altered smile, right depressor labia 
inferior paresis, and participant-noticed possible loss of movement along jawline]).  
Similar safety results have been described in the medical literature following BOTOX treatment 
of MMP in 1178 participants with various doses (ranging from 10 to 100 U/masseter) and 
numbers of treatment cycles (Section 5.2.2 of the Masseter Muscle Prominence Investigator 
Brochure). The most frequently reported AEs were pain, discomfort, or muscle ache at the sites 
of injection. Because the masseter muscle is one of the primary muscles of mastication, its 
treatment resulted in some reports of transient masticatory difficulties (weakness chewing), 
which was the next most frequently reported AE in these publications. BOTOX injection of the 
masseter and/or adjacent facial muscles also resulted in some cosmetic complaints, which were 
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reported less frequently. In general, adverse reactions occur within the first few days to weeks 
following injection of BOTOX and, while generally transient, may have a duration of several 
months or, in rare cases, longer. More detailed information about the known and expected 
benefits and risks and reasonably expected AEs with BOTOX treatment may be found in the 
investigator’s brochure and package insert. 
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3. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• To compare the efficacy of 
BOTOX with placebo in 
participants with bilateral MMP 
• 
Proportion of responders who achieve MMPS Grade ≤ 3 at Day 90, per 
investigator assessments of MMP using the MMPS (5 severity grades: 
1 = minimal, 2 = mild, 3 = moderate, 4 = marked, 5 = very marked) 
• To compare the safety of 
BOTOX with placebo in 
participants with MMP 
• 
Incidence of AEs and change from baseline in vital signs 
Secondary 
 
• To compare the efficacy of 
BOTOX with placebo in 
participants with MMP based 
on multiple clinical efficacy 
assessments 
• 
Proportion of responders who achieve MMPS-P Grade ≤ 3 at Day 90, per 
participant assessments of MMP using the MMPS-P (5 severity grades: 
1 = not at all pronounced, 2 = mildly pronounced, 3 = moderately 
pronounced, 4 = pronounced, 5 = very pronounced) 
• 
Proportion of responders who achieve ≥ 2-grade improvement from 
baseline at Day 90, per investigator using the MMPS  
• 
Proportion of responders who achieve ≥ 2-grade improvement from 
baseline at Day 90, per participant using the MMPS-P 
• 
Proportion of responders who achieve PSAC Grade ≥ 2 (at least 
moderately improved from baseline), per participant using the PSAC 
• 
Change from baseline in lower facial volume (cm3) at Day 90, calculated 
from standardized images 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4. 
Study Design 
4.1. 
Overall Design 
This is a 6-month, multicenter study consisting of a single treatment period and approximately 
150 enrolled participants. The study is a double-blind, randomized, placebo-controlled, 
single-study-intervention design, which will assess the safety and efficacy of BOTOX treatment 
for MMP (see Schema, Section 1.2). 
On Day 1, participants will be randomized in a 1:1:1 ratio to receive a single treatment of 
BOTOX 48 U, BOTOX 72 U, or placebo. Randomization will be stratified at each investigator 
site by the participant’s baseline MMPS Grade (4 or 5). Up to 8 scheduled visits are planned: 
screening (Day -14 to Day -1), baseline (Day 1), follow-up (Days 30, 60, 90, 120, 150), and 
study exit (Day 180). 
After verification that the participants meet all inclusion and exclusion criteria and completion of 
all baseline study procedures, participants will be randomized and enrolled. Once enrolled, 
participants will spend approximately 6 months in the study.  
On Day 1, participants will receive a single treatment of either BOTOX (48 U or 72 U) or 
placebo administered bilaterally to the masseter muscles as 3 injections/masseter in the area of 
maximal muscle bulge (Figure 6-1, Section 6.1). The final reconstituted volume for all 
interventions will be the same 1.8 mL (0.3 mL per injection site). This is to ensure the 
investigator and participant remain blinded to the study intervention administered. An IDR, who 
has no other participant-related activities for this study, will prepare all study interventions. After 
study intervention is administered on Day 1, participants will return for follow-up assessments 
(
 
4.2. 
Scientific Rationale for Study Design 
In the current study, all participants will be assessed for a minimum of 180 days after double-
blind study intervention on Day 1. A randomized double-blind design minimizes investigator and 
participant bias and the placebo control provides a comparator. Previous studies, including 
Allergan’s Study 191622-130, reported peak efficacy of botulinum toxin treatment of MMP at 
3 months (Hong 2005, Kim 2003, Kim 2007, Park 2003), therefore, Day 90 has been chosen as 
the primary timepoint in the present study. In Study 191622-130, statistically significant effects 
were lost for most efficacy measures after 6 months; therefore, a follow-up period of 180 days is 
considered appropriate for this Phase 2b study. 
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Approval Date: 
 
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Protocol 1789-202-008 
BOTOX 
 
 
Allergan developed the MMPS, a clinician’s assessment tool for evaluation of MMP. In the 
present study, the MMPS is to be used by trained clinicians to evaluate and grade the prominence 
of the masseter muscle on the left and right sides of the face as the primary endpoint measure. 
The MMPS is a static measurement encompassing both visual and palpable examination of the 
masseter muscle 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. Study 191622-130 was the first study to use the MMPS 
to assess the treatment effect of BOTOX and it demonstrated statistically significant greater 
proportions of responders in achieving both a MMPS Grade ≤ 3, and ≥ 1-grade or ≥ 2-grade 
improvements from baseline, as assessed by the investigator at the primary timepoint. Results 
from Study 191622-130 support a clinician tool (MMPS) that can immediately assess the 
relevant masseter prominence without requiring radiological exposure from CT scans or 3D 
standardized imaging that requires a trained photo analyst to confirm the aesthetic complaint 
described by the participant.  
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, CT, and MRI. Photographic technologies developed to provide 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 2005, Tzou 2011), which all measure change to the 
lower facial contour.  
The VECTRA M3 3D Stereophotogrammetry system (Canfield Scientific, Inc.; Fairfield, New 
Jersey, USA) will be used to quantify the effect of BOTOX on lower facial volume as a 
secondary endpoint measure. This system has previously been validated for use in the facial 
region (de Menezes 2010), and the lower facial area encompassing the masseter muscle (MV 
Report#1832, MV-Report#1832-Addendum). The efficacy measures used to quantitate volume 
in Study 191622-130 demonstrated that lower facial volume reductions using 3D images 
(primary endpoint) correlated well with volume reductions in masseter muscle in a defined 
region using CT scans. Similarly, decreases in lower facial width using 2D image projections 
showed improvements comparable with the 3D and CT volume results.  
 
 
 
 
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BOTOX 
 
 
Safety assessments include AEs and vital signs. In the Phase 2 Study 191622-130, the most 
frequently reported AEs included commonly-occurring conditions in the general population (eg, 
nasopharyngitis [8.0% of all BOTOX-treated participants], upper respiratory tract infection 
[6.0%], and headache [5.3%]) or events related to chewing that are not unexpected following 
injection into the masseter (eg, mastication disorder [6.0%]). Of the reported AEs among the 
1178 subjects treated with BOTOX for MMP in the published medical literature, the most 
frequently reported AEs were pain, discomfort, or muscle ache at the sites of injection. Because 
the masseter muscle is one of the primary muscles of mastication, its treatment resulted in some 
reports of transient masticatory difficulties (ie, weakness chewing), which was the next most 
frequently reported AE in these publications. BOTOX injection of the masseter and/or adjacent 
facial muscles also resulted in some cosmetic complaints, which were reported less frequently. In 
general, these AEs have been reported as mild and resolved without treatment.  
Study 191622-130 yielded no new or meaningful safety findings from dental or CT exams, rather 
analysis of AEs provided the most sensitive assessment of safety; thus, this Phase 2b study uses 
routine AE monitoring (as well as vital sign monitoring) to characterize safety. 
4.3. 
Justification for Dose 
In Allergan’s Phase 2 Study 191622-130, participants received total doses ranging from BOTOX 
24 U to 96 U. For the primary and key secondary endpoints (at Day 90), statistically significant 
positive efficacy results were demonstrated for all 4 BOTOX doses, with a dose-dependent trend 
favoring the higher 3 doses (48 U, 72 U, and 96 U), which produced statistically significant 
changes in MMP compared with placebo. The benefits of 72 U and 96 U were similar for 
duration (approximately 9 months for Kaplan-Meier median time to loss of 1-grade MMPS 
response), volume reduction, MMPS Grade change, facial width, facial angle, and facial shape. 
There was no additional benefit demonstrated with 96 U over 72 U. Statistically significant 
efficacy results were also obtained with the 24 U dose versus placebo for the majority of 
endpoints evaluated, though not all. However, the Kaplan-Meier duration of effect based on 
median time to loss of MMPS 1- or 2-grade improvement was approximately 3 to 7 weeks 
shorter in the BOTOX 24 U group than the BOTOX 48 U group.  
The proportion of responders achieving a rating of ≤ 3 (moderate) on the MMPS was 
significantly greater with all BOTOX doses compared with placebo (p < 0.008), with the greatest 
impact shown in the 48 U (83.3%), 72 U (89.5%), and 96 U (89.5%) dose groups at Day 90.  
Participants treated with BOTOX experienced significant reductions in lower facial volume 
(cm3) at Day 90 compared with placebo (p < 0.001), with the greatest mean reductions shown in 
the 3 highest BOTOX dose groups of 48 U (-6.84 cm3), 72 U (-7.41 cm3), and 96 U (-8.20 cm3).  
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BOTOX 
 
