Clinical trial NCT03223298
Conditions: Pain, Head Pain Syndrome Temporomandibular Disorder Myofascial Pain Syndrome Myofascial Pain
Keywords: Myofascial Pain Myofascial Pain Disorder Maxillofacial Pain Masseter Muscle Temporalis Muscle Botulinum Toxin
Sponsor: Weill Medical College of Cornell University
Start date: 2018-08-31; Completion date: 2020-03-13
Enrollment: 75 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study aims to determine whether the injection of botulinum toxin A or placebo (unpreserved 0.9% sodium chloride) into the masseter and temporalis muscles provides pain relief and improved jaw function in those who suffer from myofascial pain disorder. The study hypothesis is that botulinum toxin A injection is superior to placebo. The specific research questions are:

1. Is the injection of botulinum toxin A superior to placebo for the improvement in pain?
2. Is the injection of botulinum toxin A superior to placebo for the improvement in function or quality of life (QOL)?
3. Are there any adverse effects that result from injection of botulinum toxin A or placebo into the masseters and temporalis muscles? Limited data exists to support the use of botulinum toxin A in the management of myofascial pain disorder of the masticatory region. Botulinum toxin A is not FDA approved for intra-muscular injection within the masticatory region. Its use in the masticatory region is considered off-label but performed without significant known complications. This study will provide the opportunity to quantitate and qualitate any complications in a large prospective sample of patients.

Detailed description:
Myofascial pain is classically used to describe pain experienced in the masticatory muscles and its associated structures (Freund 1999). It afflicts nearly 10% of Americans (Freund 2000). There have been many described treatments such as the use of oral appliances, non-steroidal anti-inflammatory medications, physiotherapy, behavioral therapy and counseling, acupuncture, and botulinum toxin injections (Freund 2000). However, no single treatment has been found to be significantly superior to the others (Freund 2000).

This is a randomized, double-blind, placebo-controlled multicenter study. Subjects will be recruited from the divisions of Oral and Maxillofacial Surgery from all sites. Patients aged 18-65 years with myofascial pain involving the temporalis and masseters are eligible to enter the study. A complete history and physical examination will be performed for all patients in order to make an accurate diagnosis. The research diagnostic criteria (RDC/TMD) will be used to assign a diagnosis of myofascial pain of the masticatory region. All investigators and site-specific data collectors will be trained and calibrated in physical examination techniques and data collection to ensure uniformity between sites. Patients will complete a visual analog scale regarding pain during their screening appointment. To participate in the study, the subject must have greater than or equal to 3.5/10 on the visual analog scale of pain. Informed written consent will be obtained from all patients. Any patient lacking the capacity to make medical decisions will be excluded from the study, although they will be treated as deemed medically necessary. Consent will be written at the sixth grade level, and all potential subjects will be asked to verbally repeat the purpose, methods, and required follow-up to ensure adequate understanding.

The site specific PI will educate fellow faculty and referring departments that the study is enrolling new subjects, advertising is anticipated, and referring physicians will not receive any financial compensation. The intent is to enroll a total of 110 subjects from all sites. The study participants will be reimbursed $25 per treatment visit for their participation.

Previous studies have demonstrated a reduction of pain as indicated on the visual analogue scale of 45% and 32% with the use of intramuscular botulinum toxin A injections into masseter and temporalis (Freund 1999, Guarda-Nardini 2012). Von Lindern et. al. found a mean reduction of 3.2 points on a visual analog scale in the verum group. Based on the preliminary data and the sample size calculations estimating a difference in mean pre-post VAS change between groups of 1 point or greater (on a scale of 1-10), we plan to enroll a total of 110 subjects. With 50 patients in the botulinum toxin A injection group and 50 patients in the placebo group (N=100), the study will have more than 90% power to detect a difference in mean in pre-post change between groups of 1.0 point or greater on VAS, using a two-sided t-test and assuming a standard deviation of 1.5 for the mean difference. This calculation allows for 10% attrition rate. An intent-to-treat design will be followed and all subjects will have scheduled outcome evaluations until the end of the study, death of the subject, or subject refusal. Subjects will be withdrawn from their randomly assigned treatment for considerations of subject safety only.

Descriptive statistics including mean, standard deviation, median, range, frequency, and percent will be calculated for the entire cohort as well as by the study arm (botulinum toxin A and unpreserved 0.9% sodium chloride) to assess the results of randomization and identify potential confounders. The primary analyses of the data will be performed according to subjects' original treatment assignment (i.e., intention-to-treat analyses) and the inclusion of all data from all subjects randomized in the final analysis. To assess the primary endpoint of improvement of pain on a visual analog scale (VAS) between pre-op, 1, 2, and month post-op, and 3 months post-op, a repeated measure of analysis of variance will be performed with one between subject factor (botulinum toxin A versus placebo) and one within subject factor (time). This analysis will also be used for the secondary endpoints: function (MIO/jaw limitation scale) and quality of life (SF12). In the event of significant loss to follow-up, we will explore the use of a linear mixed model to assess the independent effect of the study group on VAS over the study visits. The paired t-test, or the signed-rank test as appropriate, will be used to assess change in pain, function, and QOL between pairs of relevant time points for both study arms. To assess the difference in proportion of adverse events between the botulinum toxin A and placebo groups, either the chi-square or Fisher's exact test will be used, as appropriate. All p-values will be two-sided with statistical significance evaluated at the 0.05 alpha level. Ninety-five percent confidence intervals (95% CI) will be calculated to assess the precision of the obtained estimates. All analyses will be performed in SAS Version 9.4 (SAS Institute Inc., Cary, NC). Note: This section was drafted in conjunction with Dr. Paul Christos and Gulce Askin, MPH in the Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research. They will be aiding in protocol design and development, data management, study implementation, study monitoring, and data analysis and reporting.

Adverse events will be reported to the Data and Safety Monitoring Board every six months. The participants will be provided with the phone number of the primary investigator and co-investigators for use in reporting any adverse events. The study participants will also be questioned at one, two, and and three months post-treatment for the occurrence of any adverse events. The report of any such events will provide details including severity, relationship to treatment, onset, duration, and outcome. The Data and Safety Monitoring Board will regularly review these reports, and should any trend develop that suggests significant adverse outcomes, the study will be discontinued. If any serious adverse events occur (death, life-threatening, those involving prolonged hospitalization or disability), the independent study monitor, other study sites, IRBs, and DSMB will be notified with 24 hours in the case of death or 72 hours in the event of other serious adverse events.

IRB approval for this study is currently in process (assigned protocol number 1607017383). Pending approval from the IRB for each involved site, research investigators will honor their responsibility to safeguard the rights and welfare of individuals who are or may become subjects of research. Investigators will also maintain compliance with Department of Health and Human Services regulations. All requirements and determinations made by the IRB will be followed to minimize unnecessary risks to subjects. The investigators will abide by procedures consistent with sound research design. Botulinum toxin A is currently not FDA approved for use in myofascial pain disorder of the masticatory region. If the IRB deems its use a "subject risk," an application for investigational new drug (IND) will be submitted to the FDA under the research or noncommercial category. This requirement is not anticipated given the routine use of botulinum toxin A, previous studies demonstrating benefit with minimal risk, and its existing FDA approval for use in the masseter and temporalis muscles for orofacial dystonia/dyskinesia.

