Clinical trial NCT02437383
Conditions: Temporomandibular Disorders
Sponsor: University of North Carolina, Chapel Hill
Start date: 2015-08-20; Completion date: 2018-04-25
Enrollment: 200 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Purpose:

Primary: To evaluate the efficacy of extended-release (ER) propranolol compared to placebo in the reduction of a pain index in patients with temporomandibular disorder (TMD).

Secondary: To determine if extended-release propranolol efficacy varies according to participants' catechol-O-methyltransferase (COMT) genetic polymorphisms and to investigate the efficacy of extended-release propranolol compared with placebo using secondary endpoints.

Exploratory: To investigate whether the efficacy of extended-release propranolol in the reduction of the pain index varies according to participants' polymorphisms in 3 other genetic regions and according to various phenotypic characteristics.

Participants:

200 patients with chronic TMD will be randomly assigned, in a 1:1 parallel, double-blind fashion, to receive either extended-release propranolol or placebo at one of three study sites: University of North Carolina-Chapel Hill School of Dentistry; University of Florida-Gainesville College of Dentistry; and the State University of New York at Buffalo School of Dental Medicine.

Procedures (methods):

Randomization will be to either propranolol or placebo. The 10-week study treatment period is divided into: 1 week of drug titration, 8 weeks of drug maintenance, and 1 week of drug tapering. The titration and tapering doses are 60 mg (capsules) once per day orally; the maintenance dose is 60 mg twice per day orally. Participants will attend 6 clinic visits over 12-15 weeks as follows: screening and baseline visit (Visit \[V\] 0, 7-21 days prior to V1); randomization and start of treatment (titration) (V1, study day 0); maintenance visit 2 (V2, 1 week post-randomization, study day 7+3); maintenance visit 3 (V3, 5 weeks post-randomization, study day 35 +/- 7); tapering visit (V4, 9 weeks post-randomization, study day 63 +/- 7); and tapering visit 5 (V5, 11 weeks post-randomization and 1 week after drug tapering ends, study day 77 +/- 7). Depending on the visit, procedures will include: reviews of medical history, weekly alcohol consumption, concomitant therapies and medications, adverse events, compliance, and eligibility; administration/review of questionnaires; blood draw; pregnancy test in women of childbearing potential; and dispensing of study drug.

Detailed description:
"Temporomandibular disorder" (TMD) encompasses all musculoskeletal disorders of the masticatory system and includes myalgia, arthralgia, temporomandibular joint (TMJ) disc displacements, and TMJ degenerative joint diseases. The prevalence of TMD ranges from 6% to 12% in the general population, with muscle dysfunction the most prevalent TMD diagnostic group. TMD is associated with substantial disability and suffering and negatively impacts quality of life. Jaw pain is the most common symptom that compels treatment seeking. In addition to facial pain, TMD patients frequently report comorbid pain conditions such as headache, low back pain, and fibromyalgia. New approaches to TMD therapy are urgently needed to improve clinical outcomes and reduce economic impact of this disorder.

There is currently no FDA-approved product labeled specifically to manage/treat TMD; however, classes of drugs are used to relieve TMD-associated pain, such as non-steroidal anti-inflammatory drugs (NSAIDs), anti-inflammatory drugs, corticosteroids, benzodiazepines, sedative hypnotics, muscle relaxants, opioids, antidepressants, and anticonvulsants - although evidence to establish their efficacy and safety in this population is scarce. Practitioners' justification for their use may be based on poorly controlled clinical trials or clinical trials in other pain disorders such as acute postsurgical dental pain, arthritic pain, chronic lower back pain, and neuropathic pain. Thus, there is a need for controlled clinical trials to better understand the physiological mechanisms responsible for TMD symptoms.

Evidence suggests that enhanced β-adrenergic drive contributes to the pathogenesis of TMD and other complex persistent pain conditions. For example, individuals with myofascial pain conditions have elevated catecholamine levels and augmented sympathetic responses to stressors. While increased β-adrenergic drive appears to heighten pain, β-adrenergic antagonists can reduce clinical pain and/or nociceptive sensitivity. A recent study of a single infusion of propranolol in TMD and fibromyalgia patients revealed short-term improvement in clinical pain ratings. The antagonist pindolol was similarly efficacious in alleviating cardinal symptoms of fibromyalgia pain. In addition, intramuscular injections of low-dose propranolol in rats reduced inflammatory pain associated with carrageen-induced inflammation of the gastrocnemius muscle.

The study hypothesis is that therapy with the nonselective β-adrenergic receptor antagonist propranolol extended-release capsules (FDA approved to treat many cardiac conditions, tremor, migraine, and pheochromocytoma) will provide efficacious and safe treatment for painful TMD. It has well-studied pharmacodynamic, pharmacokinetic, and side-effect profiles. Peak blood level occurs at approximately 6 hrs, and the plasma half-life is approximately 10 hrs. The primary objective is to investigate the efficacy of propranolol compared with placebo over 9 weeks to reduce pain in patients with TMD. Secondary objectives are to: investigate by treatment group whether reduction in pain varies according to polymorphisms in the COMT gene coding region; and investigate the effect of propranolol compared with placebo to affect pain sensitivity, physical and emotional function, adverse effects, and use of rescue medications. Exploratory objectives are to: investigate gene-by-treatment group interaction to determine the effect of propranolol on reduction in the pain index according to polymorphisms in the COMT, beta-2 adrenergic receptor (ADRβ2), and beta-3 adrenergic receptor (ADRβ3) genetic coding regions.

Arms: arm 1: Propranolol hydrochloride extended release (ER) capsules; 60 mg (Visit 1 and Visit 4); 120 mg (Visit 2 and Visit 3) given orally as: 60 mg once/day (Visit 1 and Visit 4) and 60 mg twice/day (Visit 2 and Visit 3). arm 2: Capsules, identical in appearance to active comparator (propranolol), to be administered orally in exactly the same manner as propranolol at Visit 1 (once/day), Visit 2 (twice/day), Visit 3 (twice/day), and Visit 4 (once/day).
Interventions: intervention 1: Propranolol ER intervention 2: Placebo
Intervention descriptions: intervention 1: Capsules given orally according to schedule at Visit 1, Visit 2, Visit 3, and Visit 4. intervention 2: Gelatin capsules with a microcrystalline cellulose filler manufactured to mimic propranolol ER 60 mg capsules

Protocol documents:
Prot_000.pdf: 
 
Effect of COMT Genetic Polymorphisms on Response to 
Propranolol Therapy in Temporomandibular Disorder 
 
 
NCT number:  02437383 
Document Date:  12 February 2018 
 


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Effect of COMT Genetic Polymorphisms on Response to 
Propranolol Therapy in Temporomandibular Disorder 
NIDCR Protocol Number: 14-067-E 
 
NIDCR Funding Mechanism: DE024169-01 
 
Principal Investigator: Inna Tchivileva, MD 
NIDCR Program Official: Gallya Gannot, DMD, PhD 
 
Version Number: 12.0 
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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by 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, and 21 CFR Part 312) 
• 
International Conference on Harmonisation (ICH) E6 
• 
National Institutes of Health (NIH) Clinical Terms of Award 
All key personnel have completed Human Subjects Protection Training. 


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SIGNATURE PAGE: UNIVERSITY OF NORTH CAROLINA 
The signature below constitutes the approval of this protocol and the attachments and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. The protocol 
should be signed by the clinical site investigator who is responsible for the day-to-day study 
implementation at his/her specific clinical site. 
Site Investigator: 
 
Signed: 
 
Date: 
 
 
Inna Tchivileva, MD 
Research Assistant Professor 
University of North Carolina School of Dentistry 
 
 
 


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SIGNATURE PAGE: UNIVERSITY OF FLORIDA 
The signature below constitutes the approval of this protocol and the attachments and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. The protocol 
should be signed by the clinical site investigator who is responsible for the day-to-day study 
implementation at his/her specific clinical site. 
Site Investigator: 
 
Signed: 
 
Date: 
 
 
Roger Fillingim, PhD 
Professor 
University of Florida College of Dentistry 
 
 
 
 
 


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SIGNATURE PAGE: UNIVERSITY AT BUFFALO 
The signature below constitutes the approval of this protocol and the attachments and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. The protocol 
should be signed by the clinical site investigator who is responsible for the day-to-day study 
implementation at his/her specific clinical site. 
Site Investigator: 
 
Signed: 
 
Date: 
 
 
Richard Ohrbach, DDS, PhD 
Associate Professor 
University at Buffalo School of Dental Medicine 
 
 


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TABLE OF CONTENTS 
 
Page 
Statement of Compliance ............................................................................................................ ii 
Signature Page: University of North Carolina ............................................................................. iii 
Signature Page: University of Florida ......................................................................................... iv 
Signature Page: University at Buffalo .......................................................................................... v 
Table of Contents ....................................................................................................................... vi 
List of Abbreviations .................................................................................................................... x 
Protocol Summary .................................................................................................................... xii 
1 
Key Roles ......................................................................................................................... 17 
2 
Introduction: Background Information and Scientific Rationale ......................................... 21 
2.1 
Background Information ........................................................................................ 21 
2.1.1 
Background on Temporomandibular Disorder ........................................... 21 
2.1.2 
Current Pharmacologic Management of TMD ............................................ 21 
2.1.3 
Adrenergic System in Pathophysiology of TMD ......................................... 21 
2.1.4 
Background on Propranolol ....................................................................... 22 
2.1.5 
Background on Catechol-O-Methyltransferase as a Genetic Marker of 
Response to Propranolol ........................................................................... 22 
2.2 
Rationale .............................................................................................................. 23 
2.3 
Potential Risks and Benefits ................................................................................. 24 
2.3.1 
Potential Risks .......................................................................................... 24 
2.3.2 
Known Potential Benefits........................................................................... 25 
2.4 
Study Objectives ................................................................................................... 25 
2.4.1 
Primary Objective ...................................................................................... 25 
2.4.2 
Secondary Objectives ............................................................................... 25 
2.4.3 
Exploratory Objectives .............................................................................. 26 
2.5 
Study Outcome Measures .................................................................................... 26 
2.5.1 
Primary Outcome Measures ...................................................................... 26 
2.5.2 
Secondary Outcome Measures ................................................................. 26 
3 
Study Design Overview .................................................................................................... 27 
4 
Study Enrollment and Withdrawal ..................................................................................... 28 
4.1 
Participant Inclusion Criteria ................................................................................. 28 
4.2 
Participant Exclusion Criteria ................................................................................ 29 
4.3 
Strategies for Recruitment and Retention ............................................................. 30 
4.4 
Treatment Assignment Procedures ....................................................................... 31 
4.4.1 
Randomization Procedures ....................................................................... 31 
4.4.2 
Blinding Procedures .................................................................................. 31 
4.4.3 
Unblinding Procedures .............................................................................. 31 
4.4.4 
Reasons for Participant Withdrawal ........................................................... 32 
4.4.5 
Handling of Withdrawals and Discontinuation ............................................ 32 
4.4.6 
Suspension or Termination of the Study .................................................... 33 


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5 
Study investigational Product and Placebo ....................................................................... 33 
5.1 
Investigational Product .......................................................................................... 33 
5.1.1 
Acquisition ................................................................................................. 33 
5.1.2 
Formulation, Packaging, and Labeling....................................................... 33 
5.1.3 
Product Storage and Stability .................................................................... 34 
5.2 
Dosage and Administration of Investigational Product .......................................... 34 
5.3 
Modification of Dosage of Investigational Product ................................................. 34 
5.4 
Placebo................................................................................................................. 34 
5.5 
Accountability Procedures .................................................................................... 35 
5.6 
Assessment of Participant Compliance ................................................................. 35 
5.7 
Concomitant Medications and Therapies .............................................................. 35 
5.7.1 
Rescue Medication .................................................................................... 35 
5.7.2 
Nonpharmacological Therapy .................................................................... 36 
5.8 
Protocol Deviations Related to the Use of Investigational Product and 
Concomitant Therapies ......................................................................................... 36 
6 
Study Schedule ................................................................................................................ 36 
6.1 
Prescreening (Day -49 to Day-7) .......................................................................... 37 
6.2 
Screening and Baseline Visit 0 (Day -21 to Day-7) ............................................... 37 
6.3 
Treatment (Visits 1-4) ........................................................................................... 38 
6.3.1 
Randomization and Titration Visit 1 (Day 0) .............................................. 38 
6.3.2 
Maintenance Visit 2 (Day 7 [+ 3 days]) ...................................................... 39 
6.3.3 
Maintenance Visit 3 (Day 35 [± 7 days]) .................................................... 39 
6.3.4 
Tapering Visit 4 (Day 63 [+6 days]) ........................................................... 40 
6.4 
Follow-up Visit 5 (Day 77 [+ 7 days])..................................................................... 41 
6.5 
Early Termination Visit .......................................................................................... 41 
6.6 
Unscheduled Visit ................................................................................................. 41 
7 
Study Procedures ............................................................................................................. 42 
7.1 
Clinical Evaluations ............................................................................................... 42 
7.1.1 
Medical History .......................................................................................... 42 
7.1.2 
Vital Signs and Physical Measurements .................................................... 42 
7.1.3 
Pregnancy Test ......................................................................................... 42 
7.1.4 
Blood Draw ............................................................................................... 42 
7.1.5 
Electrocardiogram ..................................................................................... 42 
7.1.6 
Temporomandibular Disorder Examination ............................................... 43 
7.1.7 
Tests for Heat Sensitivity ........................................................................... 43 
7.1.8 
Pressure Pain Threshold Measurements ................................................... 43 
7.1.9 
Manual Tender Point Examination ............................................................. 43 
7.1.10 Daily Symptom Diary ................................................................................. 44 
7.1.11 The Alcohol Use Disorders Identification Test ........................................... 45 
7.1.12 Smoking Questionnaire ............................................................................. 45 
7.1.13 Symptom Inventory ................................................................................... 45 
7.1.14 Outcome Measure Questionnaires ............................................................ 45 
7.2 
Laboratory Evaluations ......................................................................................... 47 


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7.2.1 
Clinical Laboratory Evaluations ................................................................. 47 
7.2.2 
Research Laboratory Evaluations .............................................................. 47 
7.2.3 
Specimen Preparation, Handling, and Shipping ........................................ 47 
8 
Assessment of Safety ....................................................................................................... 47 
8.1 
Specification of Safety Parameters ....................................................................... 47 
8.1.1 
Unanticipated Problems ............................................................................ 48 
8.1.2 
Adverse Events ......................................................................................... 48 
8.1.3 
Serious Adverse Events ............................................................................ 49 
8.2 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 49 
8.3 
Characteristics of Adverse Events ........................................................................ 49 
8.3.1 
Relationship to Study Drug ........................................................................ 49 
8.3.2 
Relationship to Study Procedures ............................................................. 50 
8.3.3 
Expectedness of AEs ................................................................................ 50 
8.3.4 
Severity of Event ....................................................................................... 50 
8.4 
Reporting Procedures ........................................................................................... 50 
8.4.1 
Adverse Event Reporting to IRB and NIDCR ............................................. 50 
8.4.2 
Unanticipated Problem Reporting to IRB and NIDCR ................................ 51 
8.4.3 
Serious Adverse Event Reporting to NIDCR.............................................. 51 
8.4.4 
Reporting Abnormal Clinical Findings ........................................................ 52 
8.4.5 
Reporting of Pregnancy ............................................................................. 52 
8.5 
Halting Rules ........................................................................................................ 53 
9 
Study Oversight ................................................................................................................ 53 
10 
Clinical Monitoring ............................................................................................................ 53 
11 
Statistical Considerations ................................................................................................. 54 
11.1 
Study Hypotheses ................................................................................................. 54 
11.1.1 Primary Hypothesis ................................................................................... 54 
11.1.2 Secondary Hypothesis .............................................................................. 54 
11.1.3 Exploratory Hypotheses ............................................................................ 55 
11.2 
Sample Size Considerations ................................................................................. 55 
11.3 
Analysis Samples ................................................................................................. 56 
11.3.1 Intention-To-Treat Sample ......................................................................... 56 
11.3.2 Per-Protocol Sample ................................................................................. 56 
11.3.3 Safety Sample ........................................................................................... 56 
11.4 
Analyses ............................................................................................................... 56 
11.4.1 Analysis of the Primary Hypothesis ........................................................... 56 
11.4.2 Analysis of the Secondary Hypotheses ..................................................... 57 
11.4.3 Analysis of the Exploratory Hypotheses .................................................... 58 
11.5 
Planned Interim Analyses ..................................................................................... 58 
12 
Source Documents and Access to Source Data and Documents ..................................... 59 
13 
Quality Control and Quality Assurance ............................................................................. 59 
14 
Protection of Human Participants ..................................................................................... 60 
14.1 
Institutional Review Board .................................................................................... 60 
14.2 
Informed Consent Process ................................................................................... 60 


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14.3 
Exclusion of Special Populations .......................................................................... 60 
14.4 
Participant Confidentiality ..................................................................................... 60 
14.5 
Future Use of Stored Specimens .......................................................................... 61 
14.6 
Data Handling and Record Keeping ...................................................................... 61 
14.7 
Data Management Responsibilities ....................................................................... 61 
14.8 
Data Capture Methods .......................................................................................... 62 
14.9 
Types of Data ....................................................................................................... 62 
14.10 Timing of Reports ................................................................................................. 62 
14.11 Study Records Retention ...................................................................................... 62 
14.12 Protocol Deviations ............................................................................................... 62 
15 
Publication/Data sharing Policy ........................................................................................ 63 
16 
Literature References ....................................................................................................... 64 
Appendix A: Schedule of Events ............................................................................................... 68 
Appendix B: Package Insert for Propranolol Hydrochloride extended-release ........................... 71 
 


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LIST OF ABBREVIATIONS 
ACR 
American College of Rheumatology 
ADRB2 
Adrenergic receptor β2 
ADRB3 
Adrenergic receptor β3 
AE 
Adverse event 
APS 
Average pain sensitive 
AUDIT 
Alcohol Use Disorders Identification Test 
CFR 
Code of Federal Regulations 
CMP 
Clinical Monitoring Plan 
COMT 
Catechol-O-methyltransferase 
CROMS 
Clinical Research Operations and Management Support  
CSQ-R 
Coping Strategies Questionnaire Revised 
DCC 
Data coordinating center 
DC/TMD 
Diagnostic Criteria for Temporomandibular Disorder 
DNA 
Deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
GCP 
Good Clinical Practice 
GCPS 
Graded Chronic Pain Scale 
GWAS 
Genome-Wide Association Studies 
HIT-6 
Headache Impact Test 
HPS 
High pain sensitive 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
LPS 
Low pain sensitive 
MOP 
Manual of Procedures 
NIDCR 
National Institute of Dental and Craniofacial Research 
NIH 
National Institutes of Health 
NRS 
Numeric rating scale 
NSAID 
Nonsteroidal anti-inflammatory drug 
OCTOM 
Office of Clinical Trials and Operations Management 
OHRP 
Office of Human Research Protection 
PGIC 
Patient Global Impression of Change 
PI 
Principal Investigator 
PPT 
Pressure pain threshold 
SAE 
Serious adverse event 
SCL-90R 
Symptom Checklist 90-Revised 


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SF-12 v2 
Short Form 12 Health Survey Version 2 
TENS 
Transcutaneous electrical nerve stimulation 
TMD 
Temporomandibular disorder 
TMJ 
Temporomandibular joint 
UB 
University at Buffalo 
UF 
University of Florida 
UNC 
University of North Carolina 
UP 
Unanticipated problem 
US 
United States 


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PROTOCOL SUMMARY 
Title: 
Effect of COMT Genetic Polymorphisms on Response to 
Propranolol Therapy in Temporomandibular Disorder 
Short Title: 
Study of Orofacial Pain and PropRANOlol (SOPPRANO) 
Précis: 
 
 
 
A total of 200 participants of either sex and any race or ethnicity, 
recruited at 3 clinical sites, aged 18 to 65 years with chronic 
temporomandibular disorder (TMD), will be randomized in a 1:1 
ratio to propranolol or placebo in a parallel-group, blinded clinical 
trial. Participants will attend 6 clinic visits over a period of 12 to 
15 weeks.  
Potential participants will be prescreened by telephone or at a 
clinic visit. During the Screening and Baseline Visit, participants 
will be consented, evaluated for eligibility, and assessed for 
baseline characteristics. Baseline procedures will include clinical 
tests and examinations and the administration of questionnaires. 
Additional questionnaires will be distributed to be completed and 
returned at the following visit.  
At the Randomization and Titration Visit, participants will be 
randomized to propranolol or placebo and will begin a 10-week 
drug treatment phase that is divided into 1 week of drug titration, 
8 weeks of drug maintenance, and 1 week of drug tapering. 
During treatment, many of the baseline assessments will be 
repeated. The final study visit will occur 1 week after drug 
tapering ends. 
The primary endpoint will be a weekly pain index derived from a 
daily symptom diary. Secondary endpoints will be additional 
ratings of clinical pain; examiner assessments of experimental 
pain sensitivity; participant ratings of physical function, emotional 
function, and global improvement; occurrence of symptoms and 
adverse events (AEs); and use of rescue medications. DNA 
analyses will be conducted to identify polymorphisms in the gene 
that encodes catechol-O-methyltransferase (COMT), an enzyme 
that metabolizes catecholamines such as epinephrine, 
norepinephrine, and dopamine, and is associated with responses 
to pain. 
Objectives: 
 
The primary objective is to investigate the efficacy of extended-
release propranolol compared with placebo in the reduction of a 
pain index in participants with TMD at week 9 of treatment (at 


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Visit 4). 
The secondary objectives are as follows: 
• 
To investigate gene-by-treatment group interaction to 
determine whether the efficacy of extended-release 
propranolol in the reduction of the pain index varies 
according to participants' polymorphisms in the coding region 
of the COMT gene. 
• 
To investigate the efficacy of extended-release propranolol 
compared with placebo using secondary endpoints. 
The exploratory objectives are as follows:  
• 
To investigate whether the efficacy of extended-release 
propranolol in the reduction of the pain index varies 
according to participants' polymorphisms in 3 other genetic 
regions. 
• 
To investigate whether the efficacy of extended-release 
propranolol in the reduction of the pain index varies 
according to various phenotypic characteristics. 
• 
To collect and archive biospecimens for future biological and 
statistical analyses. 
Population: 
200 participants of either sex and any race or ethnicity between 
18 and 65 years of age (inclusive) with chronic TMD will be 
randomized 
Phase: 
Phase II 
Number of Sites: 
Three clinical sites: 
• University of North Carolina School of Dentistry at Chapel 
Hill, NC 
• University of Florida College of Dentistry, Gainesville, FL 
• University at Buffalo School of Dental Medicine, Buffalo, NY 
Study Duration: 
Approximately 3 years 
Participant Duration: 
12 to 15 weeks 
Description of Agent: 
Propranolol hydrochloride extended-release in 60 mg capsules 
taken orally twice a day over a 10-week treatment period 
Enrollment Duration: 
Approximately 2 years 


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Figure 1:  Schematic of Study Design 
 
 
Screening 
 Baseline 
V0 
Prescreening 
Randomization 
Drug Titration 
V1 
0 
Maintenance 
V2 
1 
Maintenance 
V3 
5 
Taper 
V4 
9 
Last Visit 
V5 
11 
0 to 4 
Weeks 
Week 
Visit 
Propranolol 
Placebo 
-3 to -1 
-7 to -1 
Treatment Ends 
10 


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Prescreening 
Day -49 to Day-7 
 
 
 
Visit 0:  
Screening  
and Baseline  
Day -21 to Day-7 
 
 
 
 
 
Visit 1 
Day 0  
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 2 
Day 7 - 10 
 
 
 
 
 
Visit 3 
Day 35 ± 7 
 
 
 
 
Visit 4 
Day 63 +6 
 
Screen and baseline approximately 300 participants for study inclusion. Obtain 
informed consent. Screen potential subjects by inclusion and exclusion criteria; 
obtain history and Symptom Inventory, document. Perform baseline assessments 
(tender point and TMD exams, heat and pressure tests, 12-lead ECG) and urine 
pregnancy test (females). Dispense outcome measure questionnaires and daily 
symptom diaries.  
Obtain history and Symptom Inventory, document. Collect and assess daily 
symptom diaries. Assess AEs. Perform blood draw for DNA analyses, optional 
blood draw for future analyses, and urine pregnancy test (females). Review 
eligibility; collect outcome measure questionnaires.   
Obtain history and Symptom Inventory, document. Collect and assess daily 
symptom diaries and drug containers. Assess AEs. Perform optional blood draw 
for future analyses, urine pregnancy test (females), TMD exam, and heat and 
pressure tests. Administer outcome measure questionnaires. Dispense study 
drug. 
Obtain history and Symptom Inventory, document. Collect and assess daily 
symptom diaries and drug containers. Assess AEs. Perform urine pregnancy test 
(females), TMD exam, and heat and pressure tests. Administer outcome measure 
questionnaires. Dispense study drug. 
Arm 2 
100 subjects 
 Randomize and dispense study drug 
Arm 1 
100 subjects 
Obtain history and Symptom Inventory, document. Collect and assess daily 
symptom diaries and drug containers. Assess AEs. Perform urine pregnancy test 
(females). Administer Pain Questionnaire. Dispense study drug.  
Prescreen approximately 600 participants. Obtain verbal consent. Complete 
prescreening interview. Prescreen potential subjects by inclusion and exclusion 
criteria. Collect contact information. 