 
The responder rate for achieving a 2-grade improvement from baseline using the MMPS was 
significantly greater with all BOTOX doses compared with placebo (p < 0.001), with the greatest 
proportion of responders in the 72 U (73.7%) and the 96 U (65.8%) dose groups at Day 90; the 
proportion of responders in the 48 U dose group was 47.2%. 
BOTOX administration was shown to be safe through Day 360 for all doses (24 U, 48 U, 72 U, 
and 96 U). Facial paresis (including reports of weak or altered smile) was reported in the highest 
dose group (96 U) as a local effect. 
A review of the medical literature of BOTOX treatment of MMH found a mean dose of 
approximately 38 U per masseter (range: 10 U to 100 U/masseter) administered into 1 to 6 
injection sites/masseter (refer to the investigator’s brochure). This compares with doses of 24 U 
to 36 U per masseter to be used in this study. 
Based on efficacy and safety data obtained in the Phase 2 Study 191622-130, including duration 
of effect, and taking into account data available in the medical literature, this study will evaluate 
total doses of 48 U and 72 U BOTOX versus placebo. 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant. 
A participant is considered to have completed the study if he/she is a randomized participant who 
was treated with study intervention, has not been discontinued for any reason, and 
attends/completes the study exit visit. 
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BOTOX 
 
 
5. 
Study Population 
The study population will be adult participants with marked (Grade 4) or very marked (Grade 5) 
MMP as determined by the investigator using the MMPS AND with pronounced (Grade 4) or 
very pronounced (Grade 5) MMP as determined by the participant using the MMPS-P; and who 
meet eligibility criteria for this protocol as specified in Section 5.1 and Section 5.2. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. 
Age 
1.01 
Participant must be at least 18 years of age (or older if legal age of adulthood is > 18 
as per local regulations), at the time of signing the informed consent  
2. 
Type of Participant and Masseter Characteristics 
2.01 
 
2.02 
Participant has a marked (Grade 4) or very marked (Grade 5) bilateral MMP 
(identical grades for left and right masseter), as determined at the Day 1 visit by the 
investigator using the MMPS 
2.03 
Participant has a pronounced (Grade 4) or very pronounced (Grade 5) MMP, as 
determined at the Day 1 visit by the participant using the MMPS-P 
3. 
Weight and Body Mass Index 
3.01 
BMI ≤ 30 kg/m2 using the calculation: BMI = weight (kg)/[height (m)]2 
4. 
Sex 
4.01 
Male or female 
5. 
Contraceptives 
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BOTOX 
 
 
5.01 
Female participants willing to minimize the risk of inducing pregnancy for the 
duration of the clinical study and follow-up period 
 
A female participant is eligible to participate if she is not pregnant (has a negative 
urine pregnancy result prior to randomization), not breastfeeding, and at least one of 
the following conditions applies: 
a. Not a WOCBP as defined in Appendix 6 
OR 
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 6 
during the treatment and follow-up period 
6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. 
Medical Conditions 
1.01 
Any medical condition that may put the participant 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 
1.02 
Any uncontrolled medical condition  
1.03 
An anticipated need for surgery or overnight hospitalization during the study 
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BOTOX 
 
 
2. 
Prior/Concomitant Therapy 
2.01 
An anticipated need for treatment with botulinum toxin of any serotype for any indication 
during the study (other than study intervention)  
2.02 
History of dental or surgical procedure for lower facial shaping or masseter muscle 
reduction 
2.03 
Prior mid-facial and/or lower facial treatment with nonpermanent soft tissue fillers, 
synthetic implantations, autologous fat transplantation, fat-reducing injectables, and/or 
skin-tightening laser treatments within 6 months prior to Day 1 
2.04 
Current or planned dental or facial procedures during the study period (eg, braces, dental 
implants, and reconstructive or aesthetic surgery) that could interfere with MMPS, as 
determined by the investigator 
2.05 
Facial hair or scarring (eg, acne) significant enough to interfere with the 3D clinical 
imaging assessment, as determined by Canfield Scientific, Inc. 
3. 
Prior/Concurrent Clinical Study Experience 
3.01 
Current enrollment in an investigational drug or device study or participation in such a 
study within 30 days of Day 1 
3.02 
Prior exposure to botulinum toxin of any serotype to the masseter muscle or lower face at 
any time, or to any other part of the body within the 6 months prior to Day 1 
4. 
Diagnostic Assessments 
4.01 
Current intraoral infection, including infection of the mouth or gums, or facial skin 
infection requiring medical treatment in the opinion of the investigator 
4.02 
History of or current TMJD, or presence of signs/symptoms of possible TMJD (see 
Section 8.2.5), in the opinion of the investigator  
4.03 
Weakness of the masseter, pterygoid, or temporalis muscles due to trauma, facial nerve 
injury, or other condition that could interfere with normal chewing and jaw clenching, as 
determined by the investigator 
4.04 
Excess lower facial fat, loose or lax skin in lower face, or parotid gland prominence that 
could interfere with MMPS, as determined by the investigator 
4.05 
Significant asymmetry of left and right sides of the face that could prevent identical 
MMPS grading on both sides of the face, as determined by the investigator 
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Protocol 1789-202-008 
BOTOX 
 
 
4.06 
 
 
4.07 
Masseter prominence due to other etiologies (eg, parotid gland infection, parotiditis, 
malignancy) based upon findings from the oral examination (see Section 8.2.4) 
5. 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
5.3. 
Lifestyle Considerations 
Not applicable; no restrictions are required. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the CONSORT publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failures) may not 
be rescreened.  
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Approval Date: 
 
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Protocol 1789-202-008 
BOTOX 
 
 
6. 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. All investigators and site staff involved with preparation and injection of study 
interventions will receive training that is appropriate to their role, and the training will be 
documented. 
6.1. 
Study Interventions Administered 
The study interventions administered are summarized in Table 6–1. 
Table 6–1 
Study Interventions Administered 
Study Intervention Name 
BOTOX 48 U 
BOTOX 72 U 
Placebo 
Dosage Formulation 
BOTOX (botulinum 
toxin type A) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BOTOX (botulinum 
toxin type A) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
  
 
 
 
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Approval Date: 
 
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Protocol 1789-202-008 
BOTOX 
 
 
Study Intervention Name 
BOTOX 48 U 
BOTOX 72 U 
Placebo 
Unit Dose 
Strength(s)/Dosage 
Level(s) 
A total dose of 48 U 
(24 U/masseter) will be 
administered. 
 
 
 
 
 
 
 
 
 
A total dose of 72 U 
(36 U/masseter) will be 
administered. 
 
 
 
 
 
 
 
  
The total injection 
 
 
 
 
 
 
Route of Administration  
Intramuscular 
Intramuscular  
Intramuscular 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
.  
 
 
 
  
 
  
 
 
 
  
 
 
Manufacturer 
Allergan 
Allergan 
Allergan 
 
 
 
To identify the masseter muscle treatment area, the investigator will first draw a line with a 
surgical marker from the corner of the mouth to a point at the inferior border of the ear, where 
the ear lobe attaches to the face (Figure 6-1, Line A). The investigator will instruct the 
participant to maximally clench his/her jaw (mouth closed and teeth together), and with visual 
inspection and manual palpation, will outline the area of maximal bulge of the masseter muscle. 
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Approval Date: 
 
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CONFID
BOTOX 
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ned 
11DEC2020 CSR 1789-202-008
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Approval Date: 
 
12-Feb-2019
 
 
Protocol 1789-202-008 
BOTOX 
 
 
6.1.1. 
Other Study Supplies 
The following will be provided by the sponsor or designee: 
• Study intervention 
• Syringe labels 
• Temperature recording device for monitoring refrigerator temperature (if applicable) 
• Imaging equipment (supplied by a third-party vendor) 
• eCOA devices (supplied by a third-party vendor) 
The following will be provided by the study site: 
• Monitor and DVD player for viewing participant instructions. 
• Cotton pads and makeup remover 
• Alcohol wipes 
• Medical gloves 
• Urine pregnancy tests with a minimum sensitivity of 25 IU/mL 
• Sterile surgical marker pens 
• Appropriately-sized sterile needles and syringes for study intervention reconstitution 
and injection 
• 
 
• Lockable refrigerator, to store study intervention kits according to the study 
manual  
• Covered container for discarded medical waste materials (sharps box) 
• Internet connection (high-speed connection for eCRF completion) 
6.2. 
Preparation/Handling/Storage/Accountability 
 
 
  
 
Table 6–2 
Injection Volume 
Study Intervention 
Total Dose (U); 
Total Volume 
(mL) 
Masseter Dose (U); 
Volume per 
Masseter (mL) 
Volume per 
Injection (mL) 
BOTOX 48 U  
 
 
 
BOTOX 72 U 
 
 
Placebo (0 U) 
 
 
Detailed instructions on reconstitution and syringe preparation are provided in the Study Manual. 
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Protocol 1789-202-008 
BOTOX 
 
 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention, and only authorized site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).  
All unused study intervention must be stored secured, with limited access to a designated 
unblinded site member, and returned to the sponsor or designee once expired or at the 
termination of study. Unit counts will be performed when the study intervention is returned, and 
all study intervention must be accounted for. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
At the Screening Visit, after the participant signs the ICF, the site will log on to the IWRS to 
obtain a participant number. On Day 1, the IWRS will be used to manage the randomization and 
assignment of participants into one of the 3 study intervention groups based on a randomization 
schedule prepared by the sponsor’s Biostatistics department. The randomization will occur after 
all baseline procedures have been completed and the investigator has verified that the participant 
has met all inclusion and exclusion criteria. Randomization will be stratified at each investigator 
site by the participant’s baseline (Day 1) MMPS Grade (4 or 5), as assessed by the investigator. 
All study interventions will be provided in identical vials and cartons to maintain blinding of the 
study. In addition, the injection volume and study intervention administration will be identical 
for all groups. 
At each study site, a designated staff member will serve as the IDR who will be responsible for 
reconstituting the study interventions and preparing and labeling the injection syringes. This 
person will be a staff member with no study responsibilities that require interaction with 
participants or with participant efficacy or safety data. 
The IDR will prepare the vial of study intervention as described in Section 6.1 and the Study 
Manual. Based on the reconstitution requirements, only the IDR will know the volume of diluent 
used for reconstitution. The IDR will not know whether the study intervention is BOTOX or 
placebo. Once the study intervention vial is reconstituted, the IDR will draw the required volume 
into an appropriately sized syringe and label the syringe with the participant’s ID number to 
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Approval Date: 
 