Arms: arm 1: The intramuscular injections will be performed with the patient awake in the oral and maxillofacial surgery clinic. Three injection sites into bilateral masseter muscles and two injection sites into bilateral temporalis muscles will be identified by having the patient clench. The sites will be marked with a surgical pen prior to injections. The skin at the injection sites will be cleaned with an alcohol swab. Via a 1cc TB syringe and a 30-gauge needle, the subject will then receive 100 units of reconstituted botulinum toxin A. 37.5 units will be injected into each masseter muscle and 12.5 units into each temporalis muscle. A written post-operative instruction sheet will be provided to all patients. arm 2: The intramuscular injections will be performed with the patient awake in the oral and maxillofacial surgery clinic. Three injection sites into bilateral masseter muscles and two injection sites into bilateral temporalis muscles will be identified by having the patient clench. The sites will be marked with a surgical pen prior to injections. The skin at the injection sites will be cleaned with an alcohol swab. Via a 1cc TB syringe and a 30-gauge needle, the subject will then receive unpreserved 0.9% sodium chloride. A written post-operative instruction sheet will be provided to all patients.
Interventions: intervention 1: Botulinum toxin type A intervention 2: 0.9% Sodium Chloride Injection
Intervention descriptions: intervention 1: 37.5 units injected into each masseter muscle and 12.5 units into each temporalis muscle intervention 2: 1cc syringe

Protocol documents:
Prot_SAP_000.pdf: 
 
 
  
Page # 1 
 
TITLE:  Comparison of Botulinum Toxin Versus Placebo Injections to Temporalis and Masseter Muscles in 
the Management of Myofascial Pain Disorder: A Randomized Clinical Trial 
 
IRB Protocol #:  
1607017383 
Version Date:  
May 10, 2022 
Funding Source(s):  
Allergan 
 
 
NCT #:                       
 
Principal Investigator: 
03223298 
 
 
Gwendolyn Reeve, DMD 
Assistant Professor of Surgery 
Division of Oral and Maxillofacial Surgery 
 
525 East 68th Street, F-2132 
New York, NY 10065 
212-746-5175 
gsr9001@med.cornell.edu  
 
 
 
Co-Investigators: 
Owen Insel, DMD 
525 East 68th Street, F-2132 
New York, NY 10065 
 
 
Participating Sites:   
Weill Cornell Medicine 
525 East 68th Street, F-2132 
New York, NY 10065 
 
PI: Gwendolyn Reeve, DMD 
Assistant Professor of Surgery 
Division of Oral and Maxillofacial Surgery 
212-746-5175 
gsr9001@med.cornell.edu  
 
University of Illinois, College of Dentistry 
801 S. Paulina Street, Room 110 
Chicago, IL 60612 
 
PI: Michael Miloro, DMD, MD, FACS 
Professor and Head, Oral and Maxillofacial Surgery 
312-996-1052 


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Table of Contents 
STATEMENT OF COMPLIANCE ................................................................................................ 6 
CONFIDENTIALITY STATEMENT .............................................................................................. 7 
LIST OF ABBREVIATIONS ........................................................................................................ 8 
1. PROTOCOL SUMMARY ....................................................................................................... 9 
1.1 
Schema .................................................................................................................... 11 
1.2 
Study Objectives ...................................................................................................... 12 
1.2.1  
Primary Objectives ............................................................................................ 12 
1.2.2  
Secondary Objectives ........................................................................................ 12 
2. BACKGROUND ................................................................................................................. 12 
2.1 
Disease .................................................................................................................... 12 
2.2 
Investigational Agent ............................................................................................... 12 
2.3 
Rationale ................................................................................................................. 12 
2.4 
 Risk/Benefit Assessment ......................................................................................... 13 
2.4.1 
Known Potential Risks ....................................................................................... 13 
2.4.2 
Known Potential Benefits .................................................................................. 14 
2.4.3 
Assessment of Potential Risks and Benefits ....................................................... 14 
2.5 
Correlative Studies Background ................................................................................ 14 
3. STUDY DESIGN ................................................................................................................. 14 
3.1 
Overall Design .......................................................................................................... 14 
3.2 
Scientific Rationale for Study Design ........................................................................ 15 
3.3 
Justification for Dose ............................................................................................... 15 
3.4 
End of Study Definition ............................................................................................ 15 
4. SUBJECT SELECTION ......................................................................................................... 15 
4.1 
Study Population ..................................................................................................... 15 
4.2 
Inclusion Criteria ...................................................................................................... 16 
4.3 
Exclusion Criteria ..................................................................................................... 16 
4.4 
Lifestyle Considerations ........................................................................................... 16 
4.5 
Screen Failures ......................................................................................................... 16 
4.6 
Strategies for Recruitment and Retention ................................................................ 16 
5. REGISTRATION PROCEDURES ........................................................................................... 17 
5.1 
Subject Registration (WCM only) .............................................................................. 17 
5.2 Subject Registration (Sub-sites) .................................................................................... 17 
6. STUDY PROCEDURES ........................................................................................................ 17 
6.1 
Schedule of Assessments ......................................................................................... 17 


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6.1.1 
Pre-Study Visit .................................................................................................. 18 
6.1.2 
Treatment Visit ................................................................................................. 18 
6.1.3 
Follow-up Phase ................................................................................................ 18 
7. STUDY INTERVENTION ..................................................................................................... 19 
7.1 
Study Intervention/Device Description ..................................................................... 19 
7.2 
Availability ............................................................................................................... 19 
7.3 
Acquisition and Accountability ................................................................................. 19 
7.4 
Formulation, Appearance, Packaging, and Labeling .................................................. 19 
7.5 
Product Storage and Stability ................................................................................... 19 
7.6 
Preparation.............................................................................................................. 19 
7.7 
Dosing and Administration ....................................................................................... 19 
7.7.1 
Dosing Delays/Dose Modifications .................................................................... 20 
7.8 
General Concomitant Medication and Supportive Care Guidelines ........................... 20 
7.9 
Duration of Therapy and Criteria for Removal from Study ........................................ 20 
7.10 Duration of Follow Up ................................................................................................ 20 
7.11 Measures to Minimize Bias: Randomization and Blinding ............................................ 20 
7.12 Study Intervention/Follow-up Compliance .................................................................. 20 
8. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ...................................................................................... 20 
8.1 
Discontinuation of Study Intervention ...................................................................... 21 
8.2 
Participant Discontinuation/Withdrawal from the Study .......................................... 21 
8.3 
Lost to Follow Up ..................................................................................................... 21 
9. CORRELATIVE/SPECIAL STUDIES ....................................................................................... 21 
9.1 
Laboratory Correlative Studies ................................................................................. 21 
9.2 
Special Studies ......................................................................................................... 21 
10.  MEASUREMENT OF EFFECT ............................................................................................ 22 
11. DATA REPORTING / REGULATORY CONSIDERATIONS ...................................................... 22 
11.1 Data Collection ........................................................................................................... 22 
11.1.1 REDCap ................................................................................................................ 22 
11.2 Regulatory Considerations .......................................................................................... 22 
11.2.1 Institutional Review Board/Ethics Committee Approval ....................................... 22 
11.2.2 Ethical Conduct of the Study ................................................................................ 23 
11.2.3 Informed Consent ................................................................................................ 23 
11.2.4 Compliance with Trial Registration and Results Posting Requirements ................. 23 
11.2.5 Record Retention ................................................................................................. 24 
12.1 Study Design/Endpoints ............................................................................................. 24 
12.2 Sample Size/Accrual Rate ........................................................................................... 25 
12.3 Stratification Factors .................................................................................................. 25 
12.4 Analysis of Endpoints ................................................................................................. 25 