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Visit 5 
Day 77 + 7 
 
 
 
 
 
 
 
 
 
                         Final Assessments 
Obtain history and Symptom Inventory, document. 
Collect and assess daily symptom diaries and drug 
containers. Assess AEs. Perform urine pregnancy 
test (females). Administer Pain Questionnaire.  


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1 
KEY ROLES 
Co-Principal Investigators: 
Inna Tchivileva, MD 
Research Assistant Professor 
5417J Koury Oral Health Sciences 
School of Dentistry 
UNC Chapel Hill 
CB# 7455 
Chapel Hill, NC 27599-7455 
Phone: (919) 537-3291 
Fax: (919) 966-5339 
E-mail: chivilei@dentistry.unc.edu 
 
Gary Slade, BDSc, Dip DPH, PhD 
Distinguished Professor 
5417B Koury Oral Health Sciences 
School of Dentistry 
UNC Chapel Hill 
CB# 7455 
Chapel Hill, NC 27599-7455 
Phone: (919) 537-3273 
Fax: (919) 966-5339 
E-mail: gary_slade@dentistry.unc.edu 
 
Roger Fillingim, PhD 
Professor 
College of Dentistry, University of Florida 
1329 SW 16th Street 
PO Box 103628 
Gainesville, FL 32610-3628 
Phone: (352) 273-5963 
Fax: (352) 273-5985 
E-mail: rfilling@ufl.edu 
 
Richard Ohrbach, DDS, PhD 
Associate Professor 
University at Buffalo School of Dental Medicine 
355 Squire Hall 
Buffalo, NY 14214-1412 
Phone: (716) 829-3590 
Fax: (716) 829-3554 
Email: ohrbach@buffalo.edu 


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NIDCR Medical Monitor: 
Kevin McBryde, MD 
National Institute of Dental and Craniofacial Research/NIH 
6701 Democracy Blvd. Room 638 Bethesda, MD 20892 
Phone: (301) 594-0170 
Fax: (301) 480-8319 
Email: mcbrydekd@nidcr.nih.gov 
NIDCR Program Official:   
Gallya Gannot, DMD, PhD 
National Institute of Dental and Craniofacial Research/NIH 
6701 Democracy Boulevard, Room 632 
Bethesda, MD 20892-4878 
Phone: (301) 451-5096 
E-mail: gallya.gannot@nih.gov 
Co-Investigators: 
Alan Hinderliter, MD 
Associate Professor 
6th floor, Burnett-Womack Bldg., Division of Cardiology  
Campus Box 7075  
Chapel Hill, NC 27599-7075  
Phone: (919) 843-5447  
Fax: (919) 966-1743 
E-mail: alan_hinderliter@med.unc.edu 
 
Pei Feng Lim, BDS, MS 
Clinical Associate Professor 
5417G Koury Oral Health Sciences Building 
School of Dentistry 
UNC Chapel Hill 
CB# 7455 
Chapel Hill, NC 27599-7455 
Phone: (919) 265-3023 
Fax: (919) 966-2991 
E-mail: peifeng_lim@dentistry.unc.edu 
 
Margarete Ribeiro-Dasilva, DDS, PhD 
1395 Center Drive, D9-22 
Gainesville, FL 32610 
Phone: (352) 273-7954 
Fax: (352) 846-1643 
E-mail: mdasilva@dental.ufl.edu 
 
David Sheps, MD, MSPH 
2004 Mowry Road, Room 4234  
Gainesville, FL 32610-3010 
Phone: (352) 294-5947 
Fax: (352) 273-5365 
E-mail: dssheps@phhp.ufl.edu 
 
 
 


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John Campbell, DDS 
Associate Professor 
University at Buffalo School of Dental Medicine 
112 Squire Hall 
Buffalo, New York 14214 
Phone: (716) 829-2722 
Fax: (716) 829-3019 
E-mail: jc294@buffalo.edu 
 
Thomas Cimato, MD, PhD 
 
Associate Professor 
875 Ellicott Street, Suite 7030                                            
Division of Cardiovascular Medicine 
Clinical and Translational Research Center 
Buffalo, New York 14203 
Phone: (716) 829-2663 
Fax: (716) 854-1840 
E-mail: tcimato@buffalo.edu 
 
 


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Institutions:  
The University of North Carolina at Chapel Hill 
School of Dentistry 
Manning Drive & Columbia Street 
Campus Box 7450 
Chapel Hill, NC 27599-7450 
 
The University of Florida 
College of Dentistry 
1600 SW Archer Road 
Gainesville FL 32610-3003 
 
The University at Buffalo  
School of Dental Medicine 
3435 Main St #32 
Buffalo, NY 14214-1412 
 


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2 
INTRODUCTION: BACKGROUND INFORMATION AND 
SCIENTIFIC RATIONALE 
2.1 
Background Information 
2.1.1 
Background on Temporomandibular Disorder 
The term “temporomandibular disorder” (TMD) encompasses all musculoskeletal disorders of 
the masticatory system.1 Common TMDs include myalgia, arthralgia, temporomandibular joint 
(TMJ) disc displacements with and without reduction, and TMJ degenerative joint diseases. A 
recent study reported that the most prevalent TMD diagnostic group is muscle dysfunction.2 
TMD is among the most common chronic musculoskeletal pain conditions and has significant 
societal costs.3 The prevalence of TMD ranges from 6% to 12% in the general population.4 
Overall, TMD results in 17.8 million lost work days per year for every 100 million working adults 
in the US.5 Chronic TMD is associated with substantial disability and suffering, and it negatively 
impacts the quality of life.6 Jaw pain is the most common symptom that compels patients to 
seek treatment. One study reported an average TMD pain intensity rating of 4.3 on a 11-point 
scale, similar to the averages reported for chest pain and back pain.7 In addition to facial pain, 
TMD patients frequently report various comorbid idiopathic pain conditions such as headaches, 
low back pain, and fibromyalgia.8, 9 Novel approaches to TMD therapy are urgently needed to 
improve clinical outcomes and reduce the economic impact of this debilitating disorder.  
2.1.2 
Current Pharmacologic Management of TMD 
Although there is currently no medicinal product labeled by the Food and Drug Administration 
(FDA) specifically for the management of TMD, several classes of drugs are used to attempt to 
relieve TMD-associated pain, such as nonsteroidal anti-inflammatory drugs (NSAIDs), 
corticosteroids, benzodiazepines, sedative hypnotics, muscle relaxants, opioids, 
antidepressants, and anticonvulsants. However, evidence clearly establishing efficacy and 
safety of these drugs in the management of TMD is scarce.10, 11 The justification for their use is 
often based on uncontrolled clinical reports claiming efficacy, poorly controlled clinical trials, or 
clinical trials in other pain disorders (e.g., acute postsurgical dental pain, arthritic pain, chronic 
lower back pain, and neuropathic pain). There is a growing need for controlled clinical trials in 
the TMD population. 
2.1.3 
Adrenergic System in Pathophysiology of TMD 
The physiological mechanisms responsible for TMD symptoms are poorly understood. A 
growing body of evidence suggests that enhanced β-adrenergic drive contributes to the 
pathogenesis of TMD and other complex persistent pain conditions. For example, individuals 


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with myofascial pain conditions have elevated catecholamine levels and augmented 
sympathetic responses to stressors.12, 13 Additionally, fibromyalgia patients have higher basal 
norepinephrine levels and exaggerated norepinephrine responses to the proinflammatory 
cytokine, interleukin-6.14 In animal models, epinephrine produces mechanical hyperalgesia and 
sensitized cultured dorsal root ganglion neurons via action at a β-adrenergic receptor.15 
While increased β-adrenergic drive appears to heighten pain, β-adrenergic antagonists can 
reduce clinical pain and/or nociceptive sensitivity. A recent study of a single-dose infusion of 
propranolol in TMD and fibromyalgia patients revealed a short-term improvement in clinical pain 
ratings.16 The mixed β-adrenergic receptor/5-hydroxytryptamine (HT)1A presynaptic receptor 
antagonist pindolol was similarly efficacious in alleviating the cardinal symptoms of fibromyalgia, 
namely pain, stiffness, and nonrestful sleep.17 In a rodent model of TMD, both the nonselective 
β-adrenergic receptor antagonist propranolol and a selective β2-blocker impaired pain 
behavior.18 In addition, the intramuscular injection of low-dose propranolol in rats reduced 
inflammatory pain associated with carrageenan-induced inflammation of the gastrocnemius 
muscle.16 
2.1.4 
Background on Propranolol 
The study hypothesis is that low-dose therapy with the nonselective β-adrenergic receptor 
antagonist propranolol will provide an efficacious and safe treatment for painful TMD. 
Extended-release propranolol is approved for the treatment of hypertension, angina pectoris 
due to coronary atherosclerosis, migraine, and hypertrophic subaortic stenosis.19 It has 
well-studied pharmacodynamic and pharmacokinetic characteristics and side-effect profile. 
Peak blood level following dosing with an extended-release formulation of propranolol 
hydrochloride occurs at approximately 6 hours, and the apparent plasma half-life is 
approximately 10 hours. Data from our preliminary study suggest that low-dose short-acting 
propranolol produces minimal side effects (e.g., mild nausea, diarrhea, and fatigue occurred at 
similar rates during propranolol and placebo treatment).20  
2.1.5 
Background on Catechol-O-Methyltransferase as a Genetic Marker 
of Response to Propranolol 
Abnormalities in catecholamine physiology are associated with diminished activity of 
catechol-O-methyltransferase (COMT), a ubiquitously expressed enzyme that metabolizes 
catecholamines such as epinephrine, norepinephrine, and dopamine.21 TMD patients exhibited 
lower COMT activity relative to pain-free controls.22 Our group and others have shown that 
various functional polymorphisms in the COMT gene that result in 3- to 15-fold reductions in 
COMT activity23, 24 are associated with fibromyalgia,25 migraine,26 experimental pain 
sensitivity,27, 28 and increased morphine efficacy in cancer pain treatment.29 
Three major haplotypes of COMT, designated as low pain sensitive (LPS), average pain 
sensitive (APS), and high pain sensitive (HPS), accounted for 11% of variability in experimental 


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pain sensitivity in women.27, 30 The LPS haplotype produces higher levels of COMT enzymatic 
activity than the APS or HPS haplotypes.31 In our recent prospective cohort study, the presence 
of even a single LPS haplotype was found to diminish the risk of developing TMD as much as 
2.3-fold.27 To identify the receptor mechanism whereby elevated catecholamine levels resulting 
from reduced COMT activity modulate pain sensitivity, our group conducted a set of behavioral 
pharmacologic studies in rats receiving a COMT inhibitor. We found that COMT inhibition 
enhanced mechanical and thermal pain sensitivity comparable to that produced by 
carrageenan, a chemical well known for its ability to sensitize nociceptors and increase pain 
behavior. COMT-related mechanical and thermal hyperalgesia was blocked by propranolol or by 
combined administration of selective β2- and β3-adrenergic receptor antagonists but not by 
dopaminergic, α-, or β1-adrenergic antagonists, suggesting that the hyperalgesia is selectively 
mediated by a β2/3-adrenergic mechanism.32 
We hypothesize that individuals with lower COMT activity, such as those not carrying the LPS 
haplotype, will experience relatively greater reduction in TMD pain from propranolol therapy 
than individuals with other COMT haplotypes that confer greater COMT activity. Genotyping of 
the COMT gene will allow us to evaluate this hypothesized gene-by-treatment group interaction, 
potentially identifying a subset of TMD patients most likely to benefit from propranolol treatment. 
2.2 
Rationale 
A randomized, double–blind, placebo-controlled, crossover pilot study with a 1-week treatment 
with propranolol (20 mg twice a day) has been completed in patients with painful TMD.20 In this 
study, the number of patients reporting a reduction in pain intensity rating was greater during 
propranolol treatment (p = 0.014) compared with placebo. Propranolol also significantly reduced 
the composite pain index (p = 0.02), but did not decrease other clinical and experimental pain 
ratings. When stratified by the COMT high-activity haplotype (LPS), a beneficial effect of 
propranolol on pain perception was noted in participants not carrying this haplotype, a 
diminished benefit was observed in the heterozygotes, and no benefit was noted in the LPS 
homozygotes; this effect was statistically significant in many pain measures. In the present trial, 
the duration of therapy for TMD with propranolol will be extended to 10 weeks, an 
extended-release instead of short-acting formula of the drug will be administered to enhance 
patient compliance over a longer treatment period, and the propranolol extended-release dose 
will be increased to 60 mg twice a day. Additionally, a parallel instead of crossover design will 
be utilized to reduce the drop-out rate and avert potential carryover effects. 
Consensus recommendations for clinical trials of pain from the IMMPACT group33 encourage 
investigators to evaluate five outcomes related to pain: (1) pain; (2) physical functioning; 
(3) emotional functioning; (4) participant global ratings of improvement; and (5) symptoms and 
adverse events (AEs). They also encourage investigators to collect data to permit reporting of 
study conduct consistent with the recommendations of the CONSORT group.34 Accordingly, this 
protocol proposes endpoints and data recording that will address the requirements of both sets 
of recommendations. 


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2.3 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
Investigational Drug. The investigational product is propranolol hydrochloride 
extended-release capsules. Propranolol has been available commercially for over 40 years and 
is routinely used to treat hypertension, migraine, and essential tremor at doses much greater 
than will be administered in this study. As propranolol is FDA approved for many disorders and 
has well-characterized pharmacological and side effects profiles, the risks for TMD patients 
using this drug at the proposed dose are low. 
The package insert for propranolol hydrochloride extended-release capsules is shown in 
Appendix B. Propranolol is contraindicated in patients with cardiogenic shock, sinus bradycardia 
and greater than a first degree block, bronchial asthma, and known hypersensitivity to 
propranolol hydrochloride. Additionally, propranolol is not recommended for use in patients with 
cardiac failure, nonallergic bronchospasm, major surgery, diabetes, thyrotoxicosis, or Wolff-
Parkinson-White syndrome. Patients with the above-listed conditions will not be included in the 
study. At all clinic visits after Prescreening, resting blood pressure and heart rate will be 
monitored. A 12-lead electrocardiogram (ECG) will be performed at the Screening and Baseline 
Visit. The ECG will be reviewed by a cardiologist who will determine the clinical significance of 
any ECG abnormalities. Participants will be asked to report any planned surgical procedures to 
the study principal investigators (PIs) since propranolol hydrochloride extended-release may 
increase the risks associated with general anesthesia and surgical procedures.  
In a study in which male and female rats were exposed to propranolol hydrochloride in their 
diets, from 60 days prior to mating and throughout pregnancy and lactation for two generations, 
there were no effects on fertility. Contraception in males will not be required in this study. 
However, there are no adequate and well-controlled studies of propranolol in pregnant women.  
Pregnancy is an exclusion criterion and a participant discontinuation criterion in this study. A 
pregnancy test will be conducted on all women of childbearing potential at all visits. In addition, 
propranolol is excreted in human milk; therefore, nursing is an exclusion criterion for this study.  
Cardiovascular, central nervous system, gastrointestinal, allergic, respiratory, hematologic, 
autoimmune, skin and mucous membranes, and genitourinary AEs have been observed in 
patients using propranolol. All reportable AEs will be collected from the Screening and Baseline 
Visit through the last clinic visit. 
Electrocardiogram. Electrode stickers placed on the participant’s skin may cause discomfort 
when removed. Trained personnel will conduct the procedure. 


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Questionnaires. A participant may experience discomfort associated with being asked personal 
questions about her or his health history, symptoms, or emotional feelings. Participants will be 
told that they may choose not to answer any questions that cause discomfort. 
TMD Examination and Psychophysical Tests. Four assessments of this kind will be 
performed: the TMD examination (Section 7.1.6), tests for heat sensitivity (Section 7.1.7), tests 
for pressure pain threshold (PPT) (Section 7.1.8), and a manual tender point examination 
(Section 7.1.9). Assessments of muscle and TMJ sensitivity to digital palpation during the TMD 
examination, responses to masticatory muscle pressure threshold tests, and responses to 
painful heat stimuli are designed to evoke brief pain or discomfort during application of the 
stimulus; however, none of these assessments are expected to result in lasting discomfort or 
damage to affected tissues. Transient redness or tenderness of skin is possible after tests. All 
testing modalities will be conducted within a range of stimulus intensities that produce a level of 
pain or discomfort that is acceptable to the participant. No test will exceed this range, and all 
tests will end upon completion of the modality or upon the participant’s request, whichever 
comes first. 
Blood Collection. There is a possibility of mild pain and bruising associated with a blood draw. 
Trained personnel will perform the blood collection using standard procedures. 
Violation of Confidentiality. The risk of violation of confidentiality exists because human 
participants are providing personal information, including genetic data. Procedures to minimize 
risks to confidentiality are described in Section 14.4. 
2.3.2 
Known Potential Benefits 
Participants may or may not benefit from receiving the investigational drug by experiencing 
decreased pain and improved functionality. In the absence of any approved TMD medication, 
this search for an efficacious, safe, and affordable treatment may benefit many TMD patients in 
the future. In addition, the proposed clinical trial will advance our knowledge of the role of the 
adrenergic system in the pathogenesis of TMD. 
2.4 
Study Objectives 
2.4.1 
Primary Objective 
The primary objective is to investigate the efficacy of extended-release propranolol compared 
with placebo in the reduction of a pain index (defined in Section 2.5.1) in participants with TMD 
at week 9 of treatment (at Visit 4). 
2.4.2 
Secondary Objectives 
The secondary objectives are as follows:  


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• 
To investigate gene-by-treatment group interaction to determine whether the efficacy of 
extended-release propranolol in the reduction of the pain index varies according to 
participants' polymorphisms in the coding region of the COMT gene. 
• 
To investigate the efficacy of extended-release propranolol compared with placebo using 
secondary endpoints, namely: (1) additional pain ratings; (2) examiner assessments of 
experimental pain sensitivity; (3) participant ratings of physical function, emotional 
function, and global impression of change; (4) occurrence of symptoms and AEs; and 
(5) use of rescue medications. 
2.4.3 
Exploratory Objectives 
The exploratory objectives are as follows: 
• 
To investigate whether the efficacy of extended-release propranolol in the reduction of 
the pain index varies according to participants' polymorphisms including, but not limited 
to three other genetic regions: 1) the COMT promoter area; 2) adrenergic receptor β2 
(ADRB2) gene; and 3) the adrenergic receptor β3 (ADRB3) gene. 
• 
To investigate whether the efficacy of extended-release propranolol in the reduction of 
the pain index varies according to various phenotypic characteristics.  
• 
To collect and archive biospecimens for future biological and statistical analyses. 
2.5 
Study Outcome Measures 
2.5.1 
Primary Outcome Measures 
The primary endpoint will be a weekly mean pain index, representing the arithmetic mean of 
daily pain index values during the week prior to the study visit. The pain index will be computed 
during analysis as the product of the pain intensity score, reported on a 0-100 numeric rating 
scale (NRS), multiplied by the pain duration score, reported on a 0-100 percentage scale, each 
as reported in the Daily Symptom Diary. The weekly mean pain index will be computed for the 
week prior to randomization and for each week during the treatment phase. The weekly mean 
pain index will be calculated if a participant completes at least 4 of the 7 daily reports of pain 
intensity and duration during the 7-day period prior to the visit. When there are fewer than 
4 daily reports, the weekly mean pain index will be considered missing. 
2.5.2 
Secondary Outcome Measures 
DNA analyses of blood samples will be conducted to identify polymorphisms in the gene that 
encodes catechol-O-methyltransferase (COMT). Assessments of pain intensity (NRS 0-100) 
and pain duration (0-100 percentage scale) from the Daily Symptom Diary will be used as 
secondary outcomes. Additional assessments of clinical pain, heat and pressure pain, jaw 
function, health status, emotional status, participant ratings of global improvement, sleep, 
somatic symptoms, AEs, and the use of rescue medication will be made by questionnaires and 
examinations, as described in Section 7.1. 