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Protocol 1789-202-008 
BOTOX 
 
 
ensure the investigator remains blinded based on reconstitution volume in the vial. The IDR will 
then provide the filled syringes to the investigator, who will inject the participant according to 
the study intervention administration instructions in Section 6.1. 
Detailed instructions on reconstitution and syringe preparation will be provided in the Study 
Manual. 
The IWRS will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s study 
intervention assignment is warranted. Participant safety must always be the first consideration in 
making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding a participant’s 
study intervention assignment unless this could delay emergency treatment of the participant. If a 
participant’s study intervention assignment is unblinded, the sponsor must be notified within 
24 hours after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation. 
6.4. 
Study Intervention Compliance 
The study investigator will administer all study intervention injections to the participants.  
The study site will keep an accurate study intervention disposition record. 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, cannabis [in 
US states where its use is legal], vitamins, and/or herbal supplements) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded along with: 
• Indication/reason for medication use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
 
 
 
  
 
 
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6.6. 
Dose Modification 
Dose modification is not applicable. 
6.7. 
Intervention After the End of the Study 
No interventions after the end of the study are planned. 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
Participants may voluntarily withdraw from the study at any time. A premature discontinuation 
will occur if a participant who signs the ICF and is dosed ceases participation in the study, 
regardless of circumstances, before the completion of the protocol-defined study procedures. 
Notification of early participant discontinuation from the study and the reason for 
discontinuation will be made to the sponsor and will be clearly documented on the appropriate 
eCRF. 
Reasons for discontinuation from the study intervention and/or the study may include the 
following commonly used or other acceptable terms: 
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Protocol 1789-202-008 
BOTOX 
 
 
Commonly Used Terms 
Other Acceptable Terms 
Adverse event 
Death 
Lack of efficacy 
 
Lost to follow-up 
 
Other 
 
Physician decision 
 
Pregnancy 
 
Protocol deviation 
 
Site terminated by sponsor 
 
Study terminated by sponsor 
 
Withdrawal by participant 
 
If a pregnancy is confirmed after the participant has received study intervention, the participant 
may choose to exit the study after appropriate safety follow-up or to remain in the study for all 
safety and efficacy follow-up assessments through the end-of-study visit.   
Definitions of the standard terms are provided in Appendix 4. 
7.1. 
Discontinuation of Study Intervention 
Not applicable, as participants receive only a single treatment with study intervention on Day 1. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons. 
• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant exits the study early, every effort should be made to ensure a Study Exit Visit 
and associated measures are performed - see the SoA (
for data to be collected at 
the time of study discontinuation. 
• Notification of early participant discontinuation from the study and the reason for 
discontinuation will be made to the sponsor and will be clearly documented on the 
appropriate eCRF. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
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BOTOX 
 
 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
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BOTOX 
 
 
8. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA (
 Protocol waivers 
or exemptions are not allowed. 
• Evaluations are to be performed by the same evaluator throughout the study whenever 
possible. If it is not possible to use the same evaluator to follow the participant, then 
evaluations should overlap (examine the participant together and discuss findings) for at least 
1 visit. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
8.1. 
Efficacy Assessments 
Planned timepoints for all efficacy assessments are provided in the SoA (
 The 
measures are described in detail in Appendix 7  and Appendix 8. 
Evaluations of MMPS-P, 
 completed at screening and baseline will be 
used for test-retest evaluations of the tools.  
8.1.1. 
Primary Efficacy Assessment 
The primary efficacy assessment is to be completed at screening, baseline, and at each scheduled 
visit thereafter until study exit. 
Note: The Day 1 images will be used as the baseline images. If the baseline images are not of 
acceptable quality, the screening images will be used instead. Canfield Scientific, Inc. must 
approve each participant’s screening images to ensure a quality baseline image is available in the 
event that the Day 1 images are not of acceptable quality. If the screening images are not 
acceptable, 1 retake is permitted and must be taken before Day 1.  
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BOTOX 
 
 
MMPS 
The primary efficacy assessment is masseter muscle prominence assessed by the investigator 
using the MMPS (1 = minimal, 2 = mild, 3 = moderate, 4 = marked, 5 = very marked; see 
Appendix 7 for details). The MMPS assessment will be completed via electronic tablet provided 
to the study site. 
The MMPS is evaluated for each masseter (ie, right and left) separately every time it is rated. 
8.1.2. 
Secondary Efficacy Assessments 
MMPS-P and lower facial volume assessments will be completed at screening, baseline, and at 
each scheduled visit thereafter until study exit. The PSAC will be completed at all scheduled 
postbaseline visits (Days 30, 60, 90, 120, 150, and 180). Participants will view a training video 
on how to properly complete the MMPS-P and PSAC assessments using photos, at the Screening 
Visit (and at other visits if needed).  
For MMPS-P and PSAC, the participant will answer questions via electronic tablet that will be 
provided to the study participant at the study site. 
MMPS-P 
MMP assessed by the participant is a secondary efficacy assessment developed by the sponsor 
through concept elicitation and cognitive debriefing in accordance with the FDA Patient 
Reported Outcomes guidance. Participants will be asked to assess the severity of their masseter 
prominence using a single question composed of 5 severity grades (1 = not at all pronounced, 
2 = mildly pronounced, 3 = moderately pronounced, 4 = pronounced, 5 = very pronounced; see 
Appendix 8 for details) and a 2D image of their face collected at the current visit.  
The MMPS-P is evaluated for both masseters as a single score. 
Evaluations of MMPS-P completed at screening and baseline will be used for test-retest 
reliability assessment of the tool. 
PSAC 
The PSAC is a commonly used assessment of change scale that has been adapted for use with 
MMP by the sponsor using concept elicitation and cognitive debriefing. Participants will be 
asked to assess change of their lower face shape using images taken before study intervention (ie, 
baseline, or screening if the baseline image is not of acceptable quality) and after study 
intervention (ie, the current study visit) taking into consideration the bottom half of the face from 
the top of the cheeks to the chin. The PSAC grades are as follows: 3 = much improved, 
2 = moderately improved, 1 = minimally improved, 0 = change, -1 = minimally 
worse, -2 = moderately worse, and -3 = much worse (see Appendix 8 for details).  
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Lower Facial Volume 
Lower facial volume will be calculated by a qualified technician (from Canfield Scientific, Inc.) 
using 3D image models using 2 analysis methods. 
Investigators will follow training/instructions for use of the digital imaging system as provided 
by Canfield Scientific, Inc. 
8.1.3. 
Other/Exploratory Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
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Exit Interviews 
Participant exit interviews will be completed at the Study Exit visit by contract research 
organization personnel. Open-ended interviews will be conducted to collect data about impacts 
of the study intervention and meaningful change on their MMP. All interviews will be recorded 
for thematic analysis. Results will be summarized in a separate report. 
8.2. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (
 