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12.4.1 Analysis of Primary Endpoints ........................................................................... 25 
12.4.2 Analysis of Secondary Endpoints ....................................................................... 25 
12.5 Interim Analysis ......................................................................................................... 25 
13. ADVERSE EVENT REPORTING REQUIREMENTS ................................................................ 25 
13.1 Adverse Event Definition ............................................................................................ 26 
13.1.1 Investigational Agent or Device Risks (Expected Adverse Events) ....................... 26 
13.1.2 Adverse Event Characteristics and Related Attributions ..................................... 26 
13.1.3 Recording of Adverse Events ............................................................................. 26 
13.1.4 Reporting of AE to WCM IRB ............................................................................. 27 
13.1.5 Reporting Events to Participants ........................................................................ 27 
13.1.6 Events of Special Interest .................................................................................. 27 
13.1.7 Reporting of Pregnancy ..................................................................................... 27 
13.2 Definition of SAE ........................................................................................................ 27 
13.2.1 Reporting of SAE to IRB ..................................................................................... 27 
13.2.2 Reporting of SAE to Allergan ............................................................................. 27 
13.3 AE/SAE Follow Up ...................................................................................................... 28 
13.4 Time Period and Frequency for Event Assessment and Follow Up ............................... 28 
14. DATA AND SAFETY MONITORING PLAN (DSMP) ............................................................. 28 
REFERENCES ........................................................................................................................ 30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Statement of Compliance 
 
 
[The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for 
the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the protocol 
and the consent form must be obtained before any participant is enrolled.  Any amendment to the 
protocol will require review and approval by the IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form will be IRB-approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a previously 
approved consent form. 
 
 
 
 
 
 
 
 
 


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Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or institutional 
review boards. The contents of this document shall not be disclosed to others without written 
authorization from WCM. 
 
 
 
 
 
 
 
 
 
 
 
_________________________________________________________________ 
Institution Name 
 
 
 
 
 
 
______________________________     ______________________________     ____________________ 
Principal Investigator’s Name                 Principal Investigator’s Signature            Date 
 
 
 
 
 
 
 
 
 
 


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List of Abbreviations 
 
AE 
Adverse Event 
BTA 
Botulinum Toxin-A 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTSC 
Clinical Translational Science Center  
DSMB 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRBFA 
Human Research Billing Analysis Form 
HUD 
Humanitarian Use Device  
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MPD 
Myofascial Pain Disorder 
PHI 
Protected Health Information 
PI 
Principal Investigator 
RDC 
Research Diagnostic Criteria 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMD 
Temporomandibular Disorders 
UIRTSO 
Unanticipated Problem Involving Risks to Subjects or Others 
WCM 
Weill Cornell Medicine 


Protocol #  
Version Date 
 
  
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1. Protocol Summary 
 
Full Title: 
Comparison of Botulinum Toxin Versus Placebo Injections to Temporalis 
and Masseter Muscles in the Management of Myofascial Pain Disorder: A 
Randomized Clinical Trial    
Short Title: 
Botox Injections for MPD 
Principal Investigator: 
Gwendolyn Reeve, DMD 
Study Description: 
Double-blind placebo controlled clinical trial with participants receiving 
either a solution of placebo injected into the masseters and temporalis 
muscles or a solution of botulinum toxin A for treatment of myofascial 
pain 
Sample Size: 
N = 110 
Enrollment: 
This study will enroll 110 subjects and screen up to 175 
Study Population: 
Eligible participants will be male and female adults ages 18 – 65 identified 
as having a myofascial pain diagnosis according to the research diagnostic 
criteria 
Enrollment Period: 
18 months 
Study Design: 
The study design will be a double-blind placebo controlled clinical trial. 
The participants will receive either a solution of placebo (total 4cc 
unpreserved 0.9% sodium chloride) injected into the masseters and 
temporalis muscles or a solution of botulinum toxin A (a total of 100 units 
reconstituted with 4cc unpreserved 0.9% sodium chloride). The patients 
will be stratified into gender groups. The participants will be monitored 
for 3 months. The primary outcome measure will be pain measured on a 
visual analog scale prior to treatment and at one, two, three months 
post-treatment. Secondary outcome measures performed at the same 
intervals will be quality of life (short form 36), maximum interincisal 
opening, and functional status via the jaw functional limitation scale 
Description of Sites/ Facilities Enrolling 
Participants: 
Weill Cornell Medicine 
Division of Oral and Maxillofacial Surgery Clinic 
525 East 68th Street, F-2132 
New York, NY 10065 
 
University of Illinois, College of Dentistry 
Oral and Maxillofacial Surgery Clinic 
801 S. Paulina Street, Room 110 
Chicago, IL 60612 
Study Duration: 
December 31, 2022 
Participant Duration: 
Subjects will participate in one injection visit plus 3 follow-up visits at 1-
month, 2-months, and 3-months post-injection for a total of 4 months 
Study Agent/Device Name  
Intervention Description: The participants will receive either a solution of placebo (total 4cc 
unpreserved 0.9% sodium chloride) injected into the masseters and 
temporalis muscles or a solution of botulinum toxin A (total of 100 units 
reconstituted with 4cc unpreserved 0.9% sodium chloride) 


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Primary Objective: 
The primary objective will be to compare the pain measured on a visual 
analog scale prior to treatment and at one, two and three months post-
treatment in both the Botox and placebo groups. 
Secondary Objectives: 
The secondary objectives will be to compare the quality of life (SF-36), 
maximum interincisal opening, and functional status via the jaw 
functional limitation scale in both the Botox and placebo groups. 
Exploratory Objectives: 
None 
Endpoints: 
The primary endpoint is improvement of pain on a visual analog scale 
(VAS) between pre-op, 1, 2, and 3 months post-op. The secondary 
endpoints are function (MIO/jaw limitation scale) and quality of life 
(SF36) 


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1.1 Schema 
 
 
Prior to 
Enrollment 
 
 
 
 
 
 
 
  
 
 
 
Visit 1 
Day 0 
 
 
 
 
 
Visit 2  
1 – Month  
 
 
 
 
Visit 3 
2 – Months 
 
 
 
 
 
 
 
 
 
Visit 4 
3 – Months  
 
 
 
 
 