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3 
STUDY DESIGN OVERVIEW 
Two hundred participants with chronic TMD recruited at 3 clinical sites, will be randomized in a 
1:1 ratio to propranolol or placebo in a parallel-group, blinded clinical trial. Participants will be 
limited to age 18 – 65 years because pharmacokinetic data are not available for patients over 
65 years for extended-release propranolol hydrochloride; standard propranolol drug clearance is 
decreased and half-life increased in older populations. Additionally, with aging, arthralgia, 
osteoarthritis, and osteoarthrosis become more prevalent TMD diagnoses than myalgia; 
propranolol will not be effective for these types of TMD.35  
Participants will attend 6 clinic visits over a period of 12 to 15 weeks (Figure 1). The study 
should be completed in 3 years, with participant recruitment occurring during years 1 and 2. 
Prescreening will be performed either in the clinic or over the telephone, and potentially eligible 
participants will be scheduled for a Screening and Baseline Visit (Visit 0). During Visit 0, 
participants will be consented and evaluated for eligibility, and information including 
demographics, medical history, and concomitant medications will be collected. Additionally, 
participants will be assessed for pain, health status, jaw function, emotional functioning, sleep, 
and somatic symptoms, among other measures. Procedures will include clinical examinations 
and tests and the dispensation of various questionnaires, all of which are listed in the Schedule 
of Events (Appendix A). 
At Visit 1, participants who show compliance with the Daily Symptom Diary (at least 4 daily 
entries within 7 days) and meet the pain score and all other eligibility requirements will be 
randomized to propranolol or placebo and will begin a 10-week drug treatment phase that is 
divided into 1 week of drug titration, 8 weeks of drug maintenance, and 1 week of drug tapering. 
During that period, Visits 2-4 will take place, and many of the baseline assessments will be 
repeated. The final study visit, Visit 5, will occur 1 week after drug tapering ends and 2 weeks 
after Visit 4. 
The primary endpoint will be the weekly pain index derived from the Daily Symptom Diary. 
Efficacy will be evaluated as the difference between the propranolol and placebo arms in the 
mean change in the pain index during treatment. In addition, variation in efficacy will be 
compared between groups of participants classified according to polymorphisms in the coding 
region of the COMT gene.  
Enrollment will not be stratified according to COMT genotype because in the pilot study sample, 
the haplotype variants were sufficiently distributed for statistical evaluation of a treatment-
haplotype interaction without stratified randomization. In the pilot study, 30% of participants had 
no copies of the LPS haplotype, 50% had one copy, and 20% had two copies. Stratification by 
COMT genotype would significantly increase the complexity of enrollment and could delay the 
start of treatment for participants while their DNA test results were pending. The DNA analyses 
will be conducted after all participants have been enrolled.  


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4 
STUDY ENROLLMENT AND WITHDRAWAL 
4.1 
Participant Inclusion Criteria 
A participant must meet all of the following inclusion criteria to be eligible for initial enrollment 
and randomization: 
1) 
Provides a signed and dated informed consent form 
2) 
Is between 18 and 65 years of age (inclusive; male or female and any race or ethnicity) 
3) 
Meets diagnostic criteria for TMD, Group II: Masticatory Muscle Disorders, 1A: 
Myalgia36 
4) 
Has experienced facial pain for at least 3 months 
5) 
Has experienced facial pain for at least 10 days of the last 30 days 
6) 
At Screening and Baseline Visit (Visit 0), reports an average pain intensity rating over 
the past week of ≥ 30 on a numerical rating scale (0-100) 
7) 
At randomization (Visit 1), has satisfactorily completed at least 4 entries per week in the 
Daily Symptom Diary within the preceding week and reported an average pain intensity 
score ≥ 30 on a numerical rating scale (0-100) or reports a rating of average daily pain 
intensity of ≥30 on the same scale on at least 3 days over the past week 
8) 
If taking a prescription medication (with the exception of prescription formulations of 
NSAIDs, acetaminophen, and aspirin) episodically (or as needed) for the management 
of pain, agrees to discontinue its use prior to or at the Screening and Baseline Visit 
9) 
If taking a prescription medication daily for the management of pain, agrees to continue 
the daily use of the medication throughout the study 
10) If taking an over-the-counter pain medication daily, agrees to continue the daily use of 
the medication throughout the study 
11) Agrees to not commence any new prescription medication for the management of pain 
throughout the study 
12) Agrees to not commence any injection therapy for pain (e.g., tender or trigger point 
injections, steroid injections) during the course of the study 
13) Agrees to not use acupuncture, biofeedback, or transcutaneous electrical nerve 
stimulation (TENS) for the management of pain during the course of the study 
14) Agrees to not commence occlusal splint therapy during the course of the study 
15) Agrees to continue use of splint therapy if commenced more than 30 days previously 


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16) Females agree to limit consumption of alcohol to no more than 7 drinks* and males 
agree to limit consumption of alcohol to no more than 14 drinks* a week for the duration 
of the study 
17) Females of childbearing potential, agrees to use one of the following methods of 
contraception throughout the study: licensed hormonal method, intrauterine device, 
condoms with contraceptive foam, abstinence, or vasectomy in partner (if 
post-menopausal, must not have menstruated for at least 12 consecutive months) 
18) Willing and able to understand and comply with all study procedures and be available 
for the duration of the study 
4.2 
Participant Exclusion Criteria 
A potential participant who meets any of the following criteria will be excluded from enrollment 
and randomization: 
1) 
Has a history of congestive heart failure or the presence of any of the following 
cardiovascular conditions: clinically significant abnormal 12-lead ECG, sinus 
bradycardia (resting heart rate below 55 beats per minute although lower heart rates 
will be acceptable upon the review and approval by the site cardiologist), greater than 
first degree heart block, coronary artery disease, uncontrolled hypertension, or 
hypotension (systolic blood pressure below 90 mm Hg). In individuals with a heart rate 
below 55 beats per minute, the site cardiologist will review the participant’s medical 
history, including any concomitant medications, to ensure that they are in good general 
health and have no medical contraindications to taking propranolol. 
2) 
Has any of the following medical conditions: bronchial asthma, nonallergic 
bronchospasm (chronic obstructive pulmonary disease and emphysema), renal failure 
or dialysis, diabetes mellitus, hyperthyroidism, fibromyalgia, or uncontrolled seizures 
3) 
Has known hypersensitivity to propranolol or components of the placebo capsules 
4) 
Currently taking a β-blocker or medication that may interact with propranolol, including 
haloperidol, intravenous verapamil, and catecholamine-depleting drugs, such as 
reserpine, within 30 days prior to the Screening and Baseline Visit   
5) 
Currently taking an opioid medication, whether episodically or daily, within 30 days prior 
to the Screening and Baseline Visit 
6) 
Has commenced a new daily prescription medication for the management of pain within 
30 days prior to the Screening and Baseline Visit 
                                               
* one standard drink is defined as 12 ounces of regular beer, 5 ounces of wine, or 1.5 ounces of 80 proof 
distilled spirits. 


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7) 
Used any injection therapy (e.g., tender or trigger point injections, steroid injections) for 
the management of pain within 2 weeks prior to the Screening and Baseline Visit  
8) 
Used acupuncture, biofeedback, or TENS for the management of pain within 2 weeks 
prior to the Screening and Baseline Visit 
9) 
Has commenced occlusal splint therapy for the management of facial pain within 
30 days prior to the Screening and Baseline Visit 
10) Has experienced facial trauma or orofacial surgery within 6 weeks prior to the 
Screening and Baseline Visit 
11) Is undergoing current active orthodontic treatment (passive retainers are permitted) 
12) Has a history of major depression or other major psychiatric disorder requiring 
hospitalization within the last 6 months prior to the Screening and Baseline Visit 
13) Has a history of treatment for drug or alcohol abuse within the last year 
14) Has scored 8 or more on the Alcohol Use Disorders Identification Test (AUDIT) at the 
Screening and Baseline Visit 
15) Currently smokes at least 25 cigarettes per day  
16) Currently being treated with chemotherapy or radiation therapy 
17) Has been treated with another investigational drug or treatment within 30 days prior to 
the Screening and Baseline Visit 
18) Is pregnant or nursing 
19) Anything that, in the opinion of the investigator, would place the participant at 
increased risk or preclude the participant’s full compliance with or completion of the 
study 
4.3 
Strategies for Recruitment and Retention 
Participants will be recruited from existing TMD patient registries and from various clinics at the 
three universities. Clinicians at these sites will be made aware of the study and asked to inform 
their patients of the study and to provide their patients with study contact information. In 
addition, participants may be recruited through print and electronic media advertisements. All 
recruitment materials will be submitted to the Institutional Review Boards (IRBs) for review and 
approval prior to their use. 
Participants will be reminded of each upcoming visit by telephone, text message, email, or 
letter. Participants will be told about the importance of keeping each scheduled appointment, 
and they will be instructed to contact the study staff as soon as possible if they are unable to 
attend a scheduled appointment. Participants who miss a scheduled visit without notifying the 
study staff will be contacted by one of the previously mentioned methods to encourage their 


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continued participation in the study and to ask them to contact the study team concerning their 
next appointment. Unscheduled visits may occur at the investigator’s discretion (Section 6.6). 
Participants will be compensated for their participation in the study in an amount stated in the 
informed consent form, and in some cases, the participant may be eligible for reimbursement of 
some travel expenses. 
4.4 
Treatment Assignment Procedures 
4.4.1 
Randomization Procedures 
Prior to randomization, the inclusion and exclusion criteria will be reviewed, and any participant 
who does not meet the criteria with be discontinued from the trial. Randomization will be 
stratified across 3 clinical sites for a total of 200 randomized participants. Within each site, 
participants will be randomized in a 1:1 ratio of active drug to placebo within prespecified blocks. 
Randomization will be accomplished by a web-based randomization system developed and 
maintained by the data coordinating center. At the time of randomization, study staff, who will 
remain blinded to treatment assignment, will access the system, enter the participant’s study 
identification number, and verify that the participant is eligible for randomization. The system will 
assign a randomization code that will indicate to the pharmacy the participant’s treatment 
assignment. 
4.4.2 
Blinding Procedures 
All study staff, including the study clinicians and investigators, will be blinded to the participants’ 
treatment assignments throughout the data collection period. Propranolol hydrochloride 
extended-release capsules will be over-encapsulated and cannot be differentiated from the 
placebo capsules by appearance alone. The research pharmacies will be unblinded. The data 
coordinating center (DCC) project staff will remain blinded through the analysis for the primary 
objective. If oversight boards, such as the IRBs or Data and Safety Monitoring Board (DSMB), 
request an unblinded data report during the data collection period, an unblinded biostatistician 
at the DCC will generate the report. 
4.4.3 
Unblinding Procedures 
Unblinding before the study is completed will occur only if a participant’s well-being is 
threatened and is necessary to protect the participant. Except in extreme medical emergencies, 
before the treatment assignment for a participant is unblinded, the investigator must confer with 
the National Institute of Dental and Craniofacial Research (NIDCR) medical monitor and the site 
cardiologist as necessary. For extreme medical emergencies that occur during business hours, 
the clinical site investigator will contact the DCC to determine the participant’s treatment 
assignment. For extreme medical emergencies that occur outside of business hours, medical 
personnel will contact the site pharmacy to determine the participant’s treatment assignment. An 
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the participant necessitates knowledge of treatment assignment. Study participants will be 
provided with instructions and contact information for emergency situations. The emergency 
unblinding will be recorded and reported to the PI and to the NIDCR medical monitor as soon as 
possible. A full account of the event will be recorded, including the date and time of the 
emergency, the reason for unblinding, and the names of the medical monitor and others who 
were notified of the emergency. The unblinding will be reported to the DSMB and the IRBs 
according to reporting guidelines for those boards. 
4.4.4 
Reasons for Participant Withdrawal 
Participants are free to withdraw from participation in the study at any time, and the investigator 
may withdraw a participant for any of the following reasons: 
• 
Withdrawal of consent.  
• 
Does not meet criteria for randomization.  
• 
Pregnancy.  
• 
Continued participation deemed to be not in the participant’s best interest. 
• 
Investigator discretion.  
Participants requiring significant surgery will be withdrawn from the protocol. Investigators will 
use discretion in making this determination. Participants withdrawn after randomization will not 
be replaced. If a participant does not return for a scheduled visit, every effort should be made to 
contact the participant and document the outcome. If the participant withdraws consent, no 
further evaluations will be performed, and no attempts will be made to collect additional data. 
4.4.5 
Handling of Withdrawals and Discontinuation 
Participants who withdraw from the study voluntarily or are withdrawn by an investigator will be 
discontinued from the study. Study staff will complete a study disposition form in the electronic 
data capture (EDC) system, indicating the reason for discontinuation. If the participant is on 
study drug at discontinuation, the investigators, in consultation with the site cardiologist, will 
decide the following: (1) the need for tapering of the investigational drug, (2) whether tapering 
will be conducted by the investigator prior to discontinuation or by a referring practitioner after 
discontinuation, and (3) whether unblinding of the treatment assignment will be required. If 
unblinding is required, the investigator will follow the unblinding procedures described in Section 
4.4.3. 
Any participant with an AE that is ongoing at the time of discontinuation will be followed until the 
event returns to baseline, resolves, or stabilizes. If the AE does not meet these outcomes within 
30 days after discontinuation or the end of the study, the participant will be referred to an 
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4.4.6 
Suspension or Termination of the Study 
The study may be suspended or prematurely terminated by the NIDCR if reasonable cause 
exists, as determined by the PI, the NIDCR program official or medical monitor, the IRB, or the 
DSMB. Circumstances that may warrant suspension or termination include, but are not limited 
to, the following:  
• 
Determination of unexpected, significant, or unacceptable risk to participants.  
• 
Insufficient adherence to protocol requirements.  
• 
Data that are insufficient and/or not evaluable. 
If the study is prematurely suspended or terminated, the PI will provide written notification to the 
investigators, the NIDCR program official, the IRB, and the DSMB. 
5 
STUDY INVESTIGATIONAL PRODUCT AND PLACEBO 
The Investigators consulted with the FDA to determine whether this protocol should be 
conducted under an IND. The FDA determined that this clinical trial meets the exemption 
requirements for an IND. An overview of the investigational product and placebo are provided 
below; further details are available in the Manual of Procedures (MOP). 
5.1 
Investigational Product 
The investigational product is propranolol hydrochloride extended-release capsules, an 
approved drug for the treatment of hypertension, angina pectoris due to coronary 
atherosclerosis, migraine, and hypertrophic subaortic stenosis. The package insert for 
propranolol hydrochloride extended-release is provided in Appendix B. Propranolol 
hydrochloride extended-release is a nonselective β-adrenergic receptor-blocking agent. The 
extended-release formula provides a sustained release of propranolol hydrochloride. 
5.1.1 
Acquisition 
Propranolol hydrochloride extended-release 60 mg capsules will be acquired from a 
compounding pharmacy and shipped to the research pharmacy at each clinical site. The 
research pharmacies will dispense the drug. 
5.1.2 
Formulation, Packaging, and Labeling 
The propranolol hydrochloride extended-release capsules will be over-encapsulated by the 
compounding pharmacy to have the same appearance as the placebo. Neither the study 
personnel nor the study participants will be able to differentiate the study drug from the placebo 
by appearance alone.    
The research pharmacy will label and dispense the 60 mg capsules in tight, light-resistant 
containers. The containers will be labeled with the following information: 


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• 
Name and address of the dispensing pharmacy 
• 
Protocol number 
• 
Name of the drug labeled as “propranolol hydrochloride extended-release or placebo” to 
protect the blinding 
• 
Strength of the drug (60 mg propranolol hydrochloride extended-release or placebo) and 
number of capsules dispensed 
• 
Name of the prescribing clinician  
• 
Instructions for use  
• 
Participant name and medical record number 
• 
Date dispensed  
• 
The following statement: “Limited by Federal Law to Investigational Use Only” 
5.1.3 
Product Storage and Stability 
Propranolol hydrochloride extended-release capsules will be shipped and stored according to 
United States Pharmacopeial Convention (USP) Controlled Room Temperature guidelines and 
protected from light, moisture, freezing, and excessive heat. 
5.2 
Dosage and Administration of Investigational Product 
Propranolol hydrochloride extended-release 60 mg capsules will be dispensed at Visits 1, 2, 3, 
and 4 as described below: 
• 
Visit 1 (beginning of the 1-week titration): 1 capsule per day in the evening 
• 
Visit 2 (beginning of the first 4 weeks of maintenance): 2 capsules per day, one in the 
morning and one in the evening 
• 
Visit 3 (beginning of the last 4 weeks of maintenance): 2 capsules per day, one in the 
morning and one in the evening 
• 
Visit 4 (beginning of the 1-week tapering): 1 capsule per day in the evening 
5.3 
Modification of Dosage of Investigational Product 
If a participant cannot tolerate the scheduled titration or maintenance dosage, they will remain in 
the study at either a lower, tolerated dosage or without taking study medication. These events 
will be recorded as protocol deviations.  
5.4 
Placebo 
The placebo, which will be manufactured for this study, will be acquired, packaged, labeled, 
dispensed, and administered in the same manner as described above for the active drug. 


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Ingredients will be a microcrystalline cellulose filler and a gelatin capsule. Storage requirements 
for the placebo are the same as for the active drug. 
5.5 
Accountability Procedures 
The research pharmacies will be responsible for maintaining either paper or electronic logs for 
the acquisition and dispensing of the active drug and placebo. The pharmacies will also be 
responsible for maintaining and monitoring storage conditions for the active drug and placebo. 
The logs and records of storage conditions will be reviewed by the clinical monitor during 
periodic monitoring visits. 
5.6 
Assessment of Participant Compliance 
Participants will be asked to bring their medication containers to each visit during the treatment 
period. Study staff will count the number of capsules returned and will enter the number on a 
case report form in the EDC system. Participants will record the study medication use in the 
Daily Symptom Diary that will be reviewed by the study staff at Visits 2, 3, 4, and 5. Participant 
compliance with study medication will be defined as taking 60% or more of the study medication 
for the duration of the study. 
5.7 
Concomitant Medications and Therapies 
Prior and concomitant medication information will be collected for all participants for the 30 days 
prior to the Screening and Baseline Visit and during the study. Information collected will include 
medication, total daily dose, start date, stop date (if applicable), and primary reason for use. 
Information about treatment with injection therapy, acupuncture, biofeedback, TENS, and 
occlusal splint therapy will also be collected for all participants for the 30 days prior to the 
Screening and Baseline Visit and during the study. 
5.7.1 
Rescue Medication 
Rescue medications described below may be used to alleviate pain. Episodic use of a rescue 
medication will be defined as use for no more than 3 consecutive days and for no more than 
18 total days from Visits 1 to 4. 
5.7.1.1 
Over-the-counter medications 
NSAIDs are most often used to manage pain in TMD patients. If a participant is taking an over-
the-counter medication daily for pain management, the participant will be encouraged to 
continue the same usage of that medication throughout the study. The usage of short-acting, 
non-prescription analgesics (e.g., NSAIDs, aspirin, and/or acetaminophen) by participants 
during the study will be recorded and quantified at each visit, and the usage will be classified as 
either daily or episodic.  


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5.7.1.2 
Prescription medications 
Participants who enter the study on a daily regimen of a prescription medication for pain will be 
encouraged to continue that regimen throughout the study. The usage of all prescription 
medications for pain during the study will be recorded and quantified at each visit. 
5.7.2 
Nonpharmacological Therapy 
During the course of the trial, participants will not be restricted in the use of the 
nonpharmacological therapies, with the exception of acupuncture, biofeedback, and/or TENS. If, 
contrary to the study requirements, a participant starts acupuncture, biofeedback, and/or TENS 
treatment for the management of pain during the study, the use of these therapies will be 
recorded.  
5.8 
Protocol Deviations Related to the Use of Investigational 
Product and Concomitant Therapies 
The following protocol deviations related to the use of investigational product and concomitant 
therapies will be considered major protocol deviations and reported on a case report form in the 
EDC system. 
• 
Participant is unable to reach the maintenance dosage of the study drug or placebo or is 
unable to remain on the maintenance dosage. 
• 
Initiation of opioid medications. 
• 
Initiation of TMJ surgical treatment (including TMJ arthrocentesis). 
• 
Initiation of therapeutic injections for the management of pain. 
• 
Initiation of occlusal splint therapy. 
• 
Initiation of any of the following nonpharmacological therapies: acupuncture, 
biofeedback, and/or TENS. 
• 
Initiation after Visit 1 and usage of short-acting, non-prescription analgesics 
(e.g., NSAIDs, aspirin, and/or acetaminophen) for pain that exceeds the definition of 
episodic use as described in Section 5.7.1. 
6 
STUDY SCHEDULE 
The Schedule of Events table, which provides an overview of the study phases, timeline, and 
events by visit, is provided in Appendix A. In the following section, events are listed by study 
phase and visit, though the order of events listed within a visit does not imply the order in which 
the events will occur. A description of the procedures is provided in Section 7. 


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6.1 
Prescreening (Day -49 to Day-7) 
Prescreening may occur by telephone or at a clinic visit, and it may be combined with the 
Screening and Baseline Visit (Visit 0). After obtaining verbal consent, a brief prescreening 
interview script will be administered and basic eligibility information, specific points of medical 
history, and contact information will be recorded. If a participant expresses interest in the study 
and if the participant is eligible, the participant will be scheduled for Visit 0 within 4 weeks. 
6.2 
Screening and Baseline Visit 0 (Day -21 to Day-7) 
The following procedures and assessments will be conducted up until the time of screen failure: 
1) Obtain consent for study participation  
2) Obtain consent to store biological specimens for future studies 
3) Obtain signed Health Insurance Portability and Accountability statement (as 
applicable) 
4) Collect demographic information 
5) Obtain medical history 
6) Administer the AUDIT Questionnaire 
7) Administer the Smoking Questionnaire 
8) Administer the Symptom Inventory 
9) Record concomitant medications 
10) Record specified concomitant therapies 
11) Collect physical measurements 
12) Collect vital signs 
13) Perform a urine pregnancy test in female participants of childbearing potential 
14) Administer the Fibromyalgia Questionnaire 
15) Perform the manual tender point examination 
16) Administer the SF-McGill Pain Questionnaire 
17) Perform TMD examination 
18) Review eligibility criteria 
19) Perform pressure and heat pain tests (baseline data) 
20) Dispense outcome measure questionnaires as shown in Schedule of Events 
21) Dispense new Daily Symptom Diaries 
22) Schedule next visit 


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23) Perform a screening ECG 
6.3 
Treatment (Visits 1-4) 
6.3.1 
Randomization and Titration Visit 1 (Day 0) 
The following procedures and assessments will be conducted at Visit 1: 
1) Review medical history 
2) Record the average number of alcoholic drinks consumed per week since the previous 
visit 
3) Administer the Symptom Inventory 
4) Record concomitant medications 
5) Record specified concomitant therapies 
6) Assess and record AEs 
7) Collect vital signs 
8) Collect Daily Symptom Diaries 
9) Assess compliance with Daily Symptom Diaries 
10) Collect outcome measure questionnaires as shown in Schedule of Events 
11) Perform a urine pregnancy test in female participants of childbearing potential 
12) Review eligibility criteria 
13) Collect confidence in treatment outcome data 
14) Perform randomization to study drug, if participant is eligible 
15) Draw blood 
16) Dispense new Daily Symptom Diaries 
17) Schedule next visit 
18) Dispense study drug 
At least 4 entries in the Daily Symptom Diary must be completed satisfactorily within the week 
preceding this visit for the participant to meet the eligibility criterion for randomization. The 
participant must also have an average pain intensity score of ≥ 30 or reports a rating of average 
daily pain intensity of ≥ 30 on ate least 3 days in the preceding week, as calculated from the 
Daily Symptom Diary entries, to meet the eligibility criteria. If a participant meets these 2 
eligibility criteria during this visit, the participant will be randomized and continue in the study. 