8.2.1. 
Vital Signs 
Vital signs will be assessed as follows: 
• Pulse rate, respiratory rate, and blood pressure will be assessed. 
• Blood pressure and pulse measurements will be assessed with participants in a sitting 
position after sitting for at least 5 minutes; use of either a manual or automated device is 
acceptable. Manual techniques will be used only by adequately trained personnel; whenever 
possible, the same person should perform all manual assessments as much as possible. 
8.2.2. 
Height and Weight 
Height and weight will be measured and recorded, and BMI calculated. 
8.2.3. 
Pregnancy Testing 
Urine pregnancy testing will be conducted at the screening, baseline, and study exit visits. 
Females of childbearing potential must have a negative test result before receiving the study 
intervention. This test may also be performed at any other visit, at the investigator’s discretion. 
At each visit, the investigator should discuss contraceptive use compliance with females of 
childbearing potential. 
8.2.4. 
Oral Examination 
As referenced in Exclusion criterion 4.07, oral examinations will be conducted at the Screening 
Visit, in order to rule out other potential etiologies for MMP, such as malignancy. The 
investigator will assess extraorally for parotid gland tumors, parotiditis (gland or duct), lipoma, 
sialolith (stones), or osseous remodeling at the gonial angle including bone protrusion, and 
intraorally for osseous lesions in the angle of the mandible behind the molars, or for expansion of 
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alveolar bone supporting the teeth. The examination procedures are described in greater detail in 
the Study Manual.  
8.2.5. 
Screening for TMJD 
Screening for signs/symptoms of possible TMJD will be conducted by the investigator at the 
Screening Visit, as described in the Study Manual. Depending on the findings, the investigator 
may decide to exclude the participant from the study (per exclusion criterion 4.02), or may refer 
the participant to a dentist for further TMJD screening, to be completed prior to Day 1. The 
participant may complete the rest of the planned activities and procedures for the Screening Visit, 
with the dentist examination occurring at a later time in the screening period. If, based on 
findings from a dental examination, the dentist diagnoses the participant with TMJD, the 
participant will be considered a screen failure. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 2. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and any other study-specific terms as 
relevant and remain responsible for following up AEs that are serious, considered related to the 
study intervention or study procedures, or that caused the participant to discontinue the study 
intervention or study (see Section 7). 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All AE/SAEs from the signing of the ICF will be collected at the timepoints specified in the SoA 
 and as observed or reported spontaneously by study participants. 
Medical occurrences that begin before the start of study intervention, but after obtaining 
informed consent will be recorded in the AE section of the eCRF and will be considered 
pretreatment AEs. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 2. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
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reasonably related to the study intervention or study participation, the investigator must promptly 
notify the sponsor. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2. 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and AESIs as defined in Appendix 2 will be followed 
until resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-
up (as defined in Section 7.3). 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals. 
If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the sponsor with a copy of any postmortem findings including 
histopathology. 
New or updated information will be recorded in the originally completed eCRF. 
The investigator will submit any updated SAE data to the sponsor within 24 hours of receipt of 
the information. 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
• Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.  
• The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ IECs, and investigators. 
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• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the investigator’s brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
8.3.5. 
Pregnancy 
• If a pregnancy is confirmed after the participant has received the study intervention, the 
participant may choose to exit the study after appropriate safety follow-up or to remain in the 
study for all safety and efficacy follow-up assessments through the end-of-study visit. 
• Details of all pregnancies in female participants will be collected from the signing of the ICF 
and through the duration of the pregnancy. 
• If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 6. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6. 
Protocol-Specific Adverse Events  
The investigator should refer a participant to a qualified dentist for further evaluation in the case 
of severe (as defined in Appendix 2) mastication disorders (eg, severe reports of chewing 
weakness, abnormal chewing, difficulty chewing). For any referral, the investigator must obtain 
findings from the dentist for complete AE documentation in the eCRF. 
8.3.7. 
Adverse Events of Special Interest 
AESI will be reported as indicated in Appendix 2. 
8.3.8. 
Medication Errors 
Medication error refers to any unintended error in the dosing and/or administration of the study 
intervention as per instructions in the protocol, for example: 
• Wrong study intervention 
• Wrong dose (including dosing regimen, concentration, amount) 
• Wrong participant (ie, not administered to the intended participant) 
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8.4. 
Treatment of Overdose 
The LD50 for BOTOX in humans is estimated from primate studies to be approximately 3000 U. 
This makes accidental injection of a lethal dose highly unlikely, but significant AEs may still 
occur at doses below the LD50 (Herrero 1967, Scott 1989). 
Excessive doses may produce local or distant, generalized, and profound neuromuscular 
paralysis. Should accidental injection or oral ingestion occur or overdose be suspected, the 
participant should be medically monitored for up to several weeks for progressive signs or 
symptoms of systemic muscular weakness that could be local or distant from the site of injection, 
and which may include ptosis, diplopia, dysphagia, dysarthria, generalized weakness, or 
respiratory failure. Please refer to the general Section 6.5 of the BOTOX MMP investigator’s 
brochure for further details. 
In the event of an overdose, the investigator should: 
1. Contact the medical safety physician immediately. 
2. Closely monitor the participant for AEs and SAEs. 
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF as well as other details that led to the overdose. 
8.5. 
Pharmacokinetics 
PK parameters are not evaluated in this study. 
8.6. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers and Other Assessments 
Biomarkers are not evaluated in this study. 
8.9. 
Health Economics  
Health economics parameters are not evaluated in this study. 
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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
The following set of hypotheses will be used to compare the BOTOX groups with placebo: 
• Null hypothesis: BOTOX and placebo are equally effective in reducing MMP as 
measured by the proportion of responders achieving MMPS Grade ≤ 3 at Day 90. 
• Alternative hypothesis: BOTOX and placebo are not equally effective in reducing MMP 
as measured by the proportion of responders achieving MMPS Grade ≤ 3 at Day 90. 
9.2. 
Sample Size Determination 
The primary efficacy parameter is the proportion of responders who achieve MMPS Grade ≤ 3 at 
Day 90. Based on previous data from Study 191622-130 and the assumption of a difference of 
≥ 34% in MMPS responder rate between BOTOX 48 U or 72 U and placebo group, 
approximately 50 participants per study intervention group will provide > 90% power using a 
2-sided Mantel-Haenszel test, 10% dropout rate, and 5% significance level. 
Approximately 225 participants will be screened to achieve 150 enrolled to study intervention 
and 135 evaluable participants for an estimated total of 45 evaluable participants per intervention 
group.  
9.3. 
Populations for Analyses 
The analysis populations will consist of participants as defined below: 
• The mITT population includes all randomized participants with ≥ 1 postbaseline MMPS 
assessment. Participants will be summarized according to the randomized study 
intervention. 
• The safety population includes all treated participants who receive ≥ 1 administration of 
study intervention. Participants will be summarized according to the study intervention 
they actually received. 
9.4. 
Statistical Analyses 
The SAP will be developed and finalized before database lock and unblinding and will describe 
the participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints.  
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9.4.1. 
Efficacy Analyses 
The efficacy analyses will be based on the mITT population. The last-observation-carried-
forward approach will be used to impute missing postbaseline values. Baseline for efficacy is 
defined as the last nonmissing efficacy assessment before the first dose of study intervention. All 
statistical tests will be 2-sided hypothesis tests performed at the 5% level of significance for 
main effects. 
9.4.1.1. 
Analysis Endpoints 
The primary and secondary efficacy endpoints are listed below, and analyses will be defined in 
the following sections. All analyses for other efficacy endpoints listed below will be defined in 
the SAP. 
Primary efficacy endpoint: 
• Proportion of responders who achieve MMPS Grade ≤ 3 at Day 90 
Secondary efficacy endpoints: 
• Proportion of responders who achieve MMPS-P Grade ≤ 3 at Day 90 
• Proportion of responders who achieve ≥ 2-grade MMPS improvement from baseline at 
Day 90 
• Proportion of responders who achieve ≥ 2-grade MMPS-P improvement from baseline at 
Day 90 
• Proportion of responders who achieve PSAC Grade ≥ 2 (at least moderately improved from 
baseline) at Day 90 
• Change from baseline in lower facial volume at Day 90 (calculated from standardized 
images) 
Other efficacy endpoints: 
 
 
 
  
 
 
 
 
 
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9.4.1.2. 
Primary Analyses 
The primary efficacy endpoint will be the proportion of responders who achieve MMPS 
Grade ≤ 3 at Day 90 and will be analyzed using Cochran-Mantel-Haenszel model stratified by 
baseline MMPS Grade (4 or 5). Each BOTOX dose will be compared with placebo separately. 
9.4.1.3. 
Secondary Analyses 
The following secondary variables will be analyzed at Day 90 using the same method as the 
primary analysis: 
• Proportion of responders who achieve MMPS-P Grade ≤ 3 
• Proportion of responders who achieve ≥ 2-grade MMPS improvement from baseline 
• Proportion of responders who achieve ≥ 2-grade MMPS-P improvement from baseline  
• Proportion of responders who achieve PSAC Grade ≥ 2 
The change from baseline in lower facial volume at Day 90 (calculated from standardized images 
and analyzed by 2 methods) will be statistically analyzed using ANCOVA with study 
intervention group and investigator sites as factors and baseline MMPS Grade (4 or 5) as a 
covariate. 
9.4.2. 
Safety Analyses 
The safety analysis will be performed using the safety population and will be fully defined in the 
SAP. The safety parameters include AEs and vital signs (pulse rate, respiratory rate, and blood 
pressure). For vital signs, the last nonmissing assessment before the study intervention will be 
used as the baseline for all analyses. 
9.4.2.1. 
Adverse Events 
An AE will be considered a TEAE if: 
• The AE began on or after the date of the first dose of study intervention; or 
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• The AE was present before the date of the first dose of study intervention, but increased in 
severity or became serious on or after the date of the first dose of study intervention. 
An AE will be considered a TESAE if it is a TEAE that additionally meets any SAE criteria. 
The number and percentage of participants reporting TEAEs in each study intervention group 
will be tabulated by system organ class and preferred term and by system organ class, preferred 
term, and severity. 
The number and percentage of participants reporting treatment-related TEAEs in each study 
intervention group will be tabulated by system organ class and preferred term. 
If more than 1 AE is coded to the same preferred term for the same participant, the participant 
will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarizations by severity and by relationship to study intervention. 
Summary tables will be provided for participants with SAEs and participants with AEs leading to 
discontinuation if 5 or more participants reported such events. Listings of all AEs, SAEs, and 
AEs leading to discontinuation by participant will be presented. 
The definitions of an AE and SAE can be found in Appendix 2. 
9.4.2.2. 
Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic BP, pulse rate, and respiratory rate) at 
baseline and changes from baseline at each assessment will be presented by study intervention. 
Vital sign values will be considered to be PCS if they meet both the observed-value criteria and 
the change-from-baseline-value criteria that will be detailed in the SAP. The number and 
percentage of participants who have PCS postbaseline vital sign values will be tabulated by study 
intervention for each assessment. The percentages will be calculated relative to the number of 
participants who have available non-PCS baseline values and at least 1 postbaseline assessment. 
The numerator will be the total number of participants with at least 1 PCS postbaseline value. A 
supportive listing of participants with PCS postbaseline values will be provided for the safety 
population. 
9.4.3. 
Other Analyses 
All other analyses will be described in the SAP.  
9.5. 
Interim Analyses 
Interim analyses are not planned for this study. 
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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines 
o Applicable ICH/ISO GCP guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the overall conduct of the study at the site and adherence to 
requirements of applicable local regulations, for example 21 CFR, ICH guidelines, the 
IRB/IEC, and European regulation 536/2014 for clinical studies (if applicable) 
10.1.2. 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.  
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/IEC 
or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the participant.  
10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier. Any participant records or datasets that are 
transferred to the sponsor will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred.  
• The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.  
• The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Posting Clinical Study Data 
• Study data and information may be published in nonpromotional, peer-reviewed publications 
either by or on behalf of the sponsor.  
• Clinical study reports, safety updates, and annual reports will be provided to regulatory 
authorities as required. 
• Company-sponsored study information and tabular study results will be posted on the US 
National Institutes of Health's website www.ClinicalTrials.gov and other publicly accessible 
sites 
10.1.6. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic CRFs 
unless transmitted to the sponsor or designee electronically. The investigator is responsible 
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for verifying that data entries are accurate and correct by physically or electronically signing 
the CRF.  
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator as stated in the clinical trial agreement. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor.  
10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study.  
• Definition of what constitutes source data can be found in Section 4.0 of ICH E6, Good 
Clinical Practice: Consolidated Guidance and must follow ALCOA, ie, records must be 
attributable, legible, contemporaneous, original, and accurate. 
10.1.8. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
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Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further study intervention development 
10.1.9. 
Publication Policy 
• 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. 
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. 
• Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
10.1.10. 
Compliance with Protocol 
The investigator is responsible for compliance with the protocol at the investigational site. A 
representative of the sponsor will make frequent contact with the investigator and his/her 
research staff and will conduct regular monitoring visits at the site to review participant and 
study intervention accountability records for compliance with the protocol. Protocol deviations 
will be discussed with the investigator upon identification. The use of the data collected for the 
participant will be discussed to determine if the data are to be included in the analysis. The 
investigator will enter data that may be excluded from analysis as defined by the protocol 
deviation specifications. Significant protocol deviations will be reported to the IRB/IEC 
according to the IRB/IEC’s reporting requirements. 
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10.2. 
Appendix 2: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of study intervention. 
AESI 
An AESI is an AE of scientific and medical relevance specific to the sponsor’s study 
drug/device or program, which may warrant ongoing monitoring. Such an event might warrant 
further investigation in order to characterize and understand it.  
Facial muscle paralysis (NOT including a weak or altered smile) has been identified as an 
AESI for the study intervention in this protocol.   
Suspected AESIs should be reported to the sponsor as a typical adverse event. No AESI form 
is needed. 
If the AESI meets SAE criteria (which are listed below), it should be reported within 24 hours. 
 