Total 110 participants:  Obtain informed consent. Screen potential participants by 
inclusion and exclusion criteria; obtain history, document. 
Perform baseline assessments: Inclusion/exclusion checklist, pre-operative assessment 
(maximum interincisal opening), jaw functional limitation scale, visual analog scale, 
and SF-36 questionnaire 
 
Administer study drug.  
Follow-up assessments of study endpoints and safety: Follow-up assessment (maximum 
interincisal opening), jaw functional limitation scale, visual analog scale, and SF-36 
questionnaire 
Final Assessments 
Follow-up assessment (maximum interincisal 
opening), jaw functional limitation scale, 
visual analog scale, and SF-36 
questionnaire 
Arm 2 - Placebo 
55 participants 
Arm 1 - Botox 
55 participants 
Follow-up assessments of study endpoints and safety: Follow-up assessment (maximum 
interincisal opening), jaw functional limitation scale, visual analog scale, and SF-36 
questionnaire 
Randomize 


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1.2 
Study Objectives 
 
 
1.2.1  Primary Objectives  
 
The primary objective will be to compare the pain measured on a visual analog scale prior to 
treatment and at one, two and three months post-treatment in both the Botox and placebo 
groups. 
 
1.2.2  Secondary Objectives  
 
The secondary objectives will be to compare the quality of life (SF-36), maximum interincisal 
opening, and functional status via the jaw functional limitation scale in both the Botox and 
placebo groups. 
 
2. Background 
 
2.1 Disease 
 
Myofascial pain is classically used to describe pain experienced in the masticatory muscles and its 
associated structures (1). It afflicts nearly 10% of Americans (2). There have been many described 
treatments such as the use of oral appliances, non-steroidal anti-inflammatory medications, 
physiotherapy, behavioral therapy and counseling, acupuncture, and botulinum toxin injections (2). 
However, no single treatment has been found to be significantly superior to the others (2). 
 
2.2 Investigational Agent 
 
Botulinum Toxin-A (BTA) inhibits the release of acetylcholine at the neuromuscular junction, thus 
preventing further muscle contraction, resulting in paralysis of the affected muscles (3). It is 
reasonable to expect that those with pain associated with the muscles of mastication will have relief 
with BTA injection. There will be substantial clinical significance if BTA injections are found to reduce 
myofascial pain, as this has classically been difficult to treat. 
 
2.3 Rationale 
 
Myofascial pain is classically used to describe pain experienced in the masticatory muscles and its 
associated structures (1). It afflicts nearly 10% of Americans (2). There have been many described 
treatments such as the use of oral appliances, non-steroidal anti-inflammatory medications, 
physiotherapy, behavioral therapy and counseling, acupuncture, and botulinum toxin injections (2). 
However, no single treatment has been found to be significantly superior to another (2).  
 
Botulinum Toxin-A (BTA) inhibits the release of acetylcholine at the neuromuscular junction, thus 
preventing further muscle contraction, resulting in paralysis of the affected muscles (3). It is 
reasonable to expect that those with pain associated with the muscles of mastication will have relief 
with BTA injection. The clinical significance would be substantial if BTA injections are found to 
reduce myofascial pain as this has classically been difficult to treat. Prior investigations have been 
conducted to demonstrate the clinical effectiveness of Botulinum Toxin-A (BTA) for reduction in pain 
associated with myofascial pain disorder (4). However, no double-blinded randomized controlled 


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clinical trials have been conducted. The existing evidence is suggestive of a reduction in pain from 
BTA injections, however there has not been a robust demonstration of this in the literature.  
 
A study conducted by Freund et. al. in 1999 studied 15 subjects who were treated with BTA. 150 
units of BTA were injected into the masseter and temporalis muscles bilaterally. Subjects were 
assessed at 2 week intervals for a total of 8 weeks. There was a statistically significant reduction in 
the visual analogue scale of pain for these patients with a 45% reduction in reported pain level after 
8 weeks (1).  
 
Another study by Guarda-Nardini et al. in 2012 examined 30 patients who were randomized to 
either receive BTA injections or fascial manipulation techniques (5). A 32% reduction in pain level 
was found for patients who underwent BTA injections. The existing literature demonstrates a 
benefit from BTA in pain reduction. This should be examined more closely with a double blinded 
randomized controlled clinical trial. BTA has been previously FDA approved to treat muscle spasticity 
of the upper limb as well as chronic migraines but it is considered an off-label use for treatment of 
myofascial pain disorder in the masticatory region.  
 
Gwendolyn Reeve, DMD is a full-time faculty member of the division of oral and maxillofacial 
surgery at Weill-Cornell Medicine. She practices the full scope of oral and maxillofacial surgery but 
has developed a special interest in minimally-invasive temporomandibular disorder treatment 
efforts including arthroscopic joint surgery and intra-muscular botulinum injections into the 
masticatory region for myofascial pain disorder. She currently has other research efforts in the area 
of temporomandibular joint disorder. She is collaborating with a scientist, Dr. Mildred Embree, at 
Columbia University to grow stem cells from the cartilage, synovial tissues, and synovial fluids 
removed during the arthroscopic and open temporomandibular joint surgery Standard of care 
treatment for myofascial pain disorder at Weill Cornell/NYP involves the use of muscle relaxants, 
NSAIDS, warm compresses, night guards, and physical therapy. Botulinum injections into the 
masticatory muscles is a commonly performed adjudicative procedure for treatment of myofascial 
pain disorder at Weill-Cornell/NYP. 
 
2.4  Risk/Benefit Assessment  
 
 
2.4.1 
Known Potential Risks 
 
Risks of BTA include side effects such as: 
- 
problems swallowing, speaking, chewing, or breathing due to weakening of associated 
muscles 
- 
spread of toxin effects causing muscle weakness 
- 
allergic reactions 
- 
discomfort at the injection site 
- 
headaches 
- 
bruising at injection site 
- 
syncope due to anxiety or needle related pain 
- 
muscle atrophy 
- 
facial palsy 
- 
localized numbness 
- 
skin infections 


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2.4.2 
Known Potential Benefits  
 
Possible direct benefits of participating in the study are a decrease in pain level, increase in 
range of motion of the jaw (mouth opening), or improved jaw function. Possible indirect 
benefits of participating in the study are improvement of quality of life by decrease in pain and 
improved jaw function. Participants may have increased ability to eat and speak without pain or 
limitation in function. Information collected in the study may help benefit others who suffer 
from myofascial pain disorder. We hope to learn more about the efficacy of BTA in treatment of 
this disorder. 
 
2.4.3 
Assessment of Potential Risks and Benefits 
 
Subjects will be informed of all potential risks and benefits of BTA prior to consent and 
enrollment on the study so that they can determine whether or not they would like to 
participate in the study. 
 
2.5 Correlative Studies Background 
 
Not Applicable 
 
3. Study Design 
 
3.1 Overall Design 
 
The proposed study is a randomized clinical trial comparing BTA to placebo injections into the 
masseter and temporalis muscles in management of myofascial pain disorder. The hypothesis is that 
injections of BTA reduces the intensity of myofascial pain more than placebo. Currently, in the 
literature, there is no evidence for the best non-surgical treatment modality for treatment of 
myofascial pain disorder of the muscles of mastication. Many different approaches have been 
described such as oral appliances, medications (NSAIDS and muscle relaxants), physiotherapy, 
acupuncture, trigger point injections, and botulinum injections. To date, the literature concerning 
trigger point injections and botulinum injections for treatment of myofascial pain disorders of the 
muscles of mastication is limited. Currently, injection of BTA is not FDA approved for myofascial pain 
disorder of the masseters and temporalis muscles.  
 