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6.3.2 
Maintenance Visit 2 (Day 7 [+ 3 days]) 
The following procedures and assessments will be conducted at Visit 2: 
1) Collect study drug containers issued at previous visit 
2) Collect Daily Symptom Diaries 
3) Assess participant compliance with Daily Symptom Diaries  
4) Review medical history 
5) Record the average number of alcoholic drinks consumed per week since the previous 
visit 
6) Administer the Symptom Inventory 
7) Record concomitant medications 
8) Record specified concomitant therapies  
9) Assess and record AEs 
10) Collect vital signs 
11) Perform a urine pregnancy test in female participants of childbearing potential 
12) Administer the SF-McGill Pain Questionnaire 
13) Dispense new Daily Symptom Diaries 
14) Dispense study drug 
15) Schedule next visit 
16) When participant has left, assess participant compliance with study drug usage 
6.3.3 
Maintenance Visit 3 (Day 35 [± 7 days]) 
The following procedures and assessments will be conducted at Visit 3: 
1) Collect study drug containers issued at previous visit 
2) Collect all Daily Symptom Diaries (each diary covering one week)  
3) Assess participant compliance with Daily Symptom Diaries  
4) Review medical history 
5) Record the average number of alcoholic drinks consumed per week since the previous 
visit 
6) Administer the Symptom Inventory 
7) Record concomitant medications 
8) Record specified concomitant therapies  


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9) Assess and record AEs 
10) Collect vital signs 
11) Perform a urine pregnancy test in female participants of childbearing potential 
12) Perform TMD examination 
13) Perform heat and pressure pain tests 
14) Administer outcome measure questionnaires as shown in Schedule of Events 
15) Dispense new Daily Symptom Diaries 
16) Dispense study drug 
17) Schedule next visit 
18) When participant has left, assess participant compliance with study drug usage 
6.3.4 
Tapering Visit 4 (Day 63 [+6 days]) 
The following procedures and assessments will be conducted at Visit 4: 
1) Collect study drug containers issued at previous visit 
2) Collect all Daily Symptom Diaries (each diary covering one week) 
3) Assess participant compliance with Daily Symptom Diaries 
4) Review medical history 
5) Record the average number of alcoholic drinks consumed per week since the previous 
visit 
6) Administer the Symptom Inventory 
7) Record concomitant medications 
8) Record specified concomitant therapies 
9) Assess and record AEs 
10) Collect vital signs 
11) Perform a urine pregnancy test in female participants of childbearing potential 
12) Perform TMD examination 
13) Perform heat and pressure pain tests 
14) Administer outcome measure questionnaires as shown in Schedule of Events 
15) Dispense new Daily Symptom Diaries 
16) Dispense study drug 
17) Draw blood 


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18) Schedule next visit 
19) When participant has left, assess participant compliance with study drug usage 
6.4 
Follow-up Visit 5 (Day 77 [+ 7 days]) 
The following procedures and assessments will be conducted at Visit 5: 
1) Collect study drug containers issued at previous visit 
2) Collect Daily Symptom Diaries (each diary covering one week) 
3) Assess participant compliance with Daily Symptom Diaries  
4) Review medical history 
5) Administer Smoking Questionnaire 
6) Record the average number of alcoholic drinks consumed per week since the previous 
visit 
7) Administer the Symptom Inventory 
8) Record concomitant medications 
9) Record specified concomitant therapies  
10) Assess and record AEs 
11) Collect vital signs 
12) Perform a urine pregnancy test in female participants of childbearing potential 
13) Administer the SF-McGill Pain Questionnaire 
14) When participant has left, assess participant compliance with study drug usage 
6.5 
Early Termination Visit 
If a participant is discontinued before study completion, prior to the withdrawal of consent and 
with the participant’s permission, an Early Termination Visit may be conducted, either during a 
scheduled or unscheduled visit. Each of the procedures and assessments described for Visit 4 
(Section 6.3.4) and the administration of the Smoking Questionnaire will be conducted at the 
Early Termination Visit. 
6.6 
Unscheduled Visit 
An unscheduled visit may occur at the discretion of the investigator. Reasons for an 
unscheduled visit would include, but are not limited to, an AE, the inability of the participant to 
attend a visit within the visit window, or the need for an Early Termination Visit. 


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7 
STUDY PROCEDURES 
Standard operating procedures for all study procedures will be detailed in the MOP, which will 
be provided to study staff prior to study start-up. Overviews of the procedures are provided 
below. Data collected during these procedures will be entered into case report forms within the 
EDC system or via Teleform. 
7.1 
Clinical Evaluations 
7.1.1 
Medical History 
The medical history for each participant will be obtained by interview and entered into the case 
report form. Medical history will be updated at each visit. 
7.1.2 
Vital Signs and Physical Measurements 
After the participant has rested in a chair for 10 minutes, trained personnel will take 3 readings 
of the participant’s systolic blood pressure, diastolic blood pressure, and heart rate at 2-minute 
intervals. A physical examination will be performed at the Screening and Baseline Visit (Visit 0) 
and will include height and weight measurements. 
7.1.3 
Pregnancy Test 
Because propranolol hydrochloride extended-release is not recommended for use during 
pregnancy (Appendix B), female participants of childbearing potential will have a urine 
pregnancy test (instant type) performed at all visits. The results will be read by a member of the 
study staff. The urine will be discarded after the test. 
7.1.4 
Blood Draw 
Staff trained in phlebotomy will obtain up to 20 milliliters of blood by venipuncture. Two whole 
blood tubes for DNA analyses will be placed in short-term storage at each site at 4ºC, and 
2 additional whole blood tubes will be processed to obtain plasma and red blood cells. Plasma 
and red blood cells for future cytokine and COMT activity analyses will be divided into aliquots 
and placed in storage along with the tubes for DNA analyses at -80ºC at each site until shipping 
to the facilities that will perform DNA extraction (Section 7.2.3). 
7.1.5 
Electrocardiogram 
Trained personnel will administer a 12-lead ECG. The procedure involves having the participant 
lie prone on an examination table and placing electrode stickers on the participant’s skin. The 
original ECG will be reviewed by a cardiologist. At the University of North Carolina (UNC), the 
ECG will be performed at the Clinical and Translational Research Center, and at the University 
of Florida (UF), the ECG will be performed at the Clinical Research Center. 


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7.1.6 
Temporomandibular Disorder Examination 
Trained and calibrated study staff will perform a TMD examination based on the Diagnostic 
Criteria for Temporomandibular Disorder (DC/TMD).36 The examination assesses pain in 
masticatory muscles and the TMJ in response to palpation and maneuvering of the jaw. The 
examiner will bilaterally palpate the extraoral masticatory muscles (temporalis and masseter) 
and TMJ. For eligibility, the participant must meet 2 criteria relating to TMD: 1) reported pain or 
ache in the jaw, temple, face, preauricular area, or inside the ear that is changed by jaw 
function; and 2) finding(s) of TMD myalgia classified according to the DC/TMD criteria during the 
examination.  
7.1.7 
Tests for Heat Sensitivity 
Trained study staff will perform the heat sensitivity tests. Contact heat stimuli will be delivered 
using a computer-controlled thermal sensory analyzer as described in the MOP. Thermal 
threshold and tolerance will be measured on the ventral forearm by an ascending method of 
limits. The thermal pain threshold will be defined as the temperature at which the participant first 
perceives heat pain, whereas thermal pain tolerance will be defined as the temperature at which 
the participant can no longer tolerate the pain. The temperature will increase from a baseline of 
32°C with a 0.5°C/s rate of rise until the participant responds by pressing the button. The cutoff 
temperature for both measurements will be 50°C. Average thermal threshold and tolerance will 
be calculated from 4 assessments conducted with a 5-second interstimulus interval at different 
sites of the ventral forearm. For all heat tests, participants will be first given practice runs on a 
site distant from subsequent testing to verify the participant’s understanding of the protocol. 
7.1.8 
Pressure Pain Threshold Measurements 
Trained study staff will perform the PPT measurements. The PPT will be assessed bilaterally 
over the temporalis, masseter, and trapezius muscles, the TMJs, and the lateral epicondyles 
with a pressure algometer as described in the MOP. The PPT will be defined as the amount of 
pressure at which the participant first perceives the stimulus to be painful. One pre-trial 
assessment will be performed at each site followed by additional assessments until 2 measures 
differing by less than 0.2 kg are obtained, or 5 assessments are administered. In either case, 
the mean of the 2 closest values will be recorded as the threshold estimate. Pressure stimuli will 
be delivered at an approximate rate of 1 kg/s. The cutoff pressure for all sites will be 5 kg. The 
values from the right and left sides will be averaged to obtain a single PPT value per anatomical 
site. 
7.1.9 
Manual Tender Point Examination 
The manual tender point examination will be performed by trained study staff, as a screening 
procedure. This assessment verifies a report of pain at a minimum of 11 of 18 specific locations 
(tender points), when palpated with approximately 4 kg of digital pressure. The 18 sites (9 pairs) 
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for the classification of fibromyalgia (1990),37 which require a history of widespread pain present 
for at least 3 months with pain in 11 of 18 tender point sites on digital palpation. Pain is 
considered widespread when all of the following are present: pain in the left side of the body, 
pain in the right side of the body, pain above the waist, and pain below the waist. In addition, 
axial skeletal pain (cervical spine, anterior chest, thoracic spine, or low back) must be present. 
In this definition, shoulder and buttock pain is considered pain for each involved side. Low back 
pain is considered lower segment pain. Digital palpation should be performed with an 
approximate force of 4 kg. For a tender point to be considered positive, the participant must 
state that the palpation was “painful”; “tender” is not considered painful. For classification 
purposes, participants will be said to have fibromyalgia and be ineligible for study participation if 
both criteria are satisfied. 
Pain, on digital palpation, must be present in at least 11 of the following 18 tender point sites: 
1) 
Occiput (bilateral, at the suboccipital muscle insertions) 
2) 
Low cervical (bilateral, at the anterior aspects of the intertransverse spaces at C5-C7) 
3) 
Trapezius (bilateral, at the midpoint of the upper border) 
4) 
Supraspinatus (bilateral, at origins, above the scapula spine near the medial border) 
5) 
Second rib (bilateral, at the second costochondral junction, just lateral to the junctions 
on upper surfaces) 
6) 
Lateral epicondyle (bilateral, 2 cm distal to the epicondyles) 
7) 
Gluteal (bilateral, in upper outer quadrants of buttocks in anterior fold of muscle) 
8) 
Greater trochanter (bilateral, posterior to the trochanteric prominence) 
9) 
Knee (bilateral, at the medial fat pad proximal to the joint line) 
7.1.10 Daily Symptom Diary 
The participants will be asked to complete the Daily Symptom Diary at the end of each day 
starting at Visit 0 and ending at Visit 5. Participants who complete at least 4 out of the 7 entries 
per week at Visit 1 will be considered eligible for study participation. The diary requests 
information about the participant’s pain intensity (reported on a 0-100 numeric rating scale) and 
duration (reported on a 0-100 percentage scale), fatigue, sleep, and somatic symptoms. The 
participants will complete a Daily Symptom Diary on a new paper form each week of the study, 
as described in the MOP. The participants will return paper-based diaries either by mail or in 
person at study visits. Compliance with the Daily Symptom Diary will be defined as completion 
of at least 4 daily entries within 7 days. Any noncompliance found during Visits 2 through 5 will 
be reported as protocol deviations. 


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7.1.11 The Alcohol Use Disorders Identification Test 
The Alcohol Use Disorders Identification Test is a method to screen for excessive drinking. 38  
This questionnaire assesses recent alcohol use, alcohol dependence symptoms and alcohol-
related problems.  The AUDIT test will be performed at V0, as described in the MOP. 
Participants with a score of 8 or more will be ineligible for study participation. 
7.1.12 Smoking Questionnaire 
The Smoking Questionnaire is a method to screen for use of and exposure to tobacco smoke. 
This questionnaire assesses current and former use of combustible and smokeless tobacco, as 
well as current exposure to environmental tobacco smoke. The questionnaire will be 
administered at Visit 0 and Visit 5, as described in the MOP. Participants who self-report 
smoking at least 25 cigarettes per day at Visit 0 will be ineligible for study participation. 
7.1.13 Symptom Inventory 
The Symptom Inventory is a method to screen for AEs. Trained study staff will record participant 
responses to questions about the occurrence and severity of expected AEs known to be 
associated with propranolol hydrochloride extended-release. The Symptom Inventory will be 
administered at all visits, as described in the MOP. If a symptom has emerged or worsened, 
study personnel will evaluate the symptom for a possible AE.  
7.1.14 Outcome Measure Questionnaires 
The questionnaires that will be utilized are listed in the Schedule of Events (Appendix A) and 
are briefly described below. Copies of the questionnaires are reproduced in the attachments. 
Several questionnaires are self-administered, and others will be administered by trained study 
staff. For outcome measure questionnaires, responses will be recorded on paper Teleform case 
report forms, which will be scanned as described in the MOP.  
Short-Form McGill Pain Questionnaire. This questionnaire consists of 15 descriptors 
(11 sensory, 4 affective) which are rated on an intensity scale as 0 (“none”), 1 (“mild”), 
2 (“moderate”), or 3 (“severe”).39 
Graded Chronic Pain Scale (GCPS). The GCPS comprises 7 items and assesses 2 dimensions 
of pain: pain intensity and pain-related disability.7, 40 
Fibromyalgia Questionnaire. This questionnaire assesses the ACR criteria for fibromyalgia 
(1990)37 and includes pain-related questions and manikin drawings of participant pain location. 
Short Form 12 Health Survey Version 2 (SF-12 v2). The SF-12 v2 is a briefer measure of 
health-related quality of life derived by using 12 items from the original Short Form 36 
instrument.41 This questionnaire produces 2 scores: a mental health composite score and a 
physical health composite score. 


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Patient Global Impression of Change (PGIC). The PGIC is a participant-rated instrument that 
measures change in participant’s overall status on a scale ranging from 1 (“very much 
improved”) to 7 (“very much worse”). The PGIC is based on the Clinical Global Impression of 
Change, which is a validated scale.42 
Jaw Functional Limitation Scale. This 20-item instrument measures limitations across 
3 domains: mastication (6 items), vertical jaw mobility (4 items), and verbal and emotional 
expression (8 items).43, 44 Two items are not scored as part of these 3 subscales. A degree of 
limitation is rated on a 0-10 scale from 0 (“no limitation”) to 10 (“severe limitation”). 
Perceived Stress Scale. This questionnaire assesses 14 sources of stress and produces an 
overall perceived stress rating.45 
Hospital Anxiety and Depression Scale. This 14-item instrument evaluates anxiety and 
depression.46 
Symptom Checklist 90-Revised (SCL-90R) Somatization Subscale. The somatization subscale 
of the SCL-90R assesses a degree of somatic symptoms experienced by participants. It 
contains 12 items.47   
Pittsburgh Sleep Quality Index. This 19-item instrument assesses sleep quality during the 
previous month across several domains: subjective sleep quality, sleep latency, sleep duration, 
habitual sleep efficiency, sleep disturbances, use of sleep medication, and daytime 
dysfunction.48 
Coping Strategies Questionnaire Revised (CSQ-R). The CSQ-R consists of 27 items relating to 
how individuals cope with pain. Participants indicate the frequency with which they engage in 
specific coping activities when experiencing pain, using a 7-category numerical scale ranging 
from 0 (never do that) to 6 (always do that). It yields 6 subscales reflecting the pain coping 
strategies that individuals use: diverting attention, catastrophizing, praying and hoping, ignoring 
pain sensations, reinterpreting pain sensations, and coping self-statements.49 
Headache Questionnaire. This questionnaire assesses diagnostic criteria for tension-type 
headache and migraine according to the International Classification of Headache Disorders 3 
(beta version). 50 
Headache Impact Test (HIT-6). The HIT-6 evaluates the factors contributing to the burden of 
headache and consists of 6 items: pain, social functioning, role functioning, vitality, cognitive 
functioning, and psychological distress.51 The participant answers each question using 
responses ranging from “never” to “always.” These responses are summed to produce a total 
HIT-6 score. 


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7.2 
Laboratory Evaluations 
7.2.1 
Clinical Laboratory Evaluations 
In this study, clinical laboratory tests are not needed for the monitoring of safety or the 
evaluation of study objectives; therefore, none will be performed. 
7.2.2 
Research Laboratory Evaluations 
DNA extracted from whole blood samples will be analyzed for polymorphisms including, but not 
limited to the COMT, ADRB2, and ADRB3 genes. DNA, plasma, and red blood cells will be 
stored for possible future IRB-approved genetic, cytokine, and COMT activity analyses (Section 
14.5). 
7.2.3 
Specimen Preparation, Handling, and Shipping 
Standard operating procedures for specimen collection, preparation, handling, shipping, 
storage, and analysis will be provided in the MOP. The shipping and storage of all samples will 
be tracked by a web-based specimen tacking system programmed and maintained by the DCC. 
DNA. Whole blood samples for DNA analyses will be collected and stored at -80ºC. Whole 
blood samples collected at UF and UB will be shipped in batches to UNC. Genomic DNA will be 
purified from whole blood samples and stored at -80ºC until genotyping is performed and for 
future use.  
Future Use. Plasma and red blood cells for future cytokine and COMT activity analyses will be 
divided into aliquots and placed in short-term storage at -80ºC at each site. Plasma and red 
blood cells samples collected at UF and UB will be shipped in batches to UNC. 
8 
ASSESSMENT OF SAFETY 
8.1 
Specification of Safety Parameters 
Participants in this study will undergo close follow-up. As described in Section 2.3, risks related 
to participation include: 1) risks related to the administration of propranolol hydrochloride 
extended-release; 2) risks related to the administration of the ECG; 3) risks associated with 
questionnaires; 4) risks associated with TMD examinations and psychophysical tests; 
5) well-known and anticipated minor risks from venous phlebotomy; and 6) risks related to study 
participation such as loss of confidentiality of collected data. 
The risks described above will be characterized and monitored to protect the safety of 
participants. In addition, the study has been designed to minimize risks. Participants will be 
monitored closely for AEs with frequent visits.  Adverse events will be managed by the site 
dentist or site cardiologist depending on the nature of the event. 


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Examination and close follow-up of parameters capturing participants’ overall health will be 
collected on case report forms. These will be completed at every study visit, and data will be 
compiled into a prespecified format and reviewed by the DSMB (Section 9). 
As part of the study outcomes, study personnel will collect the occurrences of the following 
expected AEs known to be associated with propranolol hydrochloride extended-release: 
• 
Dizziness or lightheadedness 
• 
Unusual tiredness or fatigue 
• 
Nausea or vomiting 
• 
Upset stomach 
• 
Hands numbness or tingling  
• 
Sleep problems 
• 
Depression 
In this study, the following expected events will not be considered reportable AEs: 
• 
Minor bleeding or bruising resulting from the blood draw 
• 
Temporary pain or temporary increases in existing pain elicited during the TMD clinical 
examination or tests of heat, pressure, or tender points 
• 
Worsening of TMD signs and symptoms during the participant’s 12- to 15-week 
participation 
8.1.1 
Unanticipated Problems 
The Office for Human Research Protections (OHRP) considers unanticipated problems (UPs) 
involving risks to participants or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria: 
• 
Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document and (b) the 
characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (in the guidance document, 
possibly related means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
• 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized. 
8.1.2 
Adverse Events 
The International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice 
(GCP) defines an AE as “any untoward medical occurrence in a patient or clinical investigation 


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subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.”  
8.1.3 
Serious Adverse Events 
A serious adverse event (SAE) is one that meets one or more of the following criteria: 
• 
Results in death 
• 
Is life-threatening (places the participant at immediate risk of death from the event as it 
occurred) 
• 
Results in inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in a persistent or significant disability or incapacity 
• 
Results in a congenital anomaly or birth defect 
• 
An important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, the event may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
8.2 
Time Period and Frequency for Event Assessment and 
Follow-Up 
Unanticipated problems will be recorded in the data collection system throughout the study.  
The PI will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for nonserious 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 the event returns to 
baseline, resolves, or stabilizes. If the AE does not meet these outcomes within 30 days after 
discontinuation or the end of the study, the participant will be referred to an appropriate 
practitioner for continued care. 
8.3 
Characteristics of Adverse Events 
8.3.1 
Relationship to Study Drug 
The PI will make the determination of the relationship of an AE to the study drug according to 
the following guidelines: 
1. Related (Possible, Probable, Definite) 
a. The event is known to occur with the study intervention. 


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b. There is a temporal relationship between the intervention and event onset. 
c. The event abates when the intervention is discontinued. 
d. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related) 
a. There is no temporal relationship between the intervention and event onset. 
b. An alternate etiology has been established. 
8.3.2 
Relationship to Study Procedures 
The same procedure as described in Section 8.3.1 for determining the relatedness of an AE to 
study drug will be used to determine its relatedness to a study procedure. 
8.3.3 
Expectedness of AEs 
The NIDCR Medical Monitor and the Study PI will be responsible for determining whether an AE 
is expected or unexpected. An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information described in the protocol or the 
Investigator’s Brochure or discussed with the participant during the informed consent process.  
8.3.4 
Severity of Event 
Adverse events will be graded on a scale from 1 to 5 according to the following standards from 
the National Cancer Institute‘s Common Terminology Criteria for Adverse Events (v 4.0), which 
may be found in its entirety at http://ctep.cancer.gov/reporting/ctc.html: 
• 
Grade 1 = mild AE 
• 
Grade 2 = moderate AE 
• 
Grade 3 = severe or medically significant AE 
• 
Grade 4 = life-threatening AE 
• 
Grade 5 = death 
8.4 
Reporting Procedures 
8.4.1 
Adverse Event Reporting to IRB and NIDCR 
Study staff will report AEs on a case report form in the EDC system. Adverse events will be 
reported to the IRBs and DSMB according to guidelines established by those boards. 