Events Meeting the AE Definition  
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
• 
New condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction 
• 
Lack of efficacy or failure of expected pharmacological action per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments.  
 
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Events NOT Meeting the AE Definition  
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
Definition of SAE 
SAEs must meet both the AE criteria described above and the seriousness criteria listed below. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life threatening 
The term life threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or intervention 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether hospitalization occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective intervention of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
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f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive intervention in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
Recording and Follow-Up of AEs and/or SAEs 
AE and SAE Recording 
• 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE or SAE information in the eCRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Allergan in lieu of completion of the AE or SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
Allergan. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to 
Allergan. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
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Assessment of Intensity 
MILD 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities 
of daily living. 
MODERATE 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
SEVERE 
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
An event is defined as serious when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE or SAE. 
• 
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The investigator will also consult the investigator’s brochure and/or product information, 
for marketed products, in his/her assessment. 
• 
For each AE or SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE or SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Allergan. However, it is very important that 
the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to Allergan. 
• 
The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
 
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• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Reporting of SAEs 
SAE Reporting 
• 
Email is the preferred method to transmit SAE information. The email address is 
 
• 
Facsimile transmission of the SAE information is also acceptable. The fax number is +1-
(backup number is 
).  
• 
Contacts for SAE reporting can be found on the protocol title page. 
 
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10.3. 
Appendix 3: Abbreviations 
Abbreviation/Term 
Definition 
2D 
2-dimensional 
3D 
3-dimensional 
AE 
adverse event 
AESI 
adverse event of special interest 
ALCOA 
attributable, legible, contemporaneous, original, accurate 
ANCOVA 
analysis of covariance 
AOI 
area of interest 
BMI 
body mass index 
BOTOX 
Botulinum toxin type A purified neurotoxin 
BP 
blood pressure 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
COA 
clinical outcome assessments  
CONSORT 
Consolidated Standards of Reporting Trials  
CT 
computed tomography 
DVD 
digital versatile disc 
eCOA 
electronic clinical outcome assessment (via tablet) 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
hormonal replacement therapy 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
ID 
identification 
IDR 
independent drug reconstitutor 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IWRS 
interactive web response system 
LD50 
lethal dose, 50% 
 
 
 
 
 
 
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mITT 
modified intent-to-treat 
MMH 
masseter muscle hypertrophy 
MMP 
masseter muscle prominence 
MMPS 
Masseter Muscle Prominence Scale 
MMPS-P 
Masseter Muscle Prominence Scale - Participant 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
PCS 
potentially clinically significant 
 
 
PK 
pharmacokinetic 
PRO 
patient-reported outcomes 
PSAC 
Participant Self-Assessment of Change 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOA 
Schedule of Activities 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TMJD 
temporomandibular joint disorders  
U 
unit 
US 
United States 
WOCBP 
woman of childbearing potential 
 
 
 
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10.4. 
Appendix 4: Standard Discontinuation Criteria 
This table provides participant discontinuation criteria for this protocol. CDISC terminology is 
used, and thus subject or patient is used instead of participant (as used elsewhere in this 
protocol). These terms are interchangeable. 
CDISC Submission Value 
CDISC Definition 
Adverse event 
Any untoward medical occurrence in a patient or clinical investigation 
participant administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment. An AE can 
therefore be any 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. For further information, see the ICH Guideline for 
Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting (modified from ICH E2A) Synonyms: side effect, adverse 
experience. See also serious adverse event, serious adverse experience. 
(CDISC glossary) 
Completed 
To possess every necessary or normal part or component or step; having 
come or been brought to a conclusion (NCI) 
Death 
The absence of life or state of being dead (NCI) 
Lack of efficacy 
The lack of expected or desired effect related to a therapy (NCI) 
Lost to follow-up 
The loss or lack of continuation of a participant to follow-up 
Other 
Different than the one(s) previously specified or mentioned (NCI) 
Physician decision 
A position, opinion or judgment reached after consideration by a physician 
with reference to participant (NCI) 
Pregnancy 
Pregnancy is the state or condition of having a developing embryo or fetus in 
the body (uterus), after union of an ovum and spermatozoon, during the 
period from conception to birth. (NCI) 
Protocol deviation 
An event or decision that stands in contrast to the guidelines set out by the 
protocol (NCI) 
Site terminated by sponsor 
An indication that a clinical study was stopped at a particular site by its 
sponsor (NCI) 
Study terminated by sponsor 
An indication that a clinical study was stopped by its sponsor (NCI) 
Withdrawal by subject 
An indication that a study participant has removed itself from the study 
(NCI) 
 
Collection of Pregnancy Information: 
Female Participants Who Become Pregnant  
• 
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to Allergan within 24 hours of learning of a participant’s pregnancy. 
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The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, and the 
information will be forwarded to Allergan. Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of pregnancy 
will be reported, regardless of fetal status (presence or absence of anomalies) or indication 
for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
will be reported as an AE or SAE. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) or genetic 
abnormalities (whether leading to an elective abortion or not) are always considered to be 
SAEs and will be reported as such. Any poststudy pregnancy-related SAE considered 
reasonably related to the study intervention by the investigator will be reported to Allergan 
as described in Section 8.3.4. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.  
• 
If a pregnancy is confirmed after the participant has received study intervention, the 
participant may choose to exit the study after appropriate safety follow-up or to remain in 
the study for all safety and efficacy follow-up assessments through the end-of-study visit.   
 
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10.5. 
Appendix 5: Study Tabular Summary 
This table is intended for use in posting study information to registries (eg, ClinicalTrials.gov). 
Parameter Group 
Parameter 
Value 
Trial information 
Trial Title 
BOTOX® (onabotulinumtoxinA) 
Treatment of Masseter Muscle 
Prominence: A Phase 2b, Multicenter, 
Randomized, Double-Blind, Multi-Dose, 
Placebo-Controlled Study 
 
Clinical Study Sponsor 
Allergan Sales, LLC. 
 
Trial Phase Classification 
Phase 2b trial 
 
Trial Indication 
Masseter Muscle Prominence 
 
Trial Indication Type 
Treatment 
 
Trial Type 
Efficacy 
Safety 
 
Trial Length 
180 days plus a 14-day screening period 
 
Planned Country of Investigational Sites 
US  
 
Planned Number of Participants 
150 
 
FDA-Regulated Device Study 
No 
 
FDA-Regulated Drug Study 
Yes 
 
Pediatric Study 
No 
Participant 
information 
Diagnosis Group 
Masseter Muscle Prominence 
 
Healthy Participant Indicator 
Yes 
 
Planned Minimum Age of Participants 
18 
 
Planned Maximum Age of Participants 
Not specified 
 
Sex of Participants 
Both 
 
Stable Disease Minimum Duration 
Not specified 
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Parameter Group 
Parameter 
Value 
Treatments 
Investigational Therapy or Treatment 
OnabotulinumtoxinA 
 
Intervention Type 
Drug 
 
Pharmacological Class of Invest. Therapy 
Neurotoxin 
 
Dose per Administration 
48 or 72 
 
Dose Units 
U 
 
Dosing Frequency 
Single treatment 
 
Route of Administration 
Intramuscular 
 
Current Therapy or Treatment 
No 
 
Added on to Existing Treatments 
No 
 
Control Type 
Placebo  
 
Comparative Treatment Name 
Placebo 
Trial design 
Study Type 
Interventional 
 
Intervention Model 
Parallel 
 
Planned Number of Arms 
3 
 
Trial is Randomized 
Yes 
 
Randomization Quotient 
1:1:1 
 
Trial Blinding Schema 
Double blind 
 
Stratification Factor 
Day 1 MMPS Grade (4 or 5) 
 
Adaptive Design 
No 
 
Study Stop Rules 
None 
 
 
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10.6. 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
WOCBP 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.  
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the nonestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Guidance: 
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective or acceptable method of contraception consistently and correctly as described in 
Table 10-1. 
 
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Table 10-1 
Highly Effective and Acceptable Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependenta  
Failure rate of < 1% per year when used consistently and correctly  
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation 
• 
Oral  
• 
Intravaginal  
• 
Transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
Oral  
• 
Injectable  
Highly Effective Methods That Are User Independenta  
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
IUD 
• 
IUS 
• 
Etonogestrel implant (ie, Nexplanon®) 
• 
Bilateral tubal occlusion (eg. Essure, bilateral tubal ligation) 
• 
Intrauterine copper contraceptive (ie, ParaGard®) 
Vasectomized Partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used.  
Sexual Abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.  
Acceptable Methods  
Acceptable birth control methods that result in a failure of more than 1% per year include: 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of 
action 
• 
Male or female condom with or without spermicide  
• 
Cap, diaphragm, or sponge with spermicide 
• 
Nonhormonal intrauterine device  
A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier methods) 
are also considered acceptable, but not highly effective, birth control methods. 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies.  
Pregnancy Testing: 
• 
WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive pregnancy test at screening and also a negative test on Day 1. 
• 
Additional pregnancy testing should be performed at study exit, and as required locally. 
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• 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.  
• 
Urine pregnancy testing will be used unless the study site requires the use of serum testing, 
in which case serum testing will be used. 
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10.7. 
Appendix 7: Efficacy Measures 
10.7.1. 
Masseter Muscle Prominence Scale – Investigator Assessment 
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 by selecting one response per masseter. 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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10.7.2. 
Lower Facial Volume Measurement 
The lower facial volume measurement (cm3) will be performed by 
, Inc using 
2 analysis methods, as described below. 
Landmark AOI Analysis Method 
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 10-1, 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 10-1 
Lower Facial Volume Measurement 
 