Eligible participants in the clinical trial will be male and female adults ages 18 – 65 identified as 
having a myofascial pain diagnosis according to the research diagnostic criteria. All subjects will have 
myofascial pain disorder. Healthy controls will not be involved in the study.  
The study design will be a double-blind placebo controlled clinical trial. The participants will receive 
either a solution of placebo (total 4cc unpreserved 0.9% sodium chloride) injected into the 
masseters and temporalis muscles or a solution of botulinum toxin A (total of 100 units 
reconstituted with 4cc unpreserved 0.9% sodium chloride). Both treatment groups are considered 
investigative. The patients will be stratified into gender groups. The participants will be monitored 
for three months.  
 


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The primary outcome measure will be pain measured on a visual analog scale prior to treatment and 
at one, two and three months post-treatment. Secondary outcome measures performed at the 
same intervals will be quality of life (short form 36), maximum interincisal opening, and functional 
status via the jaw functional limitation scale. The only study procedures are the injection of 
botulinum toxin or placebo and the use of visual analog scale, measurement of maximum incisal 
opening and the use of visual analog scale and questionnaires. 
 
On the first visit, participants will be asked to fill out questionnaires. The questionnaires completed 
on the first visit include health history and history of present symptoms. Participants will then rate 
their pain on a visual analog scale. The visual analog scale is a 10cm line in which participants are 
asked to place a hash mark somewhere along that line to represent the amount of pain they feel. 
The other questionnaires completed on your first visit will be the short form 36 quality of life scale 
and the jaw functional limitation scale. The participant will then undergo an injection of either 
botulinum toxin or saline into the masseter and temporalis muscles. The participants are then 
reevaluated at one, two, and three months post-treatment. They will be asked to fill out the same 
questionnaires about quality of life and jaw function. They will again rate their pain on the same 
visual scale. Maximum incisor opening will be measured at these visits. 
 
3.2 Scientific Rationale for Study Design 
 
Botulinum Toxin-A (BTA) inhibits the release of acetylcholine at the neuromuscular junction, thus 
preventing further muscle contraction, resulting in paralysis of the affected muscles (3). It is 
reasonable to expect that those with pain associated with the muscles of mastication will have relief 
with BTA injection. The clinical significance would be substantial if BTA injections are found to 
reduce myofascial pain as this has classically been difficult to treat. Prior investigations have been 
conducted to demonstrate the clinical effectiveness of Botulinum Toxin-A (BTA) for reduction in pain 
associated with myofascial pain disorder (4). However, no double-blinded randomized controlled 
clinical trials have been conducted. The existing evidence is suggestive of a reduction in pain from 
BTA injections, however there has not been a robust demonstration of this in the literature.  
 
3.3 Justification for Dose  
 
Not Applicable 
 
3.4 End of Study Definition 
 
A participant is considered to have completed the study if he or she has completed the initial 
treatment visit and all three of the follow-up visits required for the study. The end of the study is 
defined as completion of the last visit or procedure shown in the SoA in the trial globally. 
 
4. Subject Selection 
 
4.1 Study Population 
 
Eligible participants in the clinical trial will be male and female adults ages 18 – 65 identified as 
having a myofascial pain diagnosis according to the research diagnostic criteria. All subjects will have 
myofascial pain disorder. Healthy controls will not be involved in the study.  


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4.2 Inclusion Criteria 
 
1. 18 – 65 years of age 
2. Able to give informed consent 
3. Myofascial pain of masticatory muscles as defined according to the RDC/TMD criteria 
4. Baseline pain measured by the subject ≥ 3.5/10 on visual analog scale 
 
4.3 Exclusion Criteria  
 
 
 
1. Baseline pain measured by the subject < 3.5/10 on visual analog scale 
2. Central/neuropathic pain disorder affecting the masticatory muscles 
3. Temporomandibular joint arthralgia that is more severe than the myofascial pain disorder 
affecting the masticatory muscles 
4. Previous temporomandibular joint surgery 
5. Systemic arthropathies 
6. Fibromyalgia 
7. Allergy to study medications 
8. Traumatic injury of masticatory muscles or temporomandibular joint within last 12 months 
9. Mandibular fracture within the last 12 months 
10. Pregnancy or breastfeeding 
11. Cervical radiculopathy or surgery 
12. Prior Botox injection in the masticatory muscles 
13. Initiation of additional treatment of MPD within the past 3 months 
 
4.4 Lifestyle Considerations 
 
Not Applicable 
 
4.5 Screen Failures  
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, 
to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
 
4.6 Strategies for Recruitment and Retention 
 
 
Physicians (neurologists, otolarygnologists, dentists) who would normally refer patients to oral and 
maxillofacial surgery at Weill-Cornell for treatment of myofascial pain disorder of the masticatory 
region will be made aware of the study and are welcome to refer patients for evaluation to 
participate in the study. 
 


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During the normal course of consultation in the office based environment, if a potential patient 
qualifies for participation in the research study, Dr. Gwendolyn Reeve will introduce the study and 
will obtain informed consent. 
 
Study information will also be posted to social media sites, such as Facebook, Twitter and Instagram. 
IRB approved study fliers will be posted throughout the hospital to help boost enrollment 
 
Participants in this study will be compensated for participation. The will receive $25 on Clincards per 
study visit for 4 visits, for a total of $100. 
 
 
5. Registration Procedures 
 
5.1 Subject Registration (WCM only) 
 
Subjects will be registered within the WRG-CT as per the standard operating procedure for Subject 
Registration.  
 
 
 
5.2 Subject Registration (Sub-sites) 
 
Sub-sites will send subject enrollment log along with redacted consent forms to WCM study staff to 
confirm Subject Registration. Sub-sites will also be entering subject data into the REDCap database 
created for this study. 
 