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8.4.2 
Unanticipated Problem Reporting to IRB and NIDCR 
Incidents or events that meet the OHRP criteria for unanticipated problems require the creation 
and completion of an unanticipated problem report form within the EDC system. If an 
unanticipated problem also meets the criteria for an AE or SAE, it will be reported as an 
unanticipated problem and an AE or SAE. The OHRP recommends that investigators include 
the following information when reporting an adverse event, or any other incident, experience, or 
outcome as an unanticipated problem to the IRB: 
• 
Appropriate identifying information for the research protocol, such as the title, 
investigator’s name, and the IRB project number 
• 
A detailed description of the adverse event, incident, experience, or outcome  
• 
An explanation of the basis for determining that the adverse event, incident, experience, 
or outcome represents an unanticipated problem  
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the unanticipated problem 
To satisfy the requirement for prompt reporting, unanticipated problems will be reported using 
the following timeline:   
• 
Unanticipated problems that are SAEs will be reported to the IRB and to NIDCR within 
1 week of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to NIDCR within 2 weeks of the investigator 
becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), 
and OHRP within one month of the IRB’s receipt of the report of the problem from the 
investigator. 
All unanticipated problems will be submitted on the UP form within the EDC system to NIDCR’s 
centralized reporting system via Rho Product Safety. However, in cases when the EDC system 
is not available, the investigator may report the UP by fax or email: 
• 
Product Safety Fax Line (US): 1-888-746-3293 
• 
Product Safety Email: rho_productsafety@rhoworld.com  
General questions about UP reporting can be directed to the Rho Product Safety Help Line 
(available 8:00AM – 5:00PM Eastern Time):   
• 
US: 1-888-746-7231 
8.4.3 
Serious Adverse Event Reporting to NIDCR 
Any AE meeting the specified serious adverse event criteria will be submitted on an SAE form 
within the EDC system to NIDCR’s centralized safety system via Rho Product Safety. However, 
in cases when the EDC system is not available, the investigator may report the SAE by fax or 
email. Once submitted, Rho Product Safety will send a confirmation email to the investigator 


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within 1 business day. The investigator should contact Rho Product Safety if this confirmation is 
not received. This process applies to both initial and follow-up SAE reports.  
SAE Reporting Contact Information:    
• 
Product Safety Fax Line (US):  1-888-746-3293 
• 
Product Safety Email: rho_productsafety@rhoworld.com  
General questions about SAE reporting can be directed to the Rho Product Safety Help Line 
(available 8:00AM – 5:00PM Eastern Time):   
• 
US: 1-888-746-7231 
The study clinician will complete a Serious Adverse Event Form and submit within the EDC 
system (or via fax or email if the EDC system is not available) within the following timelines:  
• 
All deaths and immediately life-threatening events, whether related or unrelated to the 
study drug, will be recorded on the Serious Adverse Event Form and submitted to 
Product Safety within 24 hours of site awareness.  
• 
Serious adverse events other than death and immediately life-threatening events, 
regardless of relationship to the study drug, will be reported within 72 hours of site 
awareness.  
All SAEs will be followed until resolution or stabilization. 
Serious adverse events will be reported to the IRBs and DSMB according to guidelines 
established by those boards. 
8.4.4 
Reporting Abnormal Clinical Findings 
Any clinically significant worsening of a medical condition (other than TMD) established at 
baseline or the development of any new clinically significant medical condition during the study 
will be considered an AE and will be reported as described previously. 
8.4.5 
Reporting of Pregnancy 
Pregnancy will be recorded on a case report form within the EDC system if it begins any time 
during the study. Pregnancy will not be regarded as an SAE unless there is suspicion that the 
study drug may have interfered with the effectiveness of a contraceptive medication and the 
event meets the criteria for an unanticipated problem. Results of all positive pregnancy tests will 
be given to the participant and/or her legally authorized representative, as appropriate. 
Participants who become pregnant while participating in the study will be discontinued from the 
study and referred for appropriate care. If a participant becomes pregnant while receiving the 
study drug, she will be followed for safety until a pregnancy outcome is reached. If the 
pregnancy results in an outcome other than a normal birth or elective abortion of a healthy fetus, 
it will be reported as an SAE. 


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8.5 
Halting Rules 
See Section 4.4.6, Suspension or Termination of the Study. 
9 
STUDY OVERSIGHT 
In addition to the PI’s responsibility for oversight, safety oversight will be under the direction of a 
DSMB convened by NIDCR. The DSMB is composed of members with expertise in pain 
management. The DSMB will meet periodically or as needed to assess safety and efficacy data, 
study progress, and data integrity for the study. If safety concerns arise, more frequent meetings 
may be held. The DSMB will operate under the rules of an NIDCR-approved charter that will be 
written at the organizational meeting of the DSMB. At this time, most data elements that the 
DSMB needs to assess will be clearly defined. The DSMB will provide recommendations to the 
NIDCR. The PI will be responsible for responding to inquiries and recommendations made by 
the DSMB. 
10 
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights of human participants are 
protected, that the study is implemented in accordance with the protocol and/or other operating 
procedures, and that the quality and integrity of study data and data collection methods are 
maintained.  Monitoring for this study will be performed by NIDCR’s Clinical Research 
Operations and Management Support (CROMS) contractor. The monitor will evaluate study 
processes and documentation based on NIDCR standards and the ICH E6: GCP guidelines. 
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by the CROMS contractor, in collaboration with the NIDCR Office of Clinical Trials 
and Operations Management (OCTOM) and the NIDCR Program Official. The CMP will specify 
the frequency of monitoring, monitoring procedures, the level of clinical site monitoring activities 
(e.g., the percentage of participant data to be reviewed), and the distribution of monitoring 
reports. Some monitoring activities may be performed remotely, while others will take place at 
the study site(s). Staff from the CROMS contractor will conduct monitoring activities and provide 
reports of the findings and associated action items in accordance with the details described in 
the CMP. Documentation of monitoring activities and findings will be provided to the site study 
team, the study PIs, OCTOM, and the NIDCR. The NIDCR reserves the right to conduct 
independent audits as necessary. 


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11 
STATISTICAL CONSIDERATIONS 
11.1 
Study Hypotheses 
11.1.1 Primary Hypothesis 
We hypothesize that among this study population of participants with TMD, the net change in 
the mean pain index at Visit 4 will be greater in the propranolol-treated arm than in the placebo-
treated arm. Net change is defined as the difference between the participant's mean pain index 
at Visit 1 and each subsequent visit. Efficacy of propranolol is defined as the difference between 
the propranolol and placebo arms in the mean net change. Figure 2 uses hypothetical data to 
illustrate how the primary hypothesis is restricted to efficacy at Visit 4 (∆V4). 
Figure 2. Hypothetical Data Illustrating the Primary Hypothesis 
 
11.1.2 Secondary Hypothesis 
• 
We hypothesize that among this study population of participants with TMD, the efficacy 
of propranolol will vary according to the number of LPS haplotypes of the COMT gene. 
• 
We hypothesize that, compared with participants in the placebo-treated arm, participants 
in the propranolol-treated arm will have more favorable secondary endpoints, namely: 
(1) reduction in additional ratings of pain; (2) reduction in examiner-assessed levels of 
0
1
2
3
4
5
6
7
8
9
-3 0
-2 0
-1 0
0
P la c e b o
A ctive
∆V 4
V 1
V 2
V 3
V 4
W e e k s  o f tre a tm e n t
N e t c h a n g e  in  p a in  in d e x
c o m p a re d  to  V 1


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pain sensitivity (pressure and heat pain sensitivity); (3) better participant ratings of 
physical function, emotional function, and global improvement; and (4) less frequent use 
of rescue medications and over-the-counter medications for pain.  
11.1.3 Exploratory Hypotheses 
• 
We hypothesize that efficacy of propranolol will vary according to genetic variants 
including, but not limited to the COMT gene promoter and the ADRB2 and ADRB3 
genes. 
• 
We hypothesize that efficacy of propranolol will vary according to phenotypic 
characteristics. 
11.2 
Sample Size Considerations 
This study plans to randomize 200 participants, which will provide 94% power (alpha = 0.05) to 
detect a difference between a 27% reduction in pain index in the propranolol arm and a 
9% reduction in the placebo arm (primary hypothesis). Assuming haplotype distributions and 
within-haplotype treatment effects that are similar to those observed in the pilot study, the same 
sample size would provide 61% power (alpha = 0.05) to detect an interaction between 
haplotype and treatment group (secondary hypothesis). The assumptions for these power 
calculations are shown in the following table. Power calculations were made using the 
GLMPOWER procedure in SAS, which assumes a data structure of one observation per person. 
This is a simplification of the situation that will occur with the linear mixed model described in 
Section 11.4.1 in which efficacy will be evaluated using a data structure in which most 
participants will have three observations per person. The simplified power calculations are 
shown here because conventional software for power calculations does not deal with the more 
complex situation of linear mixed models. 
Primary 
Hypothesis 
 
Secondary 
Hypothesis 
COMT haplotype 
All haplotypes 
0 LPS copies 
1 LPS copy 
2 LPS copies 
Treatment arm 
Drug 
Placebo 
Drug 
Placebo 
Drug 
Placebo 
Drug 
Placebo 
% of participants (N = 200) 
50% 
50% 
15% 
15% 
25% 
25% 
10% 
10% 
Mean baseline pain index 
3000 
3000 
3000 
3000 
3000 
3000 
3000 
3000 
Net change 
-810 
-270 
-1350 
-270 
-810 
-270 
-270 
-270 
Percentage change 
-27 
-9 
-45 
-9 
-27 
-9 
-9 
-9 
∗ 
LPS stands for low pain sensitive, one of the major haplotypes of COMT. The standard deviation for the mean 
baseline pain index is estimated to be 1190. The net change takes into account a 10% lost-to-follow-up rate and 
imputation using the last observation carried forward approach. 


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11.3 
Analysis Samples 
11.3.1 Intention-To-Treat Sample 
Consistent with the primary statistical method that will use a linear mixed model (also called 
"mixed model repeated measures" model), the intention-to-treat sample is defined as all study 
participants who have at least one valid measurement of the primary endpoint at Visit 2 or later. 
A "valid" assessment for the primary endpoint is defined as at least 4 daily reports of pain 
intensity and duration collected in the 7-day period prior to the visit (Section 2.5.1). Treatment 
group allocation will be defined as the study arm into which the subject was randomized 
regardless of the actual study treatment received.  By necessity, the intention-to-treat sample 
excludes participants who provide no data for the primary endpoint after randomization. Note 
that follow-up assessments will be included in the intention-to-treat analysis when sufficient 
diary data are collected at the follow-up assessment, even if there were protocol violations. 
Likewise, the intention-to-treat sample will include all available follow-up assessments from any 
discontinued participants. 
11.3.2 Per-Protocol Sample 
Secondary statistical analysis of the primary hypothesis will be in the spirit of per-protocol 
analysis. The per-protocol sample will be a subset of the intention-to-treat sample, excluding 
any assessments made at or after a visit at which the participant is found to have any protocol 
deviation listed in Section 5.8. In addition, all assessments for participants whose compliance 
with study medication is less than 60% over all study visits will be excluded from per-protocol 
analyses. 
11.3.3 Safety Sample 
The safety sample will include all randomized participants who received at least one dose of 
study medication. Participants in the safety sample will be analyzed with the treatment group 
according to the medication they actually received, regardless of their randomized assignment. 
11.4 
Analyses 
Complete details of all statistical analyses will be provided in the Statistical Analysis Plan, which 
will be completed prior to database lock and analysis. Below is an overview of the analyses for 
the primary and secondary hypotheses. 
11.4.1 Analysis of the Primary Hypothesis 
The primary statistical analysis to evaluate the primary hypothesis will use all data from the 
intention-to-treat analytical sample in a linear mixed model. During the analysis of the primary 
hypothesis, treatment allocation will be masked (i.e., groups will be labeled A and B). Treatment 
allocation will be unmasked for further analyses. 


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The dependent variable will be the participant's change in the weekly pain index, computed as 
the weekly pain index at the follow-up visit (i.e., at Visit 2, Visit 3, or Visit 4) minus the Visit 1 
weekly pain index. Explanatory variables will comprise fixed factors and a continuous covariate. 
The fixed factors will include the following: (a) treatment allocation (two categories) (b) visit 
sequence (three categories); (c) interaction of treatment allocation and visit sequence (two 
dummy variables); and (d) covariates of study site (three categories), sex (two categories) and 
race/ethnicity (probably three categories: non-Hispanic White, non-Hispanic Black, and 
other/multiple racial or ethnic groups – the final number of conditions will be dictated by the 
frequency distribution of race/ethnicity in the study sample). The baseline score collected at Visit 
1 will be the continuous covariate, modeled as a fixed effect The study participant will be 
modeled as a random factor. 
In a linear mixed model containing all predictor variables including the interaction terms for visit 
and treatment allocation, the primary treatment effect will be tested at Visit 4. The null 
hypothesis of no treatment effect will be rejected if the P-value at Visit 4 is ≤ 0.05. For 
descriptive purposes (and regardless of the P-value for efficacy at Visit 4), efficacy estimates at 
each visit (2, 3 and 4) will be described in terms of adjusted means and 95% confidence 
intervals. 
If the propranolol treatment arm has a greater reduction in the weekly pain index than the 
placebo arm at Visit 4, a threshold of "responder analysis" will be undertaken to estimate the 
odds of at least a 30% reduction, relative to Visit 1, in the pain index at Visit 4. Likewise, another 
threshold of responder analysis will describe the odds of experiencing at least a 50% reduction. 
These estimates will be calculated from a logistic model in which the dependent variable is a 
binary variable that dichotomizes the change score at the appropriate threshold (i.e., ≥ 30% or ≥ 
50%). 
Secondary analyses of the primary hypothesis will be conducted as described above, but using 
the per-protocol sample.  
Stratified analysis in the intention-to-treat sample will estimate treatment effects separately for 
the two sexes and for the main racial-ethnic groups. The analysis will be descriptive, reporting 
means and 95% confidence intervals. There will be no hypothesis tests of efficacy within 
demographic subgroups because of the expected small numbers of males and minorities. 
11.4.2 Analysis of the Secondary Hypotheses 
To test the secondary hypothesis of gene-by-treatment interaction, the linear mixed model 
described for the primary analysis will be extended by adding three sets of predictor variables: 
(1) the number of COMT LPS haplotypes (0, 1, or 2) will be modeled as a fixed effect, either as 
a continuous variable, or as a 3-level categorical variable (i.e., two dummy variables), with the 
decision based on the approach that optimizes model fit, as determine by Akaike’s Information 
Criterion; (2) two-way interactions between haplotype effect and treatment allocation and 
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haplotype effect, treatment allocation, and visit sequence. The gene-by-treatment interaction at 
V4 is the interaction of interest.   
For descriptive purposes, an analogous model will generate efficacy estimates according to 
COMT Val158Met genotype as the genetic marker instead of the number of LPS haplotype. In an 
analogous manner, the genotype will be coded either as a continuous or categorical variable 
based on optimal model fit.  Efficacy estimates will be calculated for descriptive purposes only; 
there will be no hypothesis tests for the interaction terms.  
Another descriptive set of secondary analyses will adapt the approach for analysis of the LPS 
haplotype, restricting the model to non-Hispanic whites. This is consistent with the approach of 
some genetic researchers who advocate racial-group restriction as a preferable analytic method 
to control for population stratification. 
Linear mixed models will be used to evaluate effects of treatment group allocation on secondary 
efficacy variables (see Statistical Analysis Plan for full details). 
Linear regression or other appropriate statistical modeling will evaluate the effects of treatment 
on the number of days in which rescue medications for TMD-related pain reportedly were used 
and on the number of days in which over-the-counter analgesics (namely, NSAIDs, 
acetaminophen, and aspirin) reportedly were used for treatment of any type of pain.  
See the Statistical Analysis Plan for more details on these secondary analyses.  
11.4.3 Analysis of the Exploratory Hypotheses 
The exploratory hypotheses will extend the analytical procedures described above. In summary: 
• 
The linear mixed model described for the secondary hypothesis will be modified by 
specifying genetic variants including, but not limited to the COMT gene promoter and the 
ADRB2 and ADRB3 genes. 
• 
Other phenotypes will be evaluated as potential treatment effect modifiers using a similar 
strategy in which linear mixed models will test for phenotype-by-treatment interactions.  
Each phenotype will be categorized based on characteristics assessed either at V0 or 
V1. The phenotypes are: body mass index; smoking; migraine headache;  tenderness to 
body palpation; catastrophizing subscale of the CSQ-R questionnaire; self-rated general 
health from the SF-12v2 questionnaire; anxiety and depression subscales from the 
HADS questionnaire; sleep quality from the PSQI questionnaire; and subjects’ rating of 
confidence in treatment outcome.  Full details are provided in the Statistical Analysis 
Plan. 
The exploratory analysis will further explore the results, insights, or new questions that may 
arise during the study’s analyses and will not be limited to the exploratory analyses listed above. 
11.5 
Planned Interim Analyses 
No interim analyses are planned. 


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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA AND DOCUMENTS 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, participants’ memory aid or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, recorded 
audio tapes of counseling sessions, copies or transcriptions certified after verification as being 
accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, 
x-rays, and participant files and records kept at the pharmacy, at the laboratories, and 
medico-technical departments involved in the clinical trial. It is acceptable to use case report 
forms as source documents. For this study, some clinical examination and questionnaire data 
may be recorded directly from the participant onto the Teleform case report forms (paper), with 
the case report form being the source document. 
Each clinical site will maintain appropriate medical and research records for this trial in 
compliance with Section 4.9 of ICH E6 and regulatory and institutional requirements for the 
protection of confidentiality of participants. As part of participating in an NIDCR-funded study, 
each site will permit authorized representatives of the NIDCR, including CROMS clinical 
monitors, and regulatory agencies to examine (and when required by applicable law, to copy) 
clinical records for the purposes of quality assurance reviews, audits, and evaluation of the 
study’s safety and progress. 
13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Quality control is the ongoing, concurrent review of data collection forms for completion and 
logic. Quality assurance is a comprehensive, retrospective review of all components of research 
records to assess adherence to protocol, standard operation procedures, and regulations and to 
evaluate the accuracy of the records. Quality management is the process of assessing the 
quality of processes within a system and encompasses quality assurance and quality control. 
The quality management program will include, but will not be limited to, the following: 
• 
A study start-up list of tasks that must be completed and approved by the NIDCR 
program officer prior to the first participant visit 
• 
Training of staff on the protocol, study procedures, and use of the data collection forms 
and systems 
• 
Documentation and tracking of training for each staff member 
• 
A Clinical Monitoring Plan that describes periodic clinic visits by monitors to ensure that 
the rights of human participants are protected, the study is implemented in accordance 
with the protocol, and the integrity of study data is maintained 


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• 
A Data Management Plan that describes procedures for data entry and completion, data 
security, and data quality control and validation 
14 
PROTECTION OF HUMAN PARTICIPANTS 
14.1 
Institutional Review Board 
Each participating institution will provide for the review and approval of this protocol and the 
associated informed consent documents and recruitment materials by an appropriate IRB 
registered with the OHRP. Any amendments to the protocol or consent materials will also be 
approved by the IRB before they are placed into use. 
14.2 
Informed Consent Process 
Written documentation of informed consent will be obtained prior to an individual’s participation 
in the study. An IRB-approved consent form describing in detail the study interventions, 
procedures, and risks will be given to the participant. The participant will be asked to read and 
review the document, and upon reviewing the document, the investigator or designee will 
explain the research study to the participant and answer any questions that may arise. The 
participant will have the opportunity to discuss the study with others, such as family members, 
or to take additional time before agreeing to participate. A participant may withdraw consent at 
any time throughout the course of the trial. A copy of the informed consent document will be 
given to the participant for her records. 
14.3 
Exclusion of Special Populations 
This protocol does not exclude any special populations. 
14.4 
Participant Confidentiality 
Participant confidentiality will be strictly held in trust by the participating investigators, their staff, 
the data coordinating center, and the NIDCR and its agents. This confidentiality will be extended 
to cover testing of biological samples and genetic tests in addition to the clinical information 
relating to study participants. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the NIDCR program official. 
The clinical monitor or other authorized representatives of the NIDCR may inspect all 
documents and records required to be maintained by the investigator, including but not limited 
to medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 


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Research information about the participants will be collected on either paper or electronic forms 
that will contain a study identification number rather than a name or any other information that 
could be used to identify the participant. Only the study staff will have access to the list that links 
the name and identification number. All paper research forms will be kept under lock and key. 
14.5 
Future Use of Stored Specimens 
Biological specimens will be stored indefinitely at one or both of the clinical sites for participants 
who provide consent. The consent form will allow participants to choose whether to have their 
samples stored indefinitely for future analyses. Any new use of study specimens, i.e., uses not 
described in this protocol, will require IRB review and approval. Stored specimens will be 
identifiable by participant identification number. The link between the participant’s name and the 
identification number will be maintained and stored confidentially by the study investigators. Any 
loss or unintentional destruction of the samples will be reported to the IRBs. If it is determined 
that no additional investigations are planned on the study specimens, the specimens will be 
disposed of in accordance with environmental protection laws, local regulations, and guidelines 
of the US federal government. 
The consent for future use of specimens will include the possibility that genetic information may 
be obtained from the specimens and shared with other researchers via an NIH database. In 
accordance with the NIH Genomic Data Sharing Policy, an IRB will need to ensure that data 
submission is consistent with the informed consent provided by the research participant.   
14.6 
Data Handling and Record Keeping 
All source documents will be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black or blue ink is required to ensure clarity of reproduced copies. When 
making corrections, the original entry will be crossed out with a single line, and the correction 
will be initialed and dated. No entries will be erased or overwritten. Data reported on case report 
forms will be consistent with the source documents or the discrepancies will be explained and 
documented. For this study, case report forms (paper or electronic) may serve as the source 
document for the collection of some types of data, such as questionnaire data or clinical 
examination findings. 
14.7 
Data Management Responsibilities 
The investigator will ensure the accuracy, completeness, legibility, and timeliness of the data 
collection. During the study, the investigator will maintain complete and accurate documentation 
for the study. All source documents and laboratory reports will be reviewed by the clinical team 
and data entry staff, who will ensure that all recorded information is accurate and complete. The 
data coordinating center will be responsible for data management, data quality review, and data 
analyses. 


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14.8 
Data Capture Methods 
Study staff will complete case report forms online via a web-based EDC system that has been 
validated and is compliant with Title 21 CFR Part 11. The data will be stored remotely at a 
central database managed by the data coordinating center. Data quality will be ensured through 
the data collection system’s continuous monitoring of data and real-time detection and 
correction of errors. All elements of data entry (i.e., time, date, verbatim text, and the name of 
the person performing the data entry) will be recorded in an electronic audit trail to allow all 
changes in the database to be monitored and maintained in accordance with federal 
regulations. 
14.9 
Types of Data 
Clinical examination findings, clinical test results, demographic and medical history data, 
outcome measures obtained from questionnaires, and genetic data will be collected in this 
study. 
14.10 Timing of Reports 
The data coordinating center will post study progress reports (i.e., screening, enrollment, and 
study progress reports) to the study website periodically throughout the study period, as 
determined by the NIDCR program official and the PI. The data coordinating center will also 
post data management reports that contain measures of data quality, such as the number of 
outstanding data queries and data completion rates. Study reports will be provided to the DSMB 
and IRBs prior to their periodic meetings. No interim statistical analyses are planned. 
14.11 Study Records Retention 
Records will be maintained for at least 3 years from the date that the final financial status report 
is submitted to the NIH. No records will be destroyed without the written consent of the NIH. 
14.12 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or the MOP. The 
noncompliance may be on the part of the participant, the investigator, or the study site staff. All 
protocol deviations will be promptly reported within the EDC system and to the NIDCR program 
official. Protocol deviations will also be reported to the IRBs and the DSMB according to their 
guidelines. As a result of deviations, corrective actions will be developed by the site(s) and 
implemented promptly. 