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Statistical MMP AOI Analysis Method 
An additional method of lower facial volume analysis will be performed using a statistical MMP 
AOI model (MMP AOI) to calculate the full area of change in lower facial volume (Figure 10-2). 
The MMP AOI was developed based on a statistical shape averaging of the area of change post 
masseter treatment from multiple facial models, which defines the mask area used for 
analysis. The MMP AOI approach allows the image analysis methodology to be better targeted 
to the full change contributed from the masseter muscle on a participant-by-participant 
basis. This improved targeting also reduces the potential for non-target anatomy noise and 
variability (ie, peri-oral expression). 
To measure the difference in volume between two 3D surface models from different timepoints 
(ie, baseline, posttreatment) using the MMP AOI method, the models are also registered in 3D 
space such that relative surfaces unrelated to the treatment regions are aligned correspondingly. 
Figure 10-2 
Standardized Target AOI from a 3D Facial Shape Model 
 
 
In conclusion, the change from baseline in lower facial volume for both landmark AOI (as used 
in Study 191622-130) and statistical MMP AOI (the new method described above) will be 
analyzed using ANCOVA with study intervention and investigator site as factors, and baseline 
MMPS Grade as a covariate. 
10.7.3. 
Facial Width Measurement 
Facial width measurements (mm) will be performed by
 
To measure lower facial width, the following lines (A, B, and C) are drawn from the frontal 
facial image. In Figure 10-3 below, Line A depicts the width of the face at the level of the 
stomion, the midline point at the junction of the upper and lower lip vermillion. Line B depicts 
the alar base width. The alar base width is defined as the distance between the left and right alar 
rim, and not the left and right alar crease junction. Line C depicts the distance between the right 
and left medial canthus. Intercanthal distance (C) and alar base width (B) are anticipated to 
remain constant during the course of the study and to be unaffected by study intervention. 
The width of the face (A) as well as ratio of alar base width to facial width (B/A) and the ratio of 
intercanthal width to facial width (C/A) will be calculated for each participant and visit. 
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Figure 10-3 
Lower Facial Width Measurement 
 
 
 
C 
B 
A 
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10.7.4. 
Mandibular Facial Angle Measurement 
The mandibular facial angle measurement (degrees) will be performed by 
, 
Inc. 
To measure the mandibular angle, the following lines are drawn and angle X measured from the 
frontal facial image (see Figure 10-4 below). 
Line A is an oblique line drawn across the contour of the horizontal part of the jawline. Line B is 
another oblique line drawn from the most lateral aspect of cheek to the angle of the mandible 
outlining the plane of the face containing the vertical ramus of the mandible. Lines A and B 
intersect at the apex of the angle of the mandible. Angle X is measured as the internal angle 
between the horizontal (A) and vertical (B) lines. 
The angle X will be calculated for the left side and right side of the face and averaged for each 
participant at each visit. The percent change in the averaged angle from baseline and the 
averaged angle from posttreatment will be calculated for each participant and each posttreatment 
visit. 
Figure 10-4 
Mandibular Facial Angle Measurement 
 
 
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Approval Date: 
 
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Protocol 1789-202-008 
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1 Not at all pronounced 
The muscles in the area do not stand out; the jawline is 
not wide. 
2 Mildly pronounced 
The muscles in the area stand out slightly; the jawline is 
slightly wide. 
3 Moderately 
pronounced 
The muscles in the area stand out somewhat; the jawline 
is somewhat wide. 
4 Pronounced 
The muscles in the area stand out a great deal; the 
jawline is very wide. 
5 Very pronounced 
The muscles in the area stand out extremely; the jawline 
is extremely wide. 
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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] 
Baek SM, Kim SS, Bindiger A. The prominent mandibular angle: preoperative management, 
operative technique, and results in 42 patients. Plast Reconstr Surg. 1989;83:272-278. 
Chai G, Zhang Y, Zhu M, Ma X, Yu Z, Mu X, Qi Z. Evaluation of dynamic morphologic changes 
in the masseter muscle in patients undergoing mandibular angle sagittal split osteotomy. Arch 
Facial Plast Surg. 2011;13:301-304. 
Chang CS, Kang G C-W. Achieving ideal lower face aesthetic contours: combination of 
tridimensional fat grafting to the chin with masseter botulinum toxin injection. Aesthetic Surgery 
Journal, 2016;36(10):1093–1100. 
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. 
Deguchi M, Iio Y, Kobayashi K, Shirakabe T. Angle-splitting ostectomy for reducing the width 
of the lower face. Plast Reconstr Surg. 1997;99:1831-1839. 
Fedorowicz Z, van Zuuren EJ, Schoones J. Botulinum toxin for masseter hypertrophy.  Cochrane 
Database Syst Rev. 2013;(9):CD007510. Review. 
Herrero BA, Ecklung AE, Streett CS, Ford DF, King JK. Experimental botulism in monkeys: a 
clinical pathological study. Exp Mol Pathol. 1967;6:84-95. 
11DEC2020 CSR 1789-202-008
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Approval Date: 
 
12-Feb-2019
 
 
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BOTOX 
 
 
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. 
Jin H. Misconceptions about mandible reduction procedures. Aesthetic Plast Surg. 
2005;29:317-324. 
Jin H, Kim BG. Mandible reduction versus mandibular angle reduction. Plast Reconstr Surg. 
2004;114:1263-1269. 
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. 
Kim SK, Han JJ, Kim JT. Classification and treatment of prominent mandibular angle. Aesthetic 
Plast Surg. 2001;25:382–387. 
Klein FH, Brenner FM, Sato MS, Robert FM, Helmer KA. Lower facial remodeling with 
botulinum toxin type A for the treatment of masseter hypertrophy. An Bras Dermatol. 
2014;89:878-884. 
Lee JG, Park YW. Intraoral approach for reduction malarplasty: a simple method. Plast Reconstr 
Surg. 2003;111:453-460. 
Lee KC, Ha SU, Park JM, Kim SK, Park SH, Kim JH. Reduction malarplasty by 3-mm 
percutaneous osteotomy. Aesthetic Plast Surg. 2006;30:333–341. 
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. 
11DEC2020 CSR 1789-202-008
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Approval Date: 
 
12-Feb-2019
 
 
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BOTOX 
 
 
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. 
Morris DE, Moaveni Z, Lo L-J. Aesthetic facial skeletal contouring in the Asian patient. Clin 
Plastic Surg. 2007;34:547–556. 
Mu X. Experience in East Asian facial recontouring: reduction malarplasty and mandibular 
reshaping. Arch Facial Plast Surg. 2010;12:222-229. 
Onizuka T, Watanabe K, Takasu K, Keyama A. Reduction malar plasty. Aesthetic Plast Surg. 
1983;7:121-125. 
Park MY, Ahn KY, Jung DS. Botulinum toxin type A treatment for contouring of the lower face. 
Dermatol Surg. 2003;29:477-483. 
Park YJ, Jo YW, Bang SI, Kim HJ, Lim SY, Mun GH, et al. Radiofrequency volumetric 
reduction for masseteric hypertrophy. Aesthetic Plast Surg. 2007;31:42-52. 
Peng H-L P, Peng J-H. Complications of botulinum toxin injection for masseter hypertrophy: 
incidence rate from 2036 treatments and summary of causes and preventions. J Cosmet Dermatol. 
2017;00:1-6. 
Pu Z, Zhang Y, Yang J, Liu T, Zhang Y, Yang Q, et al. Mandibular angle ostectomy for Chinese 
women: approaches and extent determined by cephalometric analysis. J Craniofac Surg. 
2009;20:105-110. 
Rauso R, Santagata M, Colella G. Can occlusal devices prolong the effect of botulinum toxin 
type A in the contouring of the lower face? Eur J Plast Surg. 2010;33:35-40. 
Scott AB. Clostridial toxins as therapeutic agents. In: Simpson LL, editor. Botulinum neurotoxin 
and tetanus toxin. New York, Academic Press. 1989;399-412. 
Shim WH, Yoon SH, Park JH, Choi Y-C, Kim ST. Effect of botulinum toxin type A injection on 
lower facial contouring evaluated using a three-dimensional laser scan. Dermatol Surg. 
2010;36(Suppl 4):2161-2166. 
Smyth AG. Botulinum toxin treatment of bilateral masseteric hypertrophy. Br J Oral Maxillofac 
Surg. 1994;32:29-33. 
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Sumiya N, Yoshinori I, Ozumi K. Reduction malarplasty. Plast Reconstr Surg. 
2004;113:1497-1499. 
Tartaro G, Rauso R, Santagata M, Santillo V, Itro A. Lower facial contouring with botulinum 
toxin type A. J Craniofac Surg. 2008;19:1613-1617.  
To EWH, Ahuja AT, Ho WS, King WWK, Wong WK, Pang PCW, et al. A prospective study of 
the effect of botulinum toxin A on masseteric muscle hypertrophy with ultrasonographic and 
electromyographic measurement. Br J Plast Surg. 2001;54:197-200. 
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. 
Wu WTL. Botox facial slimming/facial sculpting: the role of botulinum toxin-A in the treatment 
of hypertrophic masseter muscle and parotid enlargement to narrow the lower facial width. 
Facial Plastic Surgery Clinics of North America 2010;18(1):133-140. 
Xie Y, Zhou J, Li H, Cheng C, Herrler T, Li Q. Classification of Masseter Hypertrophy for 
Tailored Botulinum Toxin Type A Treatment. Plast Reconstr Surg. 2014;134:209e-218e. 
Yang DB, Park CG. Mandibular contouring surgery for purely aesthetic reasons. Aesthetic Plast 
Surg. 1991;15:53–60. 
Yang DB, Song HS, Park CG. Unfavorable results and their resolution in mandibular contouring 
surgery. Aesthetic Plast Surg. 1995;19:93-102. 
 