 
6. Study Procedures 
 
6.1 Schedule of Assessments 
 
Table 1. Schedule of trial events 
 
Pre-Study 
Treatment 
Visit 
1-Month 
Follow-Up 
2-Month 
Follow-Up 
3-Month 
Follow-Up 
Informed Consent 
X 
 
 
 
 
Demographics 
X 
X 
 
 
 
Medical history 
X 
X 
 
 
 
Interincisal 
measurements 
 
X 
X 
X 
X 
Visual Analog Scale 
 
X 
X 
X 
X 
Jaw Functional 
Limitation Scale 
 
X 
X 
X 
X 
SF-36 
 
X 
X 
X 
X 
Botox/Placebo 
Injection 
 
X 
 
 
 
Adverse Event 
Assessment 
 
X 
X 
X 
X 
 
 


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6.1.1 
Pre-Study Visit  
 
• 
Informed consent 
• 
Inclusion/exclusion checklist 
• 
Pharmacy order form completed and sent to pharmacy for randomization and 
processing 
o Eligible subjects will be randomly assigned to Botox injections or 
placebo treatment groups in a 1:1 ratio using a randomization 
scheme developed by the Dr. Paul Christos and the Division of 
Biostatistics and Epidemiology, Department of Healthcare Policy & 
Research 
 
 
 
 
6.1.2 
Treatment Visit 
 
 
 
 
 
• Pre-operative assessment 
• Demographics 
• Medical history 
• Interincisal measurements 
• Visual Analog Scale 
• Jaw Functional Limitation Scale 
• Short Form 36 Health Survey 
• Botox/Placebo injections 
 
6.1.3 
Follow-up Phase 
 
6.1.3.1 
1-Month Visit 
 
 
 
• 
Interincisal measurements 
• 
Visual Analog Scale 
• 
Jaw Functional Limitation Scale 
• 
Short Form 36 Health Survey 
• 
Adverse event assessments 
 
6.1.3.2 
2-Month Visit 
 
• 
Interincisal measurements 
• 
Visual Analog Scale 
• 
Jaw Functional Limitation Scale 
• 
Short Form 36 Health Survey 
• 
Adverse event assessments 
 
6.1.3.3 
3-Month Visit 
 
• 
Interincisal measurements 
• 
Visual Analog Scale 
• 
Jaw Functional Limitation Scale 


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• 
Short Form 36 Health Survey 
• 
Adverse event assessments 
 
7. Study Intervention 
 
 
7.1 Study Intervention/Device Description   
 
Botulinum Toxin A will be shipped directly to the Investigation Pharmacy from Allergan. 
 
 
7.2 Availability 
 
Botulinum Toxin A is an investigational agent supplied to investigators by Allergan. 
 
7.3 Acquisition and Accountability  
 
 
 
Half of the study materials will be shipped to the study site upon full execution of the agreement 
with Allergan and study approval by the IRB. Study material is shipped directly to the Investigational 
Pharmacy for storage and accountability. 
 
The other half of the study materials will be shipped to the study site upon achieving 50% of the 
target enrollment and written confirmation that the study has been registered on 
www.clinicaltrials.gov.  
 
7.4 Formulation, Appearance, Packaging, and Labeling  
 
Not applicable 
 
7.5 Product Storage and Stability 
 
The product will be stored in the Investigational Pharmacy at WCM. 
 
7.6 Preparation 
 
Subjects will be receiving either a solution of placebo, a total of 4 cc unpreserved 0.9% sodium 
chloride, or a solution of botulinum toxin A, a total of 100 units reconstituted with 4 cc unpreserved 
0.9% sodium chloride. Study drug will be prepared by the Investigational Pharmacy at WCM. 
 
7.7 Dosing and Administration 
 
Subjects will be receiving either a solution of placebo, a total of 4 cc unpreserved 0.9% sodium 
chloride, or a solution of botulinum toxin A, a total of 100 units reconstituted with 4 cc unpreserved 
0.9% sodium chloride. Injections will take place in the Oral and Maxillofacial Surgery clinic on Baker 
21 at WCM or at the University of Illinois at Chicago Oral Surgery clinic.  


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7.7.1 
Dosing Delays/Dose Modifications 
 
Not applicable 
 
7.8 General Concomitant Medication and Supportive Care Guidelines 
 
All concomitant medications will be recorded and/or updated on follow-up assessment form 
throughout the course of the study and saved in REDCap. 
 
7.9 Duration of Therapy and Criteria for Removal from Study 
 
Study Termination Guidelines: A subject’s follow-up in the study will end after one of the follow 
applies: 
o Subject’s voluntary withdrawal 
o Subject lost to follow-up 
o Subject death 
o Completion of all scheduled study follow-up appointments 
 
7.10 Duration of Follow Up 
 
Subjects will be followed for 3-months after receiving treatment or until death, whichever occurs 
first.  Subjects removed from study for unacceptable adverse events will be followed until resolution 
or stabilization of the adverse event. 
 
 
7.11 Measures to Minimize Bias: Randomization and Blinding  
  
The investigator and co-investigators are blinded to the randomization schema and treatment. The 
randomization schema was developed by Dr. Paul Christos and Gulce Askin, MPH in the Division of 
Biostatistics and Epidemiology, Department of Healthcare Policy and Research. They have shared 
the schema with the Investigational Pharmacy who draws up the appropriate study drug for the 
subject and is picked up by the blinded study team. After all subjects are enrolled and have 
completed follow-up, the study team will be unblinded. 
 
Once the study has been fully closed to enrollment and all data collection has been completed, all 
participants who received study treatment will be unblinded. The rationale for this is to provide 
participants with the appropriate information about their treatment while on study so they can 
make decisions about future treatment and management of their TMJ. Unblinding will occur via 
email or mail (if email address is not available to the study team). The unblinding text will be 
submitted to the IRB for review and approval before use. 
 
7.12 Study Intervention/Follow-up Compliance 
 
Not applicable 
 
8. Study Intervention Discontinuation and Participant Discontinuation/Withdrawal 
 


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8.1 Discontinuation of Study Intervention 
 
There is only one study intervention, injection of BTA or placebo, so there will be no discontinuation 
of the study intervention. 
 
8.2 Participant Discontinuation/Withdrawal from the Study 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant lost to follow-up after several attempts to contact subject to schedule study visit. 
 
8.3 Lost to Follow Up 
A participant will be considered lost to follow-up if he or she fails to return for 2 scheduled visits and 
is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit and counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
9. Correlative/Special Studies  
 
Not applicable 
 
9.1 Laboratory Correlative Studies 
 
Not applicable 
 
9.2 Special Studies 
 
Not applicable 
 


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10.  Measurement of Effect 
 
Efficacy of treatment of myofascial pain disorder with BTA injections will be determined at the 
completion of the study. 
 
 
11. Data Reporting / Regulatory Considerations 
 
11.1 Data Collection 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, toxicity, efficacy, 
and adverse event data for all enrolled subjects.  
All subjects enrolled in this clinical trial will have their data entered into the appropriate data entry 
forms in REDCap by the study staff at Weill Cornell Medicine and the University of Illinois at Chicago.  
 
 
11.1.1 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software system that is 
fully supported by the Weill-Cornell Medical Center CTSC.  It is a tool for the creation of 
customized, secure data management systems that include Web-based data-entry forms, 
reporting tools, and a full array of security features including user and group based privileges, 
authentication using institution LDAP system, with a full audit trail of data manipulation and 
export procedures.  REDCap is maintained on CTSC-owned servers that are backed up nightly 
and support encrypted (SSL-based) connections.  Nationally, the software is developed, 
enhanced and supported through a multi-institutional consortium led by the Vanderbilt 
University CTSA. 
 