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15 
PUBLICATION/DATA SHARING POLICY 
This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH-funded research. It requires scientists to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. 
This study will comply with the NIH Data Sharing Policy, which ensures that data are as widely 
and freely available as possible while safeguarding the privacy of participants, and protecting 
confidential and proprietary data. Genetic and non-genetic data collected in this study will be 
stored for use by other researchers. Datasets will not contain any personal identifying 
information, and an IRB will need to determine whether the data may be released to 
researchers. 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted 
a clinical trials registration policy as a condition for publication. The ICMJE defines a clinical trial 
as any research project that prospectively assigns human participants to intervention or 
concurrent comparison or control groups to study the cause-and-effect relationship between a 
medical intervention and a health outcome. Medical interventions include drugs, surgical 
procedures, devices, behavioral treatments, process-of-care changes, and the like. Health 
outcomes include any biomedical or health-related measures obtained in patients or 
participants, including pharmacokinetic measures and AEs. The ICMJE policy requires that all 
clinical trials be registered in a public trials registry such as ClinicalTrials.gov, which is 
sponsored by the National Library of Medicine. Other biomedical journals are considering 
adopting similar policies. For interventional clinical trials performed under NIDCR grants and 
cooperative agreements, it is the grantee’s responsibility to register the trial in an acceptable 
registry, so the research results may be considered for publication in ICMJE member journals. 
The ICMJE does not review specific studies to determine whether registration is necessary; 
instead, the committee recommends that researchers who have questions about the need to 
register err on the side of registration or consult the editorial office of the journal in which they 
wish to publish. 
U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 or FDAAA), 
Title VIII, Section 801 mandates that a "responsible party" (i.e., the sponsor or designated 
principal investigator) register and report results of certain "applicable clinical trials:"  
Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I 
investigations, of a product subject to FDA regulation;  
Trials of Devices: Controlled trials with health outcomes of a product subject to FDA regulation 
(other than small feasibility studies) and pediatric post market surveillance studies. 
NIH grantees must take specific steps to ensure compliance with NIH implementation of 
FDAAA. 
 


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16 
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20. 
Tchivileva IE, Lim PF, Smith SB, Slade GD, Diatchenko L, McLean SA, Maixner W. 
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chronic musculoskeletal pain: a randomized, double-blind, placebo-controlled, crossover pilot 
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Mannisto PT, Kaakkola S. Catechol-O-methyltransferase (COMT): biochemistry, 
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22. 
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Nackley AG, Shabalina SA, Chivileva IE, Satterfield KS, Korchynskyy O, Maixner W, 
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24. 
Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J. Kinetics of 
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Erdal ME, Herken H, Yilmaz M, Bayazit YA. Significance of the catechol-O-
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Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, 
Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner W. Genetic basis for individual 


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2005;14(1):135-43. 
28. 
Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, Koeppe RA, Stohler CS, 
Goldman D. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain 
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29. 
Rakvag TT, Klepstad P, Baar C, Kvam TM, Dale O, Kaasa S, Krokan HE, Skorpen F. 
The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may 
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Diatchenko L, Nackley AG, Slade GD, Bhalang K, Belfer I, Max MB, Goldman D, 
Maixner W. Catechol-O-methyltransferase gene polymorphisms are associated with multiple 
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Nackley AG, Shabalina SA, Tchivileva IE, Satterfield K, Korchynskyi O, Makarov SS, 
Maixner W, Diatchenko L. Human catechol-O-methyltransferase haplotypes modulate protein 
expression by altering mRNA secondary structure. Science. 2006;314(5807):1930-3. 
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Nackley AG, Tan KS, Fecho K, Flood P, Diatchenko L, Maixner W. Catechol-O-
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Stucki G, Allen RR, Bellamy N, Carr DB, Chandler J, Cowan P, Dionne R, Galer BS, Hertz S, 
Jadad AR, Kramer LD, Manning DC, Martin S, McCormick CG, McDermott MP, McGrath P, 
Quessy S, Rappaport BA, Robbins W, Robinson JP, Rothman M, Royal MA, Simon L, Stauffer 
JW, Stein W, Tollett J, Wernicke J, Witter J. Core outcome measures for chronic pain clinical 
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34. 
Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for 
reporting parallel group randomized trials. Ann Intern Med. 2010;152(11):726-32. 
35. 
Manfredini D, Arveda N, Guarda-Nardini L, Segu M, Collesano V. Distribution of 
diagnoses in a population of patients with temporomandibular disorders. Oral Surg Oral Med 
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36. 
Schiffman E, Ohrbach R, Truelove E, Look J, Anderson G, Goulet J-P, List T, Svensson 
P, Gonzalez Y, Lobbezoo F, Michelotti A, Brooks SL, Ceusters W, Drangsholt M, Ettlin D, Gaul 
C, Goldberg L, Haythornthwaite J, Hollender L, Jensen R, John MT, deLaat A, deLeeuw R, 
Maixner W, van der Meulen M, Murray GM, Nixdorf DR, Palla S, Petersson A, Pionchon P, 
Smith B, Visscher CM, Zakrzewska J, Dworkin SF. Diagnostic Criteria for Temporomandibular 
Disorders (DC/TMD) for Clinical and Research Applications: Recommendations of the 
International RDC/TMD Consortium Network and Orofacial Pain Special Interest Group. J Oral 
Facial Pain Headache. 2014;28(1):6-27. 
37. 
Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell 
P, Campbell SM, Abeles M, Clark P, et al. The American College of Rheumatology 1990 Criteria 


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Rheum. 1990;33(2):160-72. 
38. 
Babor TF, Higgins-Biddle JC, Saunders JB, Monteiro MG. The Alcohol Use Disorders 
Identification Test Guidelines for Use in Primary Care, 2nd edition. WHO/MSD/MSB/01.6a, 
World Health Organization, Geneva, 2001. 
39. 
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1975;1(3):277-99. 
40. 
Underwood MR, Barnett AG, Vickers MR. Evaluation of two time-specific back pain 
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41. 
Ware J, Jr., Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of 
scales and preliminary tests of reliability and validity. Med Care. 1996;34(3):220-33. 
42. 
Guy W. ECDEU assessment manual for psychopharmacology. In: U.S. Department of 
Health EaW, editor. Rockville, MD1976. p. 217-22. 
43. 
Ohrbach R, Granger C, List T, Dworkin S. Preliminary development and validation of the 
Jaw Functional Limitation Scale. Community Dent Oral Epidemiol. 2008;36(3):228-36. 
44. 
Ohrbach R, Larsson P, List T. The jaw functional limitation scale: development, 
reliability, and validity of 8-item and 20-item versions. J Orofac Pain. 2008;22(3):219-30. 
45. 
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Soc Behav. 1983;24(4):385-96. 
46. 
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr 
Scand. 1983;67(6):361-70. 
47. 
Krogstad BS, Jokstad A, Dahl BL, Soboleva U. Somatic complaints, psychologic 
distress, and treatment outcome in two groups of TMD patients, one previously subjected to 
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48. 
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Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 
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49. 
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50. 
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51. 
Kosinski M, Bayliss MS, Bjorner JB, Ware JE, Jr., Garber WH, Batenhorst A, Cady R, 
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the HIT-6. Qual Life Res. 2003;12(8):963-74. 
 


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APPENDIX A: SCHEDULE OF EVENTS 
Study Phase: 
Pre-
screeninga 
Screening 
and 
Baseline 
Randomization and Treatment 
(1 week titration, 8 weeks maintenance, and 
1 week taper) 
Follow-Up 
Clinic Visit: 
 
V0 
V1b 
V2 
V3 
V4 
V5 
 
                    Study Day: 
≤ 28 days prior 
to V0 
7 to 21 days 
prior to V1  
0 
7 (+ 3) 
35 (± 7) 
63 (+ 6) 
77 (+ 7) 
Procedure 
 
 
 
 
 
 
 
Contact Information 
x 
 
 
 
 
 
 
Prescreening Interview Script 
x 
 
 
 
 
 
 
Informed Consentc 
 
x 
 
 
 
 
 
Eligibility Review 
x 
x 
x 
 
 
 
 
AUDIT Questionnaire 
 
x 
 
 
 
 
 
Smoking Questionnaire 
 
x 
 
 
 
 
x 
Alcohol Consumption per week  
 
 
x 
x 
x 
x 
x 
Demographic Information 
 
x 
 
 
 
 
 
Medical History and Review 
x 
x 
x 
x 
x 
x 
x 
Concomitant Medications 
 
x 
x 
x 
x 
x 
x 
Concomitant Therapies 
 
x 
x 
x 
x 
x 
x 
Dispense New Daily Symptom Diaries 
 
x 
x 
x 
x 
x 
 
Adverse Event Review 
 
 
x 
x 
x 
x 
x 
Collect Daily Symptom Diaries 
 
 
x 
x 
x 
x 
x 
Assess Compliance with Daily Symptom 
Diaries 
 
 
x 
x 
x 
x 
x 
Collect Confidence in Treatment Outcome 
 
 
x 
 
 
 
 
Randomization 
 
 
x 
 
 
 
 
Dispense Study Drug 
 
 
xd 
x 
x 
x 
 
Collect Study Drug Container(s) 
 
 
 
x 
x 
x 
x 
Assess Compliance with Study Drug 
 
 
 
x 
x 
x 
x 


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Study Phase: 
Pre-
screeninga 
Screening 
and 
Baseline 
Randomization and Treatment 
(1 week titration, 8 weeks maintenance, and 
1 week taper) 
Follow-Up 
Clinic Visit: 
 
V0 
V1b 
V2 
V3 
V4 
V5 
 
                    Study Day: 
≤ 28 days prior 
to V0 
7 to 21 days 
prior to V1  
0 
7 (+ 3) 
35 (± 7) 
63 (+ 6) 
77 (+ 7) 
Clinical Examinations and Tests 
 
 
 
 
 
 
 
Physical Measurements 
 
x 
 
 
 
 
 
Vital Signs 
 
x 
x 
x 
x 
x 
x 
Urine Pregnancy Test (females) 
 
x 
x 
x 
x 
x 
x 
Manual Tender Point Exam 
 
x 
 
 
 
 
 
TMD Examination 
 
x 
 
 
x 
x 
 
Heat and Pressure Pain Tests  
 
x 
 
 
x 
x 
 
12-Lead ECG 
 
x 
 
 
 
 
 
Blood Draw 
 
 
x 
 
 
x 
 
Schedule Next Visit 
x 
x 
x 
x 
x 
x 
 
Outcome Measure Questionnaires 
 
 
 
 
 
 
 
Symptom Inventory 
 
x 
x 
x 
x 
x 
x 
Fibromyalgia Questionnaire 
 
x 
 
 
 
 
 
Headache Questionnairee 
 
 
x 
 
 
 
 
SF-McGill Pain Questionnaire 
 
x 
 
x 
x 
x 
x 
Graded Chronic Pain Scalee 
 
 
x 
 
x 
x 
 
SF-12 Health Survey v2e 
 
 
x 
 
x 
x 
 
Jaw Functional Limitation Scalee 
 
 
x 
 
x 
x 
 
Perceived Stress Scalee 
 
 
x 
 
x 
x 
 
Hospital Anxiety and Depression Scalee 
 
 
x 
 
x 
x 
 
Pittsburgh Sleep Quality Indexe 
 
 
x 
 
x 
x 
 
Headache Impact Test (HIT-6) e 
 
 
x 
 
x 
x 
 
SCL-90R Somatization Scalee 
 
 
x 
 
x 
x 
 
Coping Strategies Questionnaire-Revisede 
 
 
x 
 
 
 
 


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Study Phase: 
Pre-
screeninga 
Screening 
and 
Baseline 
Randomization and Treatment 
(1 week titration, 8 weeks maintenance, and 
1 week taper) 
Follow-Up 
Clinic Visit: 
 
V0 
V1b 
V2 
V3 
V4 
V5 
 
                    Study Day: 
≤ 28 days prior 
to V0 
7 to 21 days 
prior to V1  
0 
7 (+ 3) 
35 (± 7) 
63 (+ 6) 
77 (+ 7) 
Patient Global Impression of Changee 
 
 
 
 
x 
x 
 
AUDIT = Alcohol Use Disorders Identification Test; ECG = electrocardiogram; SCL-90 = Symptom Checklist -90R; SF = Short Form; V = Visit 
a May occur by phone or at a clinic visit, and may be combined with the Screening and Baseline Visit (Visit 0). 
b If Visit 1 cannot occur within 3 weeks of Visit 0 and the participant is to remain in the study, then Visit 0 will be repeated as an unscheduled visit. The timing of 
Visits 3-6 and their windows are established from the date of Visit 1. 
c Includes consent for study participation, consent to store biological specimens for future studies, and Health Insurance Portability and Accountability Act 
statement, if applicable. 
d The first dose of study drug should be taken in the evening of the Day 1. 
e Questionnaires will be distributed at Visit 0 and the participant will return completed questionnaires at Visit 1.


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APPENDIX B: PACKAGE INSERT FOR PROPRANOLOL HYDROCHLORIDE 
EXTENDED-RELEASE 
 
 


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Propranolol hydrochloride extended-release capsules 
 
Rx only 
 
DESCRIPTION 
Propranolol hydrochloride is a synthetic beta-adrenergic receptor-blocking agent chemically 
described as 2-Propanol, 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-, hydrochloride,(±)-. 
Its molecular and structural formulae are: 
 
 
C16H21NO2  · HCl 
 
Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water 
and ethanol. Its molecular weight is 295.80. 
 
Propranolol hydrochloride extended-release capsules are formulated to provide a sustained 
release of propranolol hydrochloride. Propranolol hydrochloride extended-release capsules are 
available as 60 mg, 80 mg, 120 mg, and 160 mg capsules for oral administration. 
 
The inactive ingredients contained in propranolol hydrochloride extended-release capsules are: 
cellulose, ethylcellulose, gelatin capsules, hypromellose, and titanium dioxide. In addition, 
propranolol hydrochloride extended-release capsules 60 mg, 80 mg, and 120 mg capsules contain 
D&C Red No. 28 and FD&C Blue No. 1; propranolol hydrochloride extended-release capsules 
160 mg capsules contain FD&C Blue No. 1. 
 
These capsules comply with USP Dissolution Test 1. 
 
CLINICAL PHARMACOLOGY 
General 
Propranolol is a nonselective, beta-adrenergic receptor-blocking agent possessing no other 
autonomic nervous system activity. It specifically competes with beta-adrenergic receptor- 
stimulating agents for available receptor sites. When access to beta-receptor sites is blocked by 
propranolol, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation 
are decreased proportionately. At dosages greater than required for beta blockade, propranolol 
also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action 
potential. The significance of the membrane action in the treatment of arrhythmias is uncertain. 
 


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Propranolol hydrochloride extended-release capsules should not be considered a simple mg-for­ 
mg substitute for conventional propranolol and the blood levels achieved do not match (are lower 
than) those of two to four times daily dosing with the same dose (see DOSAGE AND 
ADMINISTRATION). When changing to propranolol hydrochloride extended-release capsules 
from conventional propranolol, a possible need for retitration upwards should be considered, 
especially to maintain effectiveness at the end of the dosing interval. In most clinical settings, 
however, such as hypertension or angina where there is little correlation between plasma levels 
and clinical effect, propranolol hydrochloride extended-release capsules have been 
therapeutically equivalent to the same mg dose of conventional propranolol hydrochloride 
extended-release capsules as assessed by 24-hour effects on blood pressure and on 24-hour 
exercise responses of heart rate, systolic pressure, and rate pressure product. 
 
 
Mechanism of Action 
The mechanism of the antihypertensive effect of propranolol has not been established. Among 
the factors that may be involved in contributing to the antihypertensive action include: 
(1) decreased cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of 
tonic sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral 
resistance may increase initially, it readjusts to or below the pretreatment level with chronic use 
of propranolol. Effects of propranolol on plasma volume appear to be minor and somewhat 
variable. 
 
In angina pectoris, propranolol generally reduces the oxygen requirement of the heart at any 
given level of effort by blocking the catecholamine-induced increases in the heart rate, systolic 
blood pressure, and the velocity and extent of myocardial contraction. Propranolol may increase 
oxygen requirements by increasing left ventricular fiber length, end diastolic pressure, and 
systolic ejection period. The net physiologic effect of beta-adrenergic blockade is usually 
advantageous and is manifested during exercise by delayed onset of pain and increased work 
capacity. 
 
Propranolol exerts its antiarrhythmic effects in concentrations associated with beta-adrenergic 
blockade, and this appears to be its principal antiarrhythmic mechanism of action. In dosages 
greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like 
membrane action which affects the cardiac action potential. The significance of the membrane 
action in the treatment of arrhythmias is uncertain. 
 
The mechanism of the anti-migraine effect of propranolol has not been established. Beta-
adrenergic receptors have been demonstrated in the pial vessels of the brain. 
 
 
PHARMACOKINETICS AND DRUG METABOLISM 
Absorption 
Propranolol is highly lipophilic and almost completely absorbed after oral administration. 
However, it undergoes high first pass metabolism by the liver and on average, only about 25% of 


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propranolol reaches the systemic circulation. Propranolol hydrochloride extended-release 
capsules (60, 80, 120, and 160 mg) release propranolol HCl at a controlled and predictable rate. 
Peak blood levels following dosing with propranolol hydrochloride extended-release capsules 
occur at about 6 hours. 
 
The effect of food on propranolol hydrochloride extended-release capsules bioavailability has not 
been investigated. 
 
 
Distribution 
Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha-1-
acid glycoprotein). The binding is enantiomer-selective. The S(–)-enantiomer is preferentially 
bound to alpha-1-glycoprotein and the R(+)-enantiomer preferentially bound to albumin. The 
volume of distribution of propranolol is approximately 4 liters/kg. 
 
Propranolol crosses the blood-brain barrier and the placenta, and is distributed into breast milk. 
 
 
Metabolism and Elimination 
Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol 
is metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), 
N-dealkylation followed by further side-chain oxidation, and direct glucuronidation. It has been 
estimated that the percentage contributions of these routes to total metabolism are 42%, 41% and 
17%, respectively, but with considerable variability between individuals. The four major 
metabolites are propranolol glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate 
conjugates of 4-hydroxy propranolol. 
 
In-vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly 
by polymorphic CYP2D6. Side-chain oxidation is mediated mainly by CYP1A2 and to some 
extent by CYP2D6. 4-hydroxy propranolol is a weak inhibitor of CYP2D6. 
 
Propranolol is also a substrate of CYP2C19 and a substrate for the intestinal efflux transporter, p-
glycoprotein (p-gp). Studies suggest however that p-gp is not dose-limiting for intestinal 
absorption of propranolol in the usual therapeutic dose range. 
 
In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers (EMs) 
and poor metabolizers (PMs) with respect to oral clearance or elimination half-life. Partial 
clearance of 4-hydroxy propranolol was significantly higher and naphthyloxyactic acid was 
significantly lower in EMs than PMs. 
 
When measured at steady state over a 24-hour period the areas under the propranolol plasma 
concentration-time curve (AUCs) for the propranolol hydrochloride extended-release capsules 
are approximately 60% to 65% of the AUCs for a comparable divided daily dose of propranolol 
hydrochloride extended-release capsules. The lower AUCs for the propranolol hydrochloride 


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extended-release capsules are due to greater hepatic metabolism of propranolol, resulting from 
the slower rate of absorption of propranolol. Over a twenty-four (24) hour period, blood levels 
are fairly constant for about twelve (12) hours, then decline exponentially. The apparent plasma 
half-life is about 10 hours. 
 
 
Enantiomers 
Propranolol is a racemic mixture of two enantiomers, R(+) and S(–). The S(–)-enantiomer is 
approximately 100 times as potent as the R(+)-enantiomer in blocking beta adrenergic receptors. 
In normal subjects receiving oral doses of racemic propranolol, S(–)-enantiomer concentrations 
exceeded those of the R(+)-enantiomer by 40-90% as a result of stereoselective hepatic 
metabolism. Clearance of the pharmacologically active S(–)-propranolol is lower than R(+)­ 
propranolol after intravenous and oral doses. 
 
 
Special Population 
Geriatric 
The pharmacokinetics of propranolol hydrochloride extended-release capsules have not been 
investigated in patients over 65 years of age. 
 
In a study of 12 elderly (62-79 years old) and 12 young (25-33 years old) healthy subjects, the 
clearance of S-enantiomer of propranolol was decreased in the elderly. Additionally, the half-life 
of both the R- and S-propranolol were prolonged in the elderly compared with the young 
(11 hours vs. 5 hours). 
 
Clearance of propranolol is reduced with aging due to decline in oxidation capacity (ring 
oxidation and side chain oxidation). Conjugation capacity remains unchanged. In a study of 32 
patients age 30 to 84 years given a single 20-mg dose of propranolol, an inverse correlation was 
found between age and the partial metabolic clearances to 4-hydroxypropranolol (40HP ring 
oxidation) and to naphthoxylactic acid (NLA-side chain oxidation). No correlation was found 
between age and the partial metabolic clearance to propranolol glucuronide (PPLG conjugation). 
 
Gender 
In a study of 9 healthy women and 12 healthy men, neither the administration of testosterone nor 
the regular course of the menstrual cycle affected the plasma binding of the propranolol 
enantiomers. In contrast, there was a significant, although non-enantioselective diminution of the 
binding of propranolol after treatment with ethinyl estradiol. These findings are inconsistent with 
another study, in which administration of testosterone cypionate confirmed the stimulatory role 
of this hormone on propranolol metabolism and concluded that the clearance of propranolol in 
men is dependent on circulating concentrations of testosterone. In women, none of the metabolic 
clearances for propranolol showed any significant association with either estradiol or 
testosterone. 
 
 


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Race 
A study conducted in 12 Caucasian and 13 African-American male subjects taking propranolol, 
showed that at steady state, the clearance of R(+)- and S(–)-propranolol were about 76% and 
53% higher in African-Americans than in Caucasians, respectively. 
 
Chinese subjects had a greater proportion (18% to 45% higher) of unbound propranolol in 
plasma compared to Caucasians, which was associated with a lower plasma concentration of 
alpha-1-acid glycoprotein. 
 
Renal Insufficiency 
The pharmacokinetics of propranolol hydrochloride extended-release capsules have not been 
investigated in patients with renal insufficiency. 
 
In a study conducted in 5 patients with chronic renal failure, 6 patients on regular dialysis, and 5 
healthy subjects, who received a single oral dose of 40 mg of propranolol, the peak plasma 
concentrations (Cmax) of propranolol in the chronic renal failure group were 2 to 3-fold higher 
(161±41 ng/mL) than those observed in the dialysis patients (47±9 ng/mL) and in the healthy 
subjects (26±1 ng/mL). Propranolol plasma clearance was also reduced in the patients with 
chronic renal failure. Studies have reported a delayed absorption rate and a reduced half-life of 
propranolol in patients with renal failure of varying severity. Despite this shorter plasma half-
life, propranolol peak plasma levels were 3-4 times higher and total plasma levels of metabolites 
were up to 3 times higher in these patients than in subjects with normal renal function. 
 