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Date (DD/MMM/YYYY)/Time (PT) 
Signed by: 
Justification 
  
 
 
            
 
           
 
            
 
           
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
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SAP_001.pdf: 
 
   
 
 
 
         NCT03861936 
 
Study ID: 1789-202-008 
 
 
Title: BOTOX® (onabotulinumtoxinA) Treatment of Masseter Muscle 
Prominence: A Phase 2b, Multicenter, Randomized, Double-Blind, Multi-
Dose, Placebo-Controlled Study 
 
                Statistical Analysis Plan Date: August 5, 2019 


Allergan 
BOTOX 
1.0 
B
A Pha
Final: 05
 
 
TITL
BOTOX® (on
ase 2b, Mul
STA
5 Aug 2019 
LE PAGE 
nabotulinum
ticenter, Ra
ATISTICAL
178
mtoxinA) T
andomized, 
L ANALYS
1 
 
89-202-008
reatment of
Double-Bli
Study 
SIS PLAN -
f Masseter M
nd, Multi-D
Clinical Stu
 
Muscle Pro
Dose, Placeb
udy Report
SAP 1789-20
minence:  
bo-Controlle
 
02-008 
ed 


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2.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE .................................................................................................................................................. 1 
2.0 
TABLE OF CONTENTS ................................................................................................................................ 2 
3.0 
LIST OF ABBREVIATIONS ......................................................................................................................... 3 
4.0 
INTRODUCTION ........................................................................................................................................... 4 
5.0 
OBJECTIVES ................................................................................................................................................. 7 
6.0 
PATIENT POPULATIONS ............................................................................................................................ 7 
6.1 
Modified Intent-to-Treat Population ................................................................................................. 7 
6.2 
Safety Population .............................................................................................................................. 7 
7.0 
PATIENT DISPOSITION ............................................................................................................................... 7 
8.0 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................................................ 8 
8.1 
Demographics and Baseline Characteristics ..................................................................................... 8 
8.2 
Medical History ................................................................................................................................ 8 
8.3 
Prior and Concomitant Medications .................................................................................................. 8 
9.0 
EFFICACY ANALYSES ................................................................................................................................ 9 
9.1 
Primary Efficacy Parameter .............................................................................................................. 9 
9.2 
Secondary Efficacy Parameters ......................................................................................................... 9 
9.3 
Additional Efficacy parameters ....................................................................................................... 10 
10.0 
SAFETY ANALYSES .................................................................................................................................. 11 
10.1 
Adverse Events ............................................................................................................................... 11 
10.2 
Vital Signs ....................................................................................................................................... 14 
11.0 
INTERIM ANALYSIS.................................................................................................................................. 14 
12.0 
DETERMINATION OF SAMPLE SIZE ...................................................................................................... 14 
13.0 
STATISTICAL SOFTWARE ....................................................................................................................... 15 
14.0 
DATA HANDLING CONVENTIONS ........................................................................................................ 15 
14.1 
Visit Time Windows ....................................................................................................................... 15 
14.2 
Derived Variables ........................................................................................................................... 15 
14.3 
Repeated or Unscheduled Assessments of Safety Parameters ........................................................ 16 
14.4 
Missing Severity Assessment for Adverse Events .......................................................................... 16 
14.5 
Missing Causal Relationship to Study Intervention for Adverse Events ........................................ 16 
14.6 
Missing Date Information for Adverse Events................................................................................ 16 
14.7 
 
 


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3.0 
LIST OF ABBREVIATIONS  
 
AE 
adverse event 
AOI 
area of interest 
ANCOVA 
analysis of covariance 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
 
 
mITT 
modified Intent-to-Treat 
MMP 
masseter muscle prominence  
MMPS 
Masseter Muscle Prominence – Investigator Assessment 
MMPS-P 
Masseter Muscle Prominence – Participant Assessment 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCS 
potentially clinically significant 
PDSOT 
possible distant spread of toxin 
PID 
patient ID 
 
 
PSAC 
Participant Self-Assessment of Change 
PT 
Preferred Term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 


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4.0 
INTRODUCTION 
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of the 
statistical analyses of the efficacy and safety data as outlined and/or specified in the approved 
protocol of Study 1789-202-008 (dated 12 Feb 2019). Specifications of tables, figures, and data 
listings are contained in a separate document.  
Study 1789-202-008 is a Phase 2b, 6-month, double-blind, randomized, placebo-controlled, 
single-treatment trial to assess the safety and efficacy of BOTOX treatment for MMP.  
Approximately 150 participants were planned to be randomly assigned (1:1:1) to receive a single 
treatment of BOTOX 48 U (n=50), BOTOX 72 U (n=50), or placebo (n=50) on Day 1. 
Randomization will be stratified at each investigator site by the participant’s baseline MMPS 
Grade (4 or 5). Up to 8 scheduled visits are planned: screening (Day -14 to Day -1), 
randomization/baseline (Day 1), follow-up (Days 30, 60, 90, 120, 150, and 180). On Day 180, 
final study exit assessments will be collected.  
  
 


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5.0 
OBJECTIVES 
The objectives of this study are: 
• To compare the efficacy and safety of BOTOX with placebo in participants with bilateral 
masseter muscle prominence (MMP) 
• To compare the efficacy of BOTOX with placebo in participants with MMP based on 
multiple clinical efficacy assessments 
6.0 
PATIENT POPULATIONS 
The patient populations will be summarized in total and by study intervention group for all 
randomized or treated participants. 
6.1 
MODIFIED INTENT-TO-TREAT POPULATION 
The modified Intent-to-Treat (mITT) Population will consist of all randomized participants with 
at least 1 postbaseline MMPS assessment. Participants will be summarized according to the 
randomized study intervention.  
6.2 
SAFETY POPULATION 
The Safety Population will consist of all participants who received at least 1 administration of 
study intervention. Participants will be summarized according to the study intervention received. 
7.0 
PATIENT DISPOSITION 
Participant disposition encompasses the distribution of participants screened, randomized, 
treated, and who completed or discontinued the study (along with reasons for 
withdrawal/discontinuation). Participant disposition will be summarized for all screened 
participants in total and by study intervention group. 


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8.0 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
8.1 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographic parameters (age; age group; sex; race; ethnicity), baseline characteristics (weight; 
height; body mass index, calculated as weight [kg]/(height [m])2; baseline MMPS and MMPS-P) 
will be summarized descriptively for the mITT Population by study intervention group and in 
total. Continuous variables will be summarized by number of participants and mean, SD, 
median, minimum, and maximum values. Categorical variables will be summarized by number 
and percentage of participants. 
8.2 
MEDICAL HISTORY 
Medical history, encompassing abnormalities and surgeries reported as occurring before Day 1, 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 22.0 or 
newer. Unique participants who report medical history events will be summarized by MedDRA 
system organ class (SOC) and preferred term (PT) for the mITT Population by study intervention 
group. Medical history will be summarized separately for those ongoing at Day 1 and those not 
ongoing at Day 1. 
8.3 
PRIOR AND CONCOMITANT MEDICATIONS 
Medications will be coded using the World Health Organization (WHO) Drug Dictionary. Prior 
medications are medications taken ≥ 1 time before the study intervention start date, regardless of 
medication end date. Concomitant medications are medications taken ≥ 1 time on or after the 
study intervention start date, regardless of medication start date. Unique participants who 
reported medications will be summarized by WHO Drug class and preferred drug name for the 
mITT Population by study intervention group. Prior and concomitant medications will be 
summarized separately. 


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9.0 
EFFICACY ANALYSES 
The efficacy analyses will be based on the mITT Population, defined as randomized participants 
with at least 1 postbaseline MMPS assessment. The last-observation-carried-forward approach 
will be used to impute missing postbaseline values. Baseline for efficacy is defined as the last 
approved non-missing efficacy assessment before the first dose of study intervention. Pairwise 
comparisons will be conducted between each BOTOX group and the placebo group. All 
statistical tests will be 2-sided hypothesis tests performed at the 5% level of significance for 
main effects. All confidence intervals will be 2-sided 95% confidence intervals, unless stated 
otherwise. 
9.1 
PRIMARY EFFICACY PARAMETER 
The primary efficacy variable is the investigator’s assessment of MMP using the MMPS 
(1 = minimal, 2 = mild, 3 = moderate, 4 = marked, 5 = very marked). Each participant’s MMPS 
score will be based on the worst score of the left and right side of the face. If a score is missing 
for 1 side of the face, then the participant’s MMPS score will be based on the score for the other 
side of the face. The primary efficacy endpoint will be the proportion of responders who achieve 
MMPS Grade ≤ 3 at Day 90.  
The following set of hypotheses will be used to compare the BOTOX groups with placebo: 
• Null hypothesis: BOTOX and placebo are equally effective in reducing MMP as 
measured by the proportion of responders achieving MMPS Grade ≤ 3 at Day 90. 
• Alternative hypothesis: BOTOX and placebo are not equally effective in reducing MMP 
as measured by the proportion of responders achieving MMPS Grade ≤ 3 at Day 90. 
Frequency counts of participants achieving a MMPS Grade ≤ 3 will be tabulated by study 
intervention group at each postbaseline visit. The difference between each BOTOX dose and 
placebo in the proportion of participants with MMPS ≤ 3 will be analyzed using Cochran-Matel-
Haenszel (CMH) model stratified by baseline MMPS Grade (4 or 5).  
A sensitivity analysis will be performed based on all observed data for the mITT Population. 
9.2 
 SECONDARY EFFICACY PARAMETERS 
The following are considered secondary endpoints at Day 90: 
• Proportion of responders who achieve MMPS-P Grade ≤ 3 
• Proportion of responders who achieve ≥ 2-grade MMPS improvement from baseline 


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• Proportion of responders who achieve ≥ 2-grade MMPS-P improvement from baseline 
•  Proportion of responders who achieve PSAC Grade ≥ 2 (at least moderately improved 
from baseline) 
• Change from baseline in lower facial volume by VECTRA M3 measured using landmark 
area of interest (AOI) and statistical MMP AOI 
 
For all the responder analyses, frequency counts of responders for each of the responder 
definitions above will be tabulated by study intervention group at each postbaseline visit. The 
difference between each BOTOX dose and placebo in the proportion of responders will be 
analyzed using CMH model stratified by baseline MMPS Grade (4 or 5). 
The change from baseline in lower facial volume using both landmark AOI and statistical MMP 
AOI will be analyzed using analysis of covariance (ANCOVA) with study intervention and 
investigator site as factors and baseline MMPS Grade (4 or 5) as a covariate. Missing values for 
change from baseline in lower facial volume at Day 30 will be imputed using the average of 
participants with non-missing values. 
Summary statistics for each endpoint will be tabulated by study intervention group at each 
postbaseline visit. 
Each of the responder analyses will be analyzed using CMH model stratified by baseline MMPS 
grade. 