11.2 Regulatory Considerations 
 
11.2.1 Institutional Review Board/Ethics Committee Approval  
 
As required by local regulations, the Investigator will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, before study initiation.  
Before initiation of the study at each study center, the protocol, the ICF, other written material 
given to the patients, and any other relevant study documentation will be submitted to the 
appropriate Ethics Committee. Written approval of the study and all relevant study information 
must be obtained before the study center can be initiated or the IP is released to the Investigator. 
Any necessary extensions or renewals of IEC/IRB approval must be obtained for changes to the 
study, such as amendments to the protocol, the ICF, or other study documentation. The written 
approval of the IEC/IRB together with the approved ICF must be filed in the study files.  
The Investigator will report promptly to the IEC/IRB any new information that may adversely 
affect the safety of the patients or the conduct of the study. The Investigator will submit written 
summaries of the study status to the IEC/IRB as required. On completion of the study, the IEC/IRB 
will be notified that the study has ended.  


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Neither the Investigator nor BMS will modify or alter this protocol without the agreement of the 
other. All agreed protocol amendments will be clearly recorded on a protocol amendment form 
and will be signed and dated by the original protocol approving signatories. All protocol 
amendments will be submitted to the relevant institutional IEC/IRB for approval before 
implementation, as required by local regulations. The only exception will be when the 
amendment is necessary to eliminate an immediate hazard to the trial participants. In this case, 
the necessary action will be taken first, with the relevant protocol amendment following shortly 
thereafter.  
Once protocol amendments or consent form modifications are implemented at the lead site, Weill 
Cornell Medicine, updated documents will be provided to participating sites. Weill Cornell 
Medicine must approve all consent form changes prior to local IRB submission.  
Relevant study documentation will be submitted to the regulatory authorities of the participating 
countries, according to local/national requirements, for review and approval before the beginning 
of the study. On completion of the study, the regulatory authorities will be notified that the study 
has ended.  
 
11.2.2 Ethical Conduct of the Study  
The Investigators and all parties involved should conduct this study in adherence to the ethical 
principles based on the Declaration of Helsinki, GCP, ICH guidelines and the applicable national 
and local laws and regulatory requirements.  
 
This study will be conducted under a protocol reviewed and approved by the applicable ethics 
committees and investigations will be undertaken by scientifically and medically qualified 
persons, where the benefits of the study are in proportion to the risks. 
 
11.2.3 Informed Consent 
 
The investigator or qualified designee must obtain documented consent according to ICH-GCP 
and local regulations, as applicable, from each potential subject or each subject’s legally 
authorized representative prior to participating in the research study. Subjects who agree to 
participate will sign the approved informed consent form and will be provided a copy of the signed 
document.   
 
The initial ICF, any subsequent revised written ICF and any written information provided to the 
subject must approved by IRB prior to use. The ICF will adhere to IRB/IEC requirements, applicable 
laws and regulations. 
 
11.2.4 Compliance with Trial Registration and Results Posting Requirements  
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food 
and Drug Administration Amendments Act (FDAAA), the Sponsor-Investigator of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to http://www.clinicaltrials.gov. Information posted will allow subjects to identify 


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potentially appropriate trials for their disease conditions and pursue participation by calling a 
central contact number for further information on appropriate trial locations and trial site contact 
information. 
 
 
11.2.5 Record Retention 
 
Essential documents are those documents that individually and collectively permit evaluation of 
the study and quality of the data produced.  After completion of the study, all documents and 
data relating to the study will be kept in an orderly manner by the Investigator in a secure study 
file, locked in the Principal Investigator’s office. Paper and electronic records will be maintained 
for 2 years after the investigation is discontinued according to FDA guidelines.  In addition, all 
subjects medical records and other source documentation will be kept for the maximum time 
permitted by the hospital, institution, or medical practice.   
 
12. Statistical Considerations 
 
12.1 Study Design/Endpoints 
 
Based on the preliminary data and the sample size calculations estimating a difference in mean pre-
post VAS change between groups of 1 point or greater (on a scale of 1-10), we plan to enroll a total 
of 110 subjects between the two study sites. Estimated 55 subjects will be enrolled at Weill-Cornell 
Medical Center/ New York Presbyterian Hospital and 55 subjects will be enrolled at the University of 
Illinois at Chicago. With 55 patients in the botulinum toxin A injection group and 55 patients in the 
placebo group (N=110), the study will have more than 90% power to detect a difference in mean in 
pre-post change between groups of 1.0 point or greater on VAS, using a two-sided t-test and 
assuming a standard deviation of 1.5 for the mean difference. This calculation allows for 10% 
attrition rate.  
 
An intent-to-treat design will be followed and all subjects will have scheduled outcome evaluations 
until the end of the study, death of the subject, or subject refusal. Subjects will be withdrawn from 
their randomly assigned treatment for considerations of subject safety only. Descriptive statistics 
including mean, standard deviation, median, range, frequency, and percent will be calculated for the 
entire cohort as well as by the study arm (botulinum toxin A and unpreserved 0.9% sodium chloride) 
to assess the results of randomization and identify potential confounders.  
 
The primary analyses of the data will be performed according to subjects' original treatment 
assignment (i.e., intention-to-treat analyses) and the inclusion of all data from all subjects 
randomized in the final analysis. To assess the primary endpoint of improvement of pain on a visual 
analog scale (VAS) between pre-op, 1, 2, and 3 months post-op, a repeated measure of analysis of 
variance will be performed with one between subject factor (botulinum toxin A versus placebo) and 
one within subject factor (time). This analysis will also be used for the secondary endpoints: function 
(MIO/jaw limitation scale) and quality of life (SF12). In the event of significant loss to follow-up, we 
will explore the use of a linear mixed model to assess the independent effect of the study group on 
VAS over the study visits. The paired t-test, or the signed-rank test as appropriate, will be used to 
assess change in pain, function, and QOL between pairs of relevant time points for both study arms.  
 


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To assess the difference in proportion of adverse events between the botulinum toxin A and placebo 
groups, either the chi-square or Fisher's exact test will be used, as appropriate. All p-values will be 
two-sided with statistical significance evaluated at the 0.05 alpha level. Ninety-five percent 
confidence intervals (95% CI) will be calculated to assess the precision of the obtained estimates. 
 
All analyses will be performed in SAS Version 9.4 (SAS Institute Inc., Cary, NC). Note: This section was 
drafted in conjunction with Dr. Paul Christos and Gulce Askin, MPH in the Division of Biostatistics 
and Epidemiology, Department of Healthcare Policy and Research. They will be aiding in protocol 
design and development, data management, study implementation, study monitoring, and data 
analysis and reporting. 
 
12.2 Sample Size/Accrual Rate 
 
We plan to enroll 110 subjects in 18 months. About 55 subjects will be enrolled at Weill Cornell 
Medicine and the remaining 55 will be enrolled at the University of Illinois at Chicago. 
 
12.3 Stratification Factors  
 
Not applicable 
 
 12.4 Analysis of Endpoints 
 
12.4.1 Analysis of Primary Endpoints 
 
To assess the primary endpoint of improvement of pain on a visual analog scale (VAS) between 
pre-op, 1, 2, and 3 months post-op, a repeated measure of analysis of variance will be 
performed with one between subject factor (botulinum toxin A versus placebo) and one within 
subject factor (time). In the event of significant loss to follow-up, we will explore the use of a 
linear mixed model to assess the independent effect of the study group on VAS over the study 
visits. 
 