Chronic renal failure has been associated with a decrease in drug metabolism via down 
regulation of hepatic cytochrome P450 activity resulting in a lower “first-pass” clearance. 
Propranolol is not significantly dialyzable. Hepatic Insufficiency 
The pharmacokinetics of propranolol hydrochloride extended-release capsules have not been 
investigated in patients with hepatic insufficiency. 
 
Propranolol is extensively metabolized by the liver. In a study conducted in 6 patients with 
cirrhosis and 7 healthy subjects receiving 160 mg of a long-acting preparation of propranolol 
once a day for 7 days, the steady-state propranolol concentration in patients with cirrhosis was 
increased 2.5-fold in comparison to controls. In the patients with cirrhosis, the half-life obtained 
after a single intravenous dose of 10 mg propranolol increased to 7.2 hours compared to 
2.9 hours in control (see PRECAUTIONS). 
 
Drug Interactions 
All drug interaction studies were conducted with propranolol. There are no data on drug 
interactions with propranolol hydrochloride extended-release capsules capsules. 
 
Interactions with Substrates, Inhibitors or Inducers of Cytochrome P-450 Enzymes 
Because propranolol’s metabolism involves multiple pathways in the Cytochrome P-450 system 
(CYP2D6, 1A2, 2C19), co-administration with drugs that are metabolized by, or affect the 


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activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant 
drug interactions (see Drug Interactions under PRECAUTIONS). 
 
Substrates or Inhibitors of CYP2D6 
Blood levels and/or toxicity of propranolol may be increased by co-administration with 
substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavudin, fluoxetine, 
paroxetine, quinidine, and ritonavir. No interactions were observed with either ranitidine or 
lansoprazole. 
 
Substrates or Inhibitors of CYP1A2 
Blood levels and/or toxicity of propranolol may be increased by co-administration with 
substrates or inhibitors of CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, 
isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan. 
 
Substrates or Inhibitors of CYP2C19 
Blood levels and/or toxicity of propranolol may be increased by co-administration with 
substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, 
tenioposide, and tolbutamide. No interaction was observed with omeprazole. 
 
Inducers of Hepatic Drug Metabolism 
Blood levels of propranolol may be decreased by co-administration with inducers such as 
rifampin, ethanol, phenytoin, and phenobarbital. Cigarette smoking also induces hepatic 
metabolism and has been shown to increase up to 77% the clearance of propranolol, resulting in 
decreased plasma concentrations. 
 
Cardiovascular Drugs 
Antiarrhythmics 
The AUC of propafenone is increased by more than 200% by co-administration of propranolol. 
 
The metabolism of propranolol is reduced by co-administration of quinidine, leading to a two to 
three fold increased blood concentration and greater degrees of clinical beta-blockade. 
 
The metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25% 
increase in lidocaine concentrations. 
 
Calcium Channel Blockers 
The mean Cmax and AUC of propranolol are increased respectively, by 50% and 30% by 
co-administration of nisoldipine and by 80% and 47%, by co-administration of nicardipine. 
 
The mean Cmax and AUC of nifedipine are increased by 64% and 79%, respectively, by co-
administration of propranolol. 
 
Propranolol does not affect the pharmacokinetics of verapamil and norverapamil. Verapamil does 
not affect the pharmacokinetics of propranolol. 


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Non-Cardiovascular Drugs 
Migraine Drugs 
Administration of zolmitriptan or rizatriptan with propranolol resulted in increased 
concentrations of zolmitriptan (AUC increased by 56% and Cmax by 37%) or rizatriptan (the 
AUC and Cmax were increased by 67% and 75%, respectively). 
 
Theophylline 
Co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% 
to 52%. 
 
Benzodiazepines 
Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of 
diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of propranolol. 
 
The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by 
co-administration of propranolol. 
 
Neuroleptic Drugs 
Co-administration of long-acting propranolol at doses greater than or equal to 160 mg/day 
resulted in increased thioridazine plasma concentrations ranging from 55% to 369% and 
increased thioridazine metabolite (mesoridazine) concentrations ranging from 33% to 209%. 
 
Co-administration of chlorpromazine with propranolol resulted in a 70% increase in propranolol 
plasma level. 
 
Anti-Ulcer Drugs 
Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased 
propranolol AUC and Cmax by 46% and 35%, respectively. Co-administration with aluminum 
hydroxide gel (1200 mg) may result in a decrease in propranolol concentrations. 
 
Co-administration of metoclopramide with the long-acting propranolol did not have a significant 
effect on propranolol’s pharmacokinetics. 
 
Lipid Lowering Drugs 
Co-administration of cholestyramine or colestipol with propranolol resulted in up to 50% 
decrease in propranolol concentrations. 
 
Co-administration of propranolol with lovastatin or pravastatin, decreased 18% to 23% the AUC 
of both, but did not alter their pharmacodynamics. Propranolol did not have an effect on the 
pharmacokinetics of fluvastatin. 
 
Warfarin 
Concomitant administration of propranolol and warfarin has been shown to increase warfarin 
bioavailability and increase prothrombin time. 


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PHARMACODYNAMICS AND CLINICAL EFFECTS 
Hypertension 
In a retrospective, uncontrolled study, 107 patients with diastolic blood pressure 
110 to 150 mmHg received propranolol 120 mg t.i.d. for at least 6 months, in addition to 
diuretics and potassium, but with no other hypertensive agent. Propranolol contributed to control 
of diastolic blood pressure, but the magnitude of the effect of propranolol on blood pressure 
cannot be ascertained. 
 
Four double-blind, randomized, crossover studies were conducted in a total of 74 patients with 
mild or moderately severe hypertension treated with propranolol hydrochloride extended-release 
capsules 160 mg once daily or propranolol 160 mg given either once daily or in two 80 mg 
doses. Three of these studies were conducted over a 4-week treatment period. One study was 
assessed after a 24-hour period. Propranolol hydrochloride extended-release capsules were as 
effective as propranolol in controlling hypertension (pulse rate, systolic and diastolic blood 
pressure) in each of these trials. 
 
Angina Pectoris 
In a double-blind, placebo-controlled study of 32 patients of both sexes, aged 32 to 69 years,  
with stable angina, propranolol 100 mg t.i.d. was administered for 4 weeks and shown to be more 
effective than placebo in reducing the rate of angina episodes and in prolonging total exercise 
time. 
 
Twelve male patients with moderately severe angina pectoris were studied in a double-blind, 
crossover study. Patients were randomized to either Propranolol hydrochloride extended-release 
capsules 160 mg daily or conventional propranolol 40 mg four times a day for 2 weeks. 
 
Nitroglycerine tablets were allowed during the study. Blood pressure, heart rate and ECG's were 
recorded during serial exercise treadmill testing. Propranolol hydrochloride extended-release 
capsules were as effective as conventional propranolol for exercise heart rate, systolic and 
diastolic blood pressure, duration of anginal pain and ST-segment depression before or after 
exercise, exercise duration, angina attack rate and nitroglycerine consumption. 
 
In another double-blind, randomized, crossover trial, the effectiveness of propranolol 
hydrochloride extended-release capsules 160 mg daily and conventional propranolol 40 mg four 
times a day were evaluated in 13 patients with angina. ECG's were recorded while patients 
exercised until angina developed. Propranolol hydrochloride extended-release capsules were as 
effective as conventional propranolol for amount of exercise performed, ST-segment depression, 
number of anginal attacks, amount of nitroglycerine consumed, systolic and diastolic blood 
pressures and heart rate at rest and after exercise. 
 


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Migraine 
In a 34-week, placebo-controlled, 4-period, dose-finding crossover study with a double-blind 
randomized treatment sequence, 62 patients with migraine received propranolol 20 to 80 mg 3 or 
4 times daily. The headache unit index, a composite of the number of days with headache and the 
associated severity of the headache, was significantly reduced for patients receiving propranolol 
as compared to those on placebo. 
 
Hypertrophic Subaortic Stenosis 
In an uncontrolled series of 13 patients with New York Heart Association (NYHA) class 2 or 3 
symptoms and hypertrophic subaortic stenosis diagnosed at cardiac catheterization, oral 
propranolol 40-80 mg t.i.d. was administered and patients were followed for up to 17 months. 
Propranolol was associated with improved NYHA class for most patients. 
 
INDICATIONS AND USAGE 
Hypertension 
Propranolol hydrochloride extended-release capsules are indicated in the management of 
hypertension. It may be used alone or used in combination with other antihypertensive agents, 
particularly a thiazide diuretic. Propranolol hydrochloride extended-release capsules is not 
indicated in the management of hypertensive emergencies. 
 
Angina Pectoris Due to Coronary Atherosclerosis 
Propranolol hydrochloride extended-release capsules are indicated to decrease angina frequency 
and increase exercise tolerance in patients with angina pectoris. 
 
Migraine 
Propranolol hydrochloride extended-release capsules are indicated for the prophylaxis of 
common migraine headache. The efficacy of propranolol in the treatment of a migraine attack 
that has started has not been established, and propranolol is not indicated for such use. 
 
Hypertrophic Subaortic Stenosis 
Propranolol hydrochloride extended-release capsules improve NYHA functional class in 
symptomatic patients with hypertrophic subaortic stenosis. 
 
CONTRAINDICATIONS 
Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than 
first-degree block; 3) bronchial asthma; and 4) in patients with known hypersensitivity to 
propranolol hydrochloride. 
 
WARNINGS 
Angina Pectoris 
There have been reports of exacerbation of angina and, in some cases, myocardial infarction, 
following abrupt discontinuance of propranolol therapy. Therefore, when discontinuance of 
propranolol is planned, the dosage should be gradually reduced over at least a few weeks, and the 
patient should be cautioned against interruption or cessation of therapy without the physician's 


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advice. If propranolol therapy is interrupted and exacerbation of angina occurs, it usually is 
advisable to reinstitute propranolol therapy and take other measures appropriate for the 
management of unstable angina pectoris. Since coronary artery disease may be unrecognized, it 
may be prudent to follow the above advice in patients considered at risk of having occult 
atherosclerotic heart disease who are given propranolol for other indications. 
 
Hypersensitivity and Skin Reactions 
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated 
with the administration of propranolol (see ADVERSE REACTIONS). 
 
Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, 
exfoliative dermatitis, erythema multiforme, and urticaria, have been reported with use of 
propranolol (see ADVERSE REACTIONS). 
 
Cardiac Failure 
Sympathetic stimulation may be a vital component supporting circulatory function in patients 
with congestive heart failure, and its inhibition by beta blockade may precipitate more severe 
failure. Although beta blockers should be avoided in overt congestive heart failure, some have 
been shown to be highly beneficial when used with close follow-up in patients with a history of 
failure who are well compensated and are receiving diuretics as needed. Beta-adrenergic 
blocking agents do not abolish the inotropic action of digitalis on heart muscle. 
 
In Patients without a History of Heart Failure, continued use of beta blockers can, in some cases, 
lead to cardiac failure. 
 
Nonallergic Bronchospasm (e.g., Chronic Bronchitis, Emphysema) 
In general, patients with bronchospastic lung disease should not receive beta-blockers. 
Propranolol should be administered with caution in this setting since it may provoke a bronchial 
asthmatic attack by blocking bronchodilation produced by endogenous and exogenous 
catecholamine stimulation of beta-receptors. 
 
Major Surgery 
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major 
surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may 
augment the risks of general anesthesia and surgical procedures. 
 
Diabetes and Hypoglycemia 
Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and 
symptoms (pulse rate and pressure changes) of acute hypoglycemia, especially in labile insulin- 
dependent diabetics. In these patients, it may be more difficult to adjust the dosage of insulin. 
 
Propranolol therapy, particularly when given to infants and children, diabetic or not, has been 
associated with hypoglycemia especially during fasting as in preparation for surgery. 


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Hypoglycemia has been reported in patients taking propranolol after prolonged physical exertion 
and in patients with renal insufficiency. 
 
Thyrotoxicosis 
Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism. Therefore, abrupt 
withdrawal of propranolol may be followed by an exacerbation of symptoms of hyperthyroidism, 
including thyroid storm. Propranolol may change thyroid-function tests, increasing T4 and 
reverse T3, and decreasing T3. 
 
Wolff-Parkinson-White Syndrome 
Beta-adrenergic blockade in patients with Wolff-Parkinson-White syndrome and tachycardia has 
been associated with severe bradycardia requiring treatment with a pacemaker. In one case, this 
result was reported after an initial dose of 5 mg propranolol. 
 
PRECAUTIONS 
General 
Propranolol should be used with caution in patients with impaired hepatic or renal function. 
Propranolol hydrochloride extended-release capsules are not indicated for the treatment of 
hypertensive emergencies. 
 
Beta-adrenergic receptor blockade can cause reduction of intraocular pressure. Patients should be 
told that propranolol hydrochloride extended-release capsules may interfere with the glaucoma 
screening test. Withdrawal may lead to a return of increased intraocular pressure. 
 
While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of 
allergens may be more reactive to repeated challenge, either accidental, diagnostic, or 
therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat 
allergic reaction. 
 
Clinical Laboratory Tests 
In patients with hypertension, use of propranolol has been associated with elevated levels of 
serum potassium, serum transaminases, and alkaline phosphatase. In severe heart failure, the use 
of propranolol has been associated with increases in Blood Urea Nitrogen. 
 
Drug Interactions 
Caution should be exercised when propranolol hydrochloride extended-release capsules are 
administered with drugs that have an affect on CYP2D6, 1A2, or 2C19 metabolic pathways. Co­ 
administration of such drugs with propranolol may lead to clinically relevant drug interactions 
and changes on its efficacy and/or toxicity (see Drug Interactions in PHARMACOKINETICS 
AND DRUG METABOLISM). Alcohol when used concomitantly with propranolol, may 
increase plasma levels of propranolol. 
 
 
 


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Cardiovascular Drugs 
Antiarrhythmics 
Propafenone has negative inotropic and beta-blocking properties that can be additive to those of 
propranolol. 
 
Quinidine increases the concentration of propranolol and produces greater degrees of clinical 
beta-blockade and may cause postural hypotension. 
 
Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be 
additive to those seen with β-blockers such as propranolol. 
 
The clearance of lidocaine is reduced with administration of propranolol. Lidocaine toxicity has 
been reported following co-administration with propranolol. 
 
Caution should be exercised when administering propranolol hydrochloride extended-release 
capsules with drugs that slow A-V nodal conduction, e.g., lidocaine and calcium channel 
blockers. 
 
Digitalis Glycosides 
 
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart 
rate. Concomitant use can increase the risk of bradycardia. 
 
Calcium Channel Blockers 
Caution should be exercised when patients receiving a beta-blocker are administered a calcium- 
channel-blocking drug with negative inotropic and/or chronotropic effects. Both agents may 
depress myocardial contractility or atrioventricular conduction. 
 
There have been reports of significant bradycardia, heart failure, and cardiovascular collapse 
with concurrent use of verapamil and beta-blockers. 
 
Co-administration of propranolol and diltiazem in patients with cardiac disease has been 
associated with bradycardia, hypotension, high degree heart block, and heart failure. 
 
ACE Inhibitors 
When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the 
setting of acute myocardial infarction. 
 
The antihypertensive effects of clonidine may be antagonized by beta-blockers. Propranolol 
hydrochloride extended-release capsules should be administered cautiously to patients 
withdrawing from clonidine. 
 
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Prazosin has been associated with prolongation of first dose hypotension in the presence of beta-
blockers. 
 
Postural hypotension has been reported in patients taking both beta-blockers and terazosin or 
doxazosin. 
 
Reserpine 
Patients receiving catecholamine-depleting drugs, such as reserpine should be closely observed 
for excessive reduction of resting sympathetic nervous activity, which may result in hypotension, 
marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension. 
 
Inotropic Agents 
Patients on long-term therapy with propranolol may experience uncontrolled hypertension if 
administered epinephrine as a consequence of unopposed alpha-receptor stimulation. 
Epinephrine is therefore not indicated in the treatment of propranolol overdose (see 
OVERDOSAGE). 
 
Isoproterenol and Dobutamine 
Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by 
administration of such agents, e.g., dobutamine or isoproterenol. Also, propranolol may reduce 
sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for 
myocardial ischemia. 
 
Non-Cardiovascular Drugs 
Nonsteroidal Anti-Inflammatory Drugs 
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to blunt the antihypertensive 
effect of beta-adrenoreceptor blocking agents. 
 
Administration of indomethacin with propranolol may reduce the efficacy of propranolol in 
reducing blood pressure and heart rate. 
 
Antidepressants 
The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when 
administered with beta-blockers by interfering with the beta blocking activity of propranolol. 
 
Anesthetic Agents 
Methoxyflurane and trichloroethylene may depress myocardial contractility when administered 
with propranolol. 
 
Warfarin 
Propranolol when administered with warfarin increases the concentration of warfarin. 
Prothrombin time, therefore, should be monitored. 
 
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Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and 
haloperidol. 
 
Thyroxine 
Thyroxine may result in a lower than expected T3 concentration when used concomitantly with 
propranolol. 
 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
In dietary administration studies in which mice and rats were treated with propranolol 
hydrochloride for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of 
drug-related tumorigenesis. On a body surface area basis, this dose in the mouse and rat is, 
respectively, about equal to and about twice the maximum recommended human oral daily dose 
(MRHD) of 640 mg propranolol hydrochloride. In a study in which both male and female rats 
were exposed to propranolol hydrochloride in their diets at concentrations of up to 0.05% (about 
50 mg/kg body weight and less than the MRHD), from 60 days prior to mating and throughout 
pregnancy and lactation for two generations, there were no effects on fertility. Based on differing 
results from Ames Tests performed by different laboratories, there is equivocal evidence for a 
genotoxic effect of propranolol in bacteria (S. typhimurium strain TA 1538). 
 
Pregnancy: Pregnancy Category C 
In a series of reproductive and developmental toxicology studies, propranolol was given to rats 
by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day, but not 
at doses of 80 mg/kg/day (equivalent to the MRHD on a body surface area basis), treatment was 
associated with embryotoxicity (reduced litter size and increased resorption rates) as well as 
neonatal toxicity (deaths). Propranolol hydrochloride also was administered (in the feed) to 
rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times 
the maximum recommended human oral daily dose). No evidence of embryo or neonatal toxicity 
was noted. 
 
There are no adequate and well-controlled studies in pregnant women. Intrauterine growth 
retardation, small placentas, and congenital abnormalities have been reported in neonates whose 
mothers received propranolol during pregnancy. Neonates whose mothers are receiving 
propranolol at parturition have exhibited bradycardia, hypoglycemia and/or respiratory 
depression. Adequate facilities for monitoring such infants at birth should be available. 
Propranolol hydrochloride extended-release capsules should be used during pregnancy only if the 
potential benefit justifies the potential risk to the fetus. 
 
Nursing Mothers 
Propranolol is excreted in human milk. Caution should be exercised when propranolol 
hydrochloride extended-release capsules are administered to a nursing woman. 
 
Pediatric Use 
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Bronchospasm and congestive heart failure have been reported coincident with the 
administration of propranolol therapy in pediatric patients. 
 
Geriatric Use 
Clinical studies of propranolol hydrochloride extended-release capsules did not include sufficient 
numbers of subjects aged 65 and over to determine whether they respond differently from 
younger subjects. Other reported clinical experience has not identified differences in responses 
between the elderly and younger patients. In general, dose selection for an elderly patient should 
be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency 
of the decreased hepatic, renal or cardiac function, and of concomitant disease or other drug 
therapy. 
 
ADVERSE REACTIONS 
The following adverse events were observed and have been reported in patients using 
propranolol. 
 
Cardiovascular: Bradycardia; congestive heart failure; intensification of AV block; 
hypotension; paresthesia of hands; thrombocytopenic purpura; arterial insufficiency, usually of 
the Raynaud type. 
 
Central Nervous System: Light-headedness; mental depression manifested by insomnia, 
lassitude, weakness, fatigue; catatonia; visual disturbances; hallucinations; vivid dreams; an acute 
reversible syndrome characterized by disorientation for time and place, short-term memory loss, 
emotional lability, slightly clouded sensorium, and decreased performance on 
neuropsychometrics. For immediate release formulations, fatigue, lethargy, and vivid dreams 
appear dose related. 
 
Gastrointestinal: Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, 
constipation, mesenteric arterial thrombosis, ischemic colitis. 
 
Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions; pharyngitis 
and agranulocytosis; erythematous rash; fever combined with aching and sore throat; 
laryngospasm; respiratory distress. 
 
Respiratory: Bronchospasm. 
 
Hematologic: Agranulocytosis, nonthrombocytopenic purpura, and thrombocytopenic purpura. 
 
Autoimmune: Systemic lupus erythematosus (SLE). 
 
Skin and mucous membranes: Stevens-Johnson Syndrome, toxic epidermal necrolysis, dry 
eyes, exfoliative dermatitis, erythema multiforme, urticaria, alopecia, SLE-like reactions, and 
psoriasisiform rashes. Oculomucocutaneous syndrome involving the skin, serous membranes, 


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and conjunctivae reported for a beta-blocker (practolol) have not been associated with 
propranolol. 
 
Genitourinary: Male impotence; Peyronie's disease. 
 
OVERDOSAGE 
Propranolol is not significantly dialyzable. In the event of overdosage or exaggerated response, 
the following measures should be employed: 
 
General: If ingestion is or may have been recent, evacuate gastric contents, taking care to 
prevent pulmonary aspiration. 
 
Supportive Therapy: Hypotension and bradycardia have been reported following propranolol 
overdose and should be treated appropriately. Glucagon can exert potent inotropic and 
chronotropic effects and may be particularly useful for the treatment of hypotension or depressed 
myocardial function after a propranolol overdose. Glucagon should be administered as 
50-150 mcg/kg intravenously followed by continuous drip of 1-5 mg/hour for positive 
chronotropic effect. Isoproterenol, dopamine or phosphodiesterase inhibitors may also be useful. 
Epinephrine, however, may provoke uncontrolled hypertension. Bradycardia can be treated with 
atropine or isoproterenol. Serious bradycardia may require temporary cardiac pacing. 
 
The electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output 
balance must be monitored. Isoproterenol and aminophylline may be used for bronchospasm. 
 
DOSAGE AND ADMINISTRATION 
General 
Propranolol hydrochloride extended-release capsules provide propranolol hydrochloride in a 
sustained-release capsule for administration once daily. If patients are switched from propranolol 
hydrochloride tablets to propranolol hydrochloride extended-release capsules, care should be 
taken to assure that the desired therapeutic effect is maintained. Propranolol hydrochloride 
extended-release capsules should not be considered a simple mg-for-mg substitute for 
propranolol hydrochloride tablets. Propranolol hydrochloride extended-release capsules have 
different kinetics and produces lower blood levels. Retitration may be necessary, especially to 
maintain effectiveness at the end of the 24-hour dosing interval. 
 
Hypertension 
The usual initial dosage is 80 mg propranolol hydrochloride extended-release capsules once 
daily, whether used alone or added to a diuretic. The dosage may be increased to 120 mg once 
daily or higher until adequate blood pressure control is achieved. The usual maintenance dosage 
is 120 to 160 mg once daily. In some instances a dosage of 640 mg may be required. The time 
needed for full hypertensive response to a given dosage is variable and may range from a few 
days to several weeks. 
 