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The change from baseline analyses will be analyzed using ANCOVA with study intervention and 
investigator site as factors and baseline MMPS grade and baseline score as covariates. 
10.0 
SAFETY ANALYSES 
The safety analysis will be performed using the Safety Population. The safety parameters will 
include adverse events (AEs) and vital signs. For each safety parameter of the vital signs, the last 
nonmissing safety assessment before the first dose of study intervention will be used as the 
baseline for all analyses of that parameter. Continuous variables will be summarized by number 
of participants and mean, SD, median, minimum, and maximum values. Categorical variables 
will be summarized by number and percentage of participants. 
10.1 
ADVERSE EVENTS 
Adverse events will be coded by SOC and PT using the MedDRA, version 22.0 or newer. 
An AE will be considered a treatment-emergent adverse event (TEAE) if the AE began or 
worsened (increased in severity or became serious) on or after the date of the first dose of study 
intervention. 
An overall summary of AEs by study intervention group will be provided. 
The number and percentage of participants reporting TEAEs will be summarized by study 
intervention group using MedDRA PT nested within SOC. Events will be in alphabetic order of 
SOC and by descending frequency of PTs within each SOC.  
The total number of TEAEs by severity will be summarized by study intervention group. 
Treatment-related TEAEs will be tabulated by descending frequency of PTs within the SOC. If 
more than 1 AE is coded to the same PT for the same patient, the patient will be counted only 
once for that PT using the greatest severity and strictest causality for the summarization by 
severity and causal relationship. 
The number and percentage of participants who have treatment emergent serious adverse events 
(TESAEs) will be summarized by SOC, PT, and study intervention group if 5 or more 
participants reported such events. 


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12 
The number and percentage of participants in the Safety Population who have TEAEs leading to 
premature discontinuation of the study intervention will be summarized by SOC, PT, and study 
intervention group if 5 or more participants reported such events. 
To assess possible distant spread of toxin (PDSOT), MedDRA preferred terms that may be 
associated with botulinum toxin effects have been identified and are shown in Table 10-1.  All 
AEs associated with PDSOT will be tabulated by PT and study intervention group; in addition, 
all PDSOT AEs will be listed by subject.  


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Table 10-1 
MedDRA System Organ Class and Preferred Terms Evaluated for Possible Distand 
Spread of Toxin 
Cardiac Disorders 
          Bradycardia  
 
Eye Disorders 
          Accommodation disorder  
          Diplopia 
          Extraocular muscles paresis 
          Eyelid function disorder 
          Eyelid ptosis 
          Pupillary reflex impaired 
          Vision blurred 
 
Gastrointestinal Disorders 
          Constipation 
          Dry mouth  
          Dysphagia 
          Ileus paralytic 
 
Infections and Infestations 
          Botulism 
 
Musculoskeletal and Connective Tissue Disorders   
          Muscular weakness 
 
 
 
 
Nervous System Disorders 
          Bulbar palsy  
         Cranial nerve palsies multiple 
         Cranial nerve paralysis 
          Dysarthria 
          Facial paralysis 
          Facial paresis 
          Hyporeflexia 
          Hypotonia     
          Paralysis 
          Paresis cranial nerve 
          Peripheral nerve palsy 
          Peripheral paralysis 
          Speech disorder 
          Vocal cord paralysis 
          Vocal cord paresis 
 
  
 Renal and Urinary Disorders 
 
 
          Urinary retention   
 
Respiratory, Thoracic and Mediastinal Disorders 
          Aspiration  
          Diaphragmatic paralysis 
          Dysphonia 
          Dyspnoea 
          Pneumonia aspiration 
          Respiratory arrest 
          Respiratory depression 
          Respiratory failure           
 
 
Reproductive System and Breast Disorders          
          Pelvic floor muscle weakness           
 
 
Note: Table is based on MedDRA 22.0; the actual list used for analysis will be based on the MedDRA version in use 
at the time of database lock. 


Allergan 
 
SAP 1789-202-008 
BOTOX 
14 
10.2 
VITAL SIGNS 
Descriptive statistics (mean, SD, median, Q1, Q3, minimum, and maximum) for vital signs 
(systolic and diastolic blood pressures, respiratory rate, and pulse rate) and changes from 
baseline values at each visit and at the end of study will be presented by study intervention 
group. 
Vital sign values will be considered PCS if they meet both the observed-value criteria and the 
change-from-baseline criteria listed in Table 10-2. A listing of patients with PCS postbaseline 
values will be provided, including the PID number, baseline and all postbaseline (including non-
PCS) values. 
Table 10-2 
Criteria for Potentially Clinically Significant Vital Signs 
Parameter 
Flag 
Criteriaa 
Observed Value 
Change From Baseline 
Sitting systolic blood 
pressure, mm Hg 
High 
> 140 
Increase of ≥ 20 
Low 
< 90 
Decrease of ≥ 20 
Sitting diastolic blood 
pressure, mm Hg 
High 
> 90 
Increase of ≥ 15 
Low 
≤ 50 
Decrease of ≥ 15 
Sitting pulse rate, bpm 
High 
> 100 
Increase of ≥ 15 
Low 
≤ 50 
Decrease of ≥ 15 
a A postbaseline value is considered potentially clinically significant if it meets both the observed-value and the 
change-from-baseline criteria. 
bpm = beats per minute. 
11.0 
INTERIM ANALYSIS 
No interim analyses are planned for this study. 
12.0 
DETERMINATION OF SAMPLE SIZE 
The primary efficacy parameter is proportion of responders who achieve MMPS Grade ≤ 3 at 
Day 90 (last observation carried forward). Based on previous data from study 191622-130 and 
the assumption of ≥ 34% difference in MMPS response rate between BOTOX 48 U or 72 U and 
placebo and 10% dropout rate, approximately 50 participants will provide > 90% power using a 
2-sided Mantel-Haenszel test at 5% significance level. 


Allergan 
 
SAP 1789-202-008 
BOTOX 
15 
13.0 
STATISTICAL SOFTWARE 
Statistical analyses will be performed using SAS version 9.4 (or newer) on a Linux operating 
system. 
14.0 
DATA HANDLING CONVENTIONS 
14.1 
VISIT TIME WINDOWS 
Table 14-1 presents the visits assigned for efficacy and safety analyses and the corresponding 
range of study intervention days (window) during which an actual visit may occur. 
Table 14-1 
Visit Time Windows 
Derived Visit 
Scheduled Visit Daya
Window 
Baseline 
Day 1 
Days ≤ 1 
Day 30 
Day 30 
Days [2, 45] 
Day 60 
Day 60 
Days [46, 75] 
Day 90 
Day 90 
Days [76, 105] 
Day 120 
Day 120 
Days [106, 135] 
Day 150 
Day 150 
Days [136, 165] 
Day 180 
Day 180 
Days ≥ 166 
End of Studyb 
Final or Termination Visit during the double-blind treatment period 
a 
Relative to the date of the first dose of study intervention. Day 1 = the date of the first dose of study intervention. There is 
no Day 0. 
b 
Presented in analysis tables for safety parameters, including but not limited to vital signs. 
If the assessment date is on or after the date of the first dose of study intervention, the study day 
is calculated by assessment date – date of the first dose of study intervention + 1. If the 
assessment date is before the date of the first dose of study intervention, the study day is 
calculated by assessment date – date of the first dose of study intervention. Therefore, a negative 
day indicates a day before the start of the study intervention. If the assessment date is 
unavailable, use the visit date instead. 
If a participant has 2 or more visits within the same window, the last visit with a nonmissing 
value will be used for analysis. 
14.2 
DERIVED VARIABLES 
Not applicable. 


Allergan 
 
SAP 1789-202-008 
BOTOX 
16 
14.3 
REPEATED OR UNSCHEDULED ASSESSMENTS OF SAFETY 
PARAMETERS 
If a participant has repeated assessments before the start of the first study intervention, the results 
from the final nonmissing assessment made prior to the start of the study intervention will be 
used as baseline. If end-of-study assessments are repeated or if unscheduled visits occur, the last 
nonmissing postbaseline assessment will be used as the end-of-study assessment for generating 
summary statistics.  
14.4 
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS 
If severity is missing for an AE that started before the date of the first dose of study intervention, 
an intensity of mild will be assigned. If severity is missing for an AE that started on or after the 
date of the first dose of study intervention (based on date, and time if known), an intensity of 
severe will be assigned. The imputed values for severity assessment will be used for the 
incidence summary; the values will be shown as missing in the data listings. 
14.5 
MISSING CAUSAL RELATIONSHIP TO STUDY INTERVENTION FOR 
ADVERSE EVENTS 
If the causal relationship to study intervention is missing for an AE that started before first dose 
of study intervention, a causality of no will be assigned. If the causal relationship to the study 
intervention (per the investigator) is missing for an AE that started on or after the date of the first 
dose of study intervention (based on date, and time if known), a causality of yes will be assigned. 
The imputed values for causal relationship to study intervention will be used for the incidence 
summary; the values will be shown as missing in the data listings. 
14.6 
MISSING DATE INFORMATION FOR ADVERSE EVENTS 
Missing/incomplete AE start dates will be imputed on a case by case basis. 
Imputed partial AE dates will only be used to determine if an AE is a TEAE. All partial dates 
will be listed “as is” in the data listings. 
14.7 
MISSING DATE INFORMATION FOR PRIOR OR CONCOMITANT 
MEDICATIONS 
 
  


Allergan 
 
SAP 1789-202-008 
BOTOX 
17 


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1789-202-008 Statistical Analysis Plan