 
12.4.2 Analysis of Secondary Endpoints 
 
The same analysis as that of the primary endpoints will also be used for the secondary 
endpoints: function (MIO/jaw limitation scale) and quality of life (SF36). 
 
12.5 Interim Analysis 
 
No interim efficacy analysis will be performed in this study because a small sample size is unlikely to 
yield any useful information.   
 
 
13. Adverse Event Reporting Requirements  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The investigator will 
be required to provide appropriate information concerning any findings that suggest significant hazards, 


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contraindications, side effects, or precautions pertinent to the safe use of the drug or device under 
investigation.  Safety will be monitored by evaluation of adverse events reported by subjects or 
observed by investigators or research staff, as well as by other investigations such as clinical laboratory 
tests, x-rays, electrocardiographs, etc. 
 
13.1 Adverse Event Definition 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a drug, and does not imply any judgment about causality. An adverse event can arise 
with any use of the drug (e.g., off-label use, use in combination with another drug) and with any 
route of administration, formulation, or dose, including an overdose.  
 
 
13.1.1 Investigational Agent or Device Risks (Expected Adverse Events) 
 
Expected risks of BTA include: 
• 
Problems swallowing, speaking, chewing or breathing due to weakening of associated 
muscles 
• 
Spread of toxin effects causing muscle weakness 
• 
Allergic reactions 
• 
Discomfort at the injection site 
• 
Syncope due to anxiety or needle related pain 
• 
Muscle atrophy 
• 
Facial palsy 
• 
Localized numbness 
• 
Skin infections 
 
 
 
13.1.2 Adverse Event Characteristics and Related Attributions 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized 
for AE reporting.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
• 
Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
 
13.1.3 Recording of Adverse Events 
 
All adverse events will be recorded on a subject specific AE log. The AE log will be maintained by 


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the research staff and kept in the subject’s research chart. All AEs that occur at the sub-site will 
be sent to WCM for review and submission to the DSMB. 
   
 
 
13.1.4 Reporting of AE to WCM IRB 
 
All AEs occurring on this study will be reported to the IRB according to the IRB policy, which can 
be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_Poli
cy.pdf.  
 
13.1.5 Reporting Events to Participants 
 
All anticipated adverse events are listed in the informed consent form that each subject receives 
a copy of after signature.  
 
All adverse events are reviewed by the DSMB and should the board determine that subjects 
need to be informed of the new potential risk, the study staff will make every effort to contact 
subjects and update them on the current risks of participation in the trial. 
 
13.1.6 Events of Special Interest 
 
Not applicable 
 
13.1.7 Reporting of Pregnancy 
 
Institution will provide written notice to Allergan within 24 hours of any occurrence of either 
pregnancy or lactation during the use of study materials. 
 
13.2 Definition of SAE 
 
SAEs include death, life threatening adverse experiences, hospitalization or prolongation of 
hospitalization, disability or incapacitation, overdose, congenital anomalies and any other 
serious events that may jeopardize the subject or require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  
 
13.2.1 Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, which can 
be accessed via the following link:   
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_Poli
cy.pdf.  
 
 
13.2.2 Reporting of SAE to Allergan 
 
Institution will send Allergan copies of any and all serious adverse event reports filed with the 


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FDA or other applicable regulatory authorities, as well as copies of any correspondence with the 
FDA or other applicable regulatory authorities, regarding any and all serious adverse events, 
irrespective of association with the Study Drug(s) in the course of the Clinical Trial, within 24 
hours after its first knowledge of the SAE in accordance with the SAE report form provided by 
Allergan. The SAE report form shall include an assessment of the causal relationship between 
the Allergan materials and the SAE.  
 
 
13.3 AE/SAE Follow Up 
 
All SAEs and AEs reported during this study will be followed until resolution or until the investigator 
confirms that the AE/SAE has stabilized and no more follow-up is required. This requirement 
indicates that follow-up may be required for some events after the subject discontinues 
participation from the study.  
 
13.4 Time Period and Frequency for Event Assessment and Follow Up 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention 
of study personnel during study visits and interviews of a study participant presenting for medical 
care. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on 
the appropriate case report form (CRF). Information to be collected includes event description, time 
of onset, clinician’s assessment of severity, relationship to study product (assessed only by those 
with the training and authority to make a diagnosis), and time of resolution/stabilization of the 
event. All AEs occurring while on study must be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates at 
any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
Study investigators will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of 
study participation.  At each study visit, the investigator will inquire about the occurrence of 
AE/SAEs since the last visit.  Events will be followed for outcome information until resolution or 
stabilization.] 
 
14. Data and Safety Monitoring Plan (DSMP) 
 
This study will use the WCM DSMB to monitor the study and ensure the safety of clinical research subjects 
and protect the validity and integrity of research data. The study participants will be questioned and 
examined at one, two and three months post-treatment for the occurrence of any adverse events. 
Anticipated adverse events for this study include: 


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• 
Problems swallowing, speaking, chewing or breathing due to weakening of associated 
muscles 
• 
Spread of toxin effects causing muscle weakness 
• 
Allergic reactions 
• 
Discomfort at the injection site 
• 
Syncope due to anxiety or needle related pain 
• 
Muscle atrophy 
• 
Facial palsy 
• 
Localized numbness 
• 
Skin infections 
A report to the DSMB will be generated in the event of any adverse event at both sites and will provide 
details such as severity, relationship to treatment, onset, duration, and outcome. Adverse events will also 
be graded based on severity, attribution and expectedness. The DSMB will meet to review these reports 
upon every submission, and should any trend develop that suggest significant adverse outcomes, the 
study will be discontinued. A trend will be determined by more than one adverse event of similar 
presentation. If any serious adverse event occurs (death, life-threatening adverse experience, those 
involving prolonged hospitalization or disability), the other study sites, IRBs, and DSMB will be notified as 
per current institutional reporting guidelines. Adverse events such as death, life-threatening, or those 
involving prolonged hospitalization or disability may cause the termination or dropout of a subject from 
the study. 
 
 
 
 
 
 


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References 
 
1. Freund B., et al. The Use of Botulinum Toxin for the Treatment of Temporomandibular 
Disorders: Preliminary Finding. J Oral Maxillofac Surg. 1999 Aug;57(8):916-920. 
2. Freund B., et al. Botulinum toxin – new treatment for temporomandibular disorders. Br J Oral 
Maxillofac Surg. 2000 Oct;38(5):466-471. 
3. Soares A., et al. Botulinum toxin for myofascial pain syndrome in adults. Chochrane Database of 
Syst Rev. 2014 Jul 25;(7):CD007533 
4. CADTH: Canadian Agency for Drugs and Technologies in Health. Botulinum Toxin A for 
Myofascial Pain Syndrome: A Review of the Clinical Effectiveness. Rapid Response Report: 
Summary with Critical Effectiveness. 22 September 2014. 
5. Guarda-Nardini L, et al. Myofascial pain of the jaw muscles: comparison of short-term 
effectiveness of botulinum toxin injections and facial manipulation technique. Cranio. 2012 
Apr;30(2):95-102.