 
 


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Angina Pectoris 
Starting with 80 mg propranolol hydrochloride extended-release capsules once daily, dosage 
should be gradually increased at three- to seven-day intervals until optimal response is obtained. 
Although individual patients may respond at any dosage level, the average optimal dosage 
appears to be 160 mg once daily. In angina pectoris, the value and safety of dosage exceeding 
320 mg per day have not been established. 
 
If treatment is to be discontinued, reduce dosage gradually over a period of a few weeks (see 
“WARNINGS”). 
 
Migraine 
The initial oral dose is 80 mg propranolol hydrochloride extended-release capsules once daily. 
The usual effective dose range is 160 to 240 mg once daily. The dosage may be increased 
gradually to achieve optimal migraine prophylaxis. If a satisfactory response is not obtained 
within four to six weeks after reaching the maximal dose, propranolol hydrochloride extended- 
release capsules therapy should be discontinued. It may be advisable to withdraw the drug 
gradually over a period of several weeks depending on the patient's age, comorbidity, and dose of 
propranolol hydrochloride extended-release capsules. 
 
Hypertrophic Subaortic Stenosis 
The usual dosage is 80 to 160 mg propranolol hydrochloride extended-release capsules once 
daily. 
 
HOW SUPPLIED 
Propranolol hydrochloride extended-release capsules 
 
Each white capsule, identified by 3 narrow bands, 1 wide band, and “AK 60,” contains 60 mg of 
propranolol hydrochloride in bottles of 100 (NDC 43478-900-88). 
 
Each white/light blue capsule, identified by 3 narrow bands, 1 wide band, and “AK 80,” contains 
80 mg of propranolol hydrochloride in bottles of 100 (NDC  43478-901-88). 
 
Each white/dark blue capsule, identified by 3 narrow bands, 1 wide band, and “AK 120,” 
contains 120 mg of propranolol hydrochloride in bottles of 100 (NDC 43478-902-88). 
 
Each dark blue/light blue capsule, identified by 3 narrow bands, 1 wide band, and “AK 160,” 
contains 160 mg of propranolol hydrochloride in bottles of 100 (NDC 43478-903-88). 
 
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See 
USP Controlled Room Temperature] 
 
Protect from light, moisture, freezing, and excessive heat. 
 
Dispense in a tight, light-resistant container as defined in the USP. 


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89 
 
 
This product’s label may have been updated. For current package insert and further product 
information, please call our medical communications department toll-free at 1-877-567-0862 
 
 
Manufactured for Rouses Point Pharmaceuticals, LLC 
Cranford, NJ 07016 
By Wyeth Pharmaceuticals, Inc. 
Philadelphia, PA 19101 
 
 
490F001 
Rev 12/10 
 

SAP_001.pdf: 
 
Effect of COMT Genetic Polymorphisms on Response to 
Propranolol Therapy in Temporomandibular Disorder 
 
 
NCT number:  02437383 
Document Date:  21 February 2018 
 


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Statistical Analysis Plan 
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21 Feb 2018 
 
Statistical Analysis Plan 
 
 
Protocol Title: Effect of COMT Genetic Polymorphisms on 
Response to Propranolol Therapy in Temporomandibular 
Disorder 
 
Protocol Number: 14-067-E 
 
Version Number and Date:  Version 3.0; 21 February 2018 
Funding Sponsor: National Institute of Dental and Craniofacial 
Research 
Study Principal Investigator: Inna Tchivileva, MD 
SAP Prepared by: Robert James / Gary Slade BDSc, Dip DPH, PhD 
Analyses to be Conducted by: Robert James / Gary Slade BDSc, Dip DPH, PhD 
 
 
 
 
This document is confidential and proprietary to the sponsor. Acceptance of this document constitutes agreement by 
the recipient that no unpublished information contained herein will be reproduced, published, or otherwise 
disclosed without the prior written approval of the sponsor, except that this document may be disclosed to 
appropriate Institutional Review Boards under the condition that they keep the information confidential. 
DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
1.0 
22 May 2013 
Created by the study team 
prior to external review of the 
protocol. 
2.0 
27 June 2017 
Added NIDCR protocol 
number and protocol short 
title; updated based on 
protocols V4.0-11.0 
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Version Number 
Date 
Comments/Changes 
3.0 
21 February 2018 
Minor changes involving 
grammar, wordsmithing, 
punctuation, and other 
editorial changes have been 
made throughout the 
document.  
 
Added and removed text to 
reflect updates based on 
protocol v12.0. 
 
APPROVALS 
Approved: 
 
Date: 
 
 
Inna Tchivileva, MD 
Principal Investigator 
UNC School of Dentistry 
 
 
 
 
Date: 
 
 
Gary Slade, BDSc, Dip DPH, PhD 
Co-Principal Investigator 
UNC School of Dentistry 
 
 
 
 
Date: 
 
 
Robert James, MS 
Statistical Scientist 
Data Coordinating Center 
Rho, Inc 
 
 
 
 
Date: 
 
 
Samuel Arbes, DDS, MPH, PhD 
Principal Investigator 
Data Coordinating Center 
Rho, Inc. 
 
 
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SIGN
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TABLE OF CONTENTS 
1. 
PURPOSE OF THE ANALYSES ............................................................................. 5 
2. 
PROTOCOL SUMMARY ......................................................................................... 5 
2.1 
Study Objectives........................................................................................... 5 
2.1.1 
Primary Objective ................................................................................ 5 
2.1.2 
Secondary Objectives ......................................................................... 5 
2.1.3 
Exploratory Objectives ........................................................................ 6 
2.2 
Overall Study Design and Plan ..................................................................... 6 
2.3 
Study Population .......................................................................................... 6 
2.4 
Treatment Regimens .................................................................................... 6 
2.5 
Treatment Group Assignments or Randomization ........................................ 6 
2.6 
Sample Size Determination .......................................................................... 7 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS ................................... 7 
4. 
ANALYSIS POPULATIONS .................................................................................... 8 
4.1 
Intention-to-Treat Population ........................................................................ 8 
4.2 
Per-Protocol Population ................................................................................ 9 
4.3 
Safety Population ......................................................................................... 9 
5. 
STUDY PATIENTS .................................................................................................. 9 
5.1 
Disposition of Patients .................................................................................. 9 
5.2 
Protocol Deviations ....................................................................................... 9 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........................ 10 
7. 
MEASUREMENTS OF TREATMENT COMPLIANCE ........................................... 10 
8. 
EFFICACY EVALUATION ..................................................................................... 11 
8.1 
Handling of Dropouts or Missing Data ........................................................ 11 
8.2 
Efficacy Variables ....................................................................................... 11 
8.3 
Analysis Methods ....................................................................................... 14 
8.3.1 
Primary Efficacy Analyses ................................................................. 14 
8.3.2 
Secondary Efficacy Analyses ............................................................ 15 
8.3.3 
Exploratory Efficacy Analyses ........................................................... 17 
9. 
SAFETY EVALUATION ......................................................................................... 18 
9.1 
Overview of Safety Analysis Methods ......................................................... 18 
9.2 
Adverse Events .......................................................................................... 18 
9.3 
Deaths, Serious Adverse Events, and Other Significant Adverse Events .... 19 
9.4 
Vital Signs and Other Observations Related to Safety ................................ 19 
9.5 
Unanticipated Problems .............................................................................. 20 
10. INTERIM ANALYSES AND DATA MONITORING ................................................. 21 
11. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ....................... 21 
12. APPENDICES ........................................................................................................ 22 
12.1 
Study Schematic......................................................................................... 22 
12.2 
Schedule of Events ..................................................................................... 23 
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LIST OF ABBREVIATIONS 
AE 
Adverse event 
COMT 
Catechol-O-methyltransferase 
DCC 
Data Coordinating Center 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
GLMM 
Generalized Linear Mixed Model 
HIT 
Headache Impact Test 
ITT 
Intention-to-Treat Population 
LPS 
Low pain sensitive 
NIDCR 
National Institute of Dental and Craniofacial Research 
NIH 
National Institutes of Health 
PP 
Per-Protocol Population 
PPT 
Pressure pain threshold 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SF-12 
Short Form 12 Health Survey 
TEAE 
Treatment emergent adverse event 
TMD 
Temporomandibular disorder 
TMJ 
Temporomandibular joint 
Val Met 
Valine allele of the COMT gene 
V1 
Study visit 1, the study of the randomization and start of study drug administration 
V2 
Study visit 2 at 1 week post-randomization 
V3 
Study visit 3 at 5 week post-randomization 
V4 
Study visit 4 at 9 week post-randomization 
 
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1. PURPOSE OF THE ANALYSES 
The purpose of the analyses is to quantify and test associations described in the primary, 
secondary, and exploratory objectives of the protocol.  
2. PROTOCOL SUMMARY 
A total of 200 participants aged 18 to 65 years with chronic temporomandibular disorder (TMD), 
at three clinic sites, will be randomized in a 1:1 ratio to propranolol or placebo in a parallel-
group, masked clinical trial. Participants will attend 6 clinic visits over a period of 12 to 15 
weeks.  
Potential participants will be prescreened by telephone or at a clinic visit. During the Screening 
and Baseline Visit, participants will be consented, evaluated for eligibility, and assessed for 
baseline characteristics. Baseline procedures will include clinical tests and examinations and the 
administration of questionnaires.  
At the Randomization and Titration Visit, participants will be randomized to propranolol or 
placebo and will begin a 10-week drug treatment phase that is divided into 1 week of drug 
titration, 8 weeks of drug maintenance, and 1 week of drug tapering. During treatment, many of 
the baseline assessments will be repeated. The final study visit will occur 1 week after drug 
tapering ends. 
The primary endpoint will be a weekly pain index derived from a daily symptom diary. 
Secondary endpoints will be additional ratings of clinical pain; examiner assessments of 
experimental pain sensitivity; participant ratings of physical function, emotional function, and 
global improvement; occurrence of symptoms and adverse events; and use of rescue 
medications. DNA analyses will be conducted to identify polymorphisms in the gene that 
encodes catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines 
such as epinephrine, norepinephrine, and dopamine and is associated with responses to pain. 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objective is to investigate the efficacy of extended-release propranolol compared to 
placebo in the reduction of the pain index in participants with TMD at week 9 of treatment (at 
Visit 4). 
2.1.2 Secondary Objectives 
The secondary objectives are: 
• To investigate gene-by-treatment group interaction to determine whether the efficacy of 
extended-release propranolol in the reduction of the pain index varies according to 
participants' polymorphisms in the coding region of the COMT gene. 
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• To investigate the efficacy of extended-release propranolol compared with placebo using 
secondary endpoints: additional pain ratings; examiner assessments of experimental pain 
sensitivity; participant ratings of physical function, emotional function, global impression 
of change; occurrence of symptoms and AEs; and use of rescue medications. 
2.1.3 Exploratory Objectives 
The exploratory objectives are: 
• To investigate whether the efficacy of extended-release propranolol in the reduction of 
the pain index varies according to participants' polymorphisms including, but not limited 
to three other genetic regions:  a) the COMT promoter area; b) adrenergic receptor β2 
(ADRB2) gene; and c) the adrenergic receptor β3 (ADRB3) gene. 
• To investigate whether the efficacy of extended-release propranolol in the reduction of 
the pain index varies according to various phenotypic characteristics.  
• To collect and archive biospecimens for future biological and statistical analyses. 
2.2 Overall Study Design and Plan 
This investigation is a two-arm, parallel-group, placebo-controlled, masked, Phase II clinical 
trial. Participants will attend 6 clinic visits over a period of 12 to 15 weeks, and the trial will take 
approximately 3 years to complete. The study schematic and schedule of events are provided in 
Sections 12.1 and 12.2. 
Throughout this statistical analysis plan (SAP), V1, V2, V3, V4, and V5 refer respectively to 
study visit 1 (randomization and start of drug treatment), visit 2 (1 week post randomization), 
visit 3 (5 weeks post randomization), visit 4 (9 weeks post randomization), and visit 5 (11 weeks 
post randomization and 1 week after the planned termination of study drug administration). 
2.3 Study Population 
A total of 200 participants aged 18 to 65 years of either sex and any race/ethnicity with chronic 
temporomandibular disorder (TMD), at three clinic sites, will be enrolled.  
2.4 Treatment Regimens 
Participants will be randomized to propranolol or placebo and will begin a 10-week drug 
treatment phase that is divided into 1 week of drug titration, 8 weeks of drug maintenance, and 1 
week of drug tapering. The titration dose and the tapering dose are 60 mg once per day by mouth 
whereas the maintenance dose is 60 mg twice per day by mouth. 
2.5 Treatment Group Assignments or Randomization 
At the Randomization and Titration Visit, participants will be randomized 1:1 to propranolol or 
placebo. Randomization will be stratified by site and conducted within blocks to insure equal 
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numbers of participants per arm. Randomization will be accomplished by a web-based 
randomization system developed and maintained by the Data Coordinating Center (DCC). 
2.6 Sample Size Determination 
This study plans to randomize 200 participants, which will provide 94% power (alpha = 0.05) to 
detect a difference between a 27% reduction in pain intensity in the propranolol arm and a 9% 
reduction in the placebo arm (primary hypothesis). Assuming haplotype distributions and within-
haplotype treatment effects that are similar to those observed in the pilot study, the same sample 
size would provide 61% power (alpha = 0.05) to detect an interaction between haplotype and 
treatment group (secondary hypothesis). 
Power calculations were made using the GLMPOWER procedure in SAS, which assumes a data 
structure of one observation per person. This is a simplification of the situation that will occur 
with the linear mixed model, described in Section 10.4.1, where efficacy will be evaluated using 
a data structure where most participants will have three observations per person. The simplified 
power calculations are shown here because conventional software for power calculations does 
not deal with the more complex situation of linear mixed models. 
3. GENERAL ANALYSIS AND REPORTING CONVENTIONS 
The following is a list of general analysis and reporting conventions to be applied for this study.  
• Categorical variables will be summarized using counts (n) and percentages (%) and will 
be presented in the form n (%). 
• Moment statistics including mean and standard deviation will be reported at 1 more 
significant digit than the precision of the data.  
• Order statistics including median, min, and max will be reported to the same level of 
precision as the original observations. If any values are calculated to have more 
significant digits then the value should be rounded so that it is the same level of precision 
as the original data. 
• Following SAS default rules, the median will be reported as the average of the two 
middle numbers if the dataset contains even numbers. 
• Test statistics including t and z test statistics will be reported to two decimal places.  
• P-values will be reported to 3 decimal places if greater than 0.001. If less than 0.001, then 
p-values will be reported as <0.001. P-values will be reported with a leading 0, e.g., 0.05 
rather than .05. 
• No preliminary rounding should be performed; rounding should only occur after analysis. 
To round, consider digit to right of last significant digit:  if < 5 then round down, if >=5 
then round up. 
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• All listings will be sorted in order of treatment group (e.g., active, placebo), participant, 
and time of assessment (e.g., visit, time, and/or event). 
If departures from these general conventions are present in specific sections of this SAP, then 
those conventions will take precedence over these general conventions.  
The items listed below will apply to all data analyses. 
• For categorical variables, summary statistics will consist of the number and percentage of 
patients in each category. All percentages will be rounded to one decimal point. The 
number and percentage of patients will always be presented in the form XX (XX.X) 
where the percentage is in parentheses. To ensure completeness, all summaries for 
categorical and discrete variables will include all categories, even if none of the patients 
had a response in a particular category. Unless otherwise noted, for all percentages, the 
number of patients in the analysis population for the treatment group who have an 
observation will be the denominator. 
• For continuous variables, summary statistics will consist of the number of patients, mean, 
median, standard error of the mean (SE), minimum, and maximum values. The summary 
statistic n will be the number of patients with non-missing values. All means and medians 
will be reported to one more significant digit than the values being analyzed. Standard 
errors will be reported to two more significant digits than the values being analyzed. The 
minimum and maximum will be reported to the same number of significant digits as the 
values being analyzed. 
• For tests of hypothesis of treatment group differences, the associated P-value will be 
reported.  
• Version 9.4 or later of the SAS® software package will be used to produce all 
summaries, listings, statistical analyses, and graphical presentations. 
4. ANALYSIS POPULATIONS 
4.1 Intention-to-Treat Population 
Section 11.3.1 of the protocol defines the intention-to-treat (ITT) sample as follows: 
Consistent with the primary statistical method that will use a linear mixed model, the 
intention-to-treat (ITT) sample is defined as all study participants who have at least one valid 
measurement of the primary endpoint (at Visit 2 or later. A "valid" assessment for the 
primary endpoint is defined as at least 4 daily reports of pain intensity and duration collected 
in the 7-day period prior to the visit (Section 2.5.1 of the protocol).  Treatment group 
allocation will be defined as the study arm into which the subject was randomized regardless 
of the actual study treatment received.  By necessity, the ITT sample excludes participants 
who provide no data for the primary endpoint after randomization. Note that follow-up 
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assessments will be included in the ITT analysis when sufficient diary data are collected at 
the follow-up assessment, even if there were protocol violations. Likewise, the ITT sample 
will include all available follow-up assessments from any discontinued participants. 
4.2 Per-Protocol Population  
As stated in Section 11.3.2 of the protocol, the per-protocol (PP) sample will be a subset of the 
ITT sample, excluding any assessments made at or after a visit at which the participant is found 
to have any major protocol deviation as listed in Section 5.2 below and excluding all assessments 
for participants whose compliance with study medication is less than 60% over all the study 
visits.  
4.3 Safety Population 
Section 11.3.3 of the protocol defines the safety population as follows: 
The safety sample will include all randomized participants who received at least one dose of 
study medication. Participants in the safety sample will be analyzed with the treatment group 
according to the medication they actually received, regardless of their randomized 
assignment. 
All adverse events (AEs) will be recorded on a case report form regardless of study 
population. For safety analyses, all AEs will be provided in listings, but only treatment 
emergent adverse events (TEAEs) within the safety population will be reported in summary 
tables. 
5. STUDY PATIENTS 
5.1 Disposition of Patients 
The screened population will consist of all consented participants and the randomized population 
will consist of all screened participants who are randomized. Any participant who does not meet 
the criteria for randomization with be discontinued from the trial. Participants who withdraw 
from the study voluntarily or are withdrawn by an investigator will be discontinued from the 
study. Study staff will complete a study disposition form in the electronic data capture system, 
indicating the reason for discontinuation. The disposition of all participants and the study 
populations to which they belong will be presented in the participant listings and summarized by 
treatment allocation in a disposition table.  
5.2 Protocol Deviations 
The protocol deviations listed below are related to the use of investigational product and 
concomitant therapies and will be considered major protocol deviations. These deviations will 
exclude a participant’s data from the PP analysis (Section 4.2).  
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• Participant is unable to reach the maintenance dosage of the study drug or placebo or is 
unable to remain on the maintenance dosage. 
• Initiation of opioid medications. 
• Initiation of TMJ surgical treatment (including TMJ arthrocentesis). 
• Initiation of therapeutic injections for the management of pain. 
• Initiation of occlusal appliance therapy. 
• Initiation of any of the following non-pharmacological therapies: acupuncture, 
biofeedback, and/or TENS. 
• Initiation after Visit 1 and usage between Visits 1 and 4 of short-acting, non-prescription 
analgesics (e.g., NSAIDs, aspirin, and/or acetaminophen) for pain that exceeds the 
definition of episodic use as described in Section 5.7.1 of the protocol. 
These and other types of protocol deviations will be reported during the study. The types of 
protocol deviations will be summarized descriptively for both the Safety and ITT populations by 
treatment group. A listing of the protocol deviations of individual participants will be included in 
the participant listings.  
6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and other baseline characteristics will be summarized descriptively for both the 
ITT and the PP populations. While no formal statistical testing will be done, all demographic and 
baseline characteristics will be assessed for clinically significant differences between the 
treatment groups. P-values from these comparisons will be considered descriptive. 
To further assess the overall health of the study participants prior to study treatment, any 
significant medical history will be included in the participant listings.  
All prior and concomitant medications will be coded to preferred drug names and therapeutic 
drug class using the WHO Drug Dictionary. Use of concomitant medications will be summarized 
for each therapeutic drug class and each preferred drug name. Concomitant medications will 
include medications reported on the Concomitant Medications page of the CRF. 
7. MEASUREMENTS OF TREATMENT COMPLIANCE 
Participants will be asked to bring their medication containers to each visit during the treatment 
period. Study staff will count the number of capsules returned and will enter the number on a 
case report form in the electronic data capture system. Participants will also record the study 
medication use in their Daily Symptom Diary that will be reviewed by the study staff at Visits 2, 
3, 4, and 5. Participant compliance with study medication will be defined as taking 60% or more 
of the study medication over all study visits. In reports, pill counts will supersede the Daily 
Symptom Diary in determining compliance. Treatment compliance will be summarized by 
treatment group and ITT population.  
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8. 
EFFICACY EVALUATION 
8.1 Handling of Dropouts or Missing Data 
There will be no imputation for missing data. Missing data will be accommodated in the linear 
mixed model. 
8.2 Efficacy Variables 
The efficacy variables are listed and described in Table 8-1. 
Table 8-1 
Efficacy Variables 
Efficacy Variables 
Description and Derivation 
Primary 
 
Net Change in the Mean Pain 
Index 
The weekly mean pain index will be computed for the week 
prior to randomization and for each week during the 
treatment phase. The weekly mean pain index will be based 
on at least 4 daily reports of facial pain intensity and 
duration collected in the 7-day period prior to the visit. 
When there are fewer than 4 daily reports, the weekly mean 
pain index will be considered missing. The net change in the 
mean pain index will be calculated as the weekly mean pain 
index at V2, V3, or V4 minus the weekly mean pain index at 
V1. 
30% Responder Status 
The binomial 30% responder status will be positive if the 
participant experiences a decrease of 30% from V1 in their 
TMD weekly mean pain index at V4.  
50% Responder Status 
The binomial 50% responder status will be positive if the 
participant experiences a decrease of 50% from V1 in their 
TMD weekly mean pain index at V4. 
Secondary 
 
Net Change in the Mean Pain 
Intensity  
The weekly mean pain intensity will be based on at least 4 
daily reports of facial pain intensity collected in the 7-day 
period prior to the visit. When there are fewer than 4 daily 
reports, the weekly mean pain intensity will be considered 
missing. The net change in the mean pain intensity will be 
calculated as the weekly mean pain intensity at V2, V3, or 
V4 minus the weekly mean pain intensity at V1. 
Net Change in the Mean Pain 
The weekly mean pain duration will be based on at least 4 
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Efficacy Variables 
Description and Derivation 
Duration 
daily reports of facial pain duration collected in the 7-day 
period prior to the visit. When there are fewer than 4 daily 
reports, the weekly mean pain duration will be considered 
missing. The net change in the mean pain duration will be 
calculated as the weekly mean pain duration at V2, V3, or 
V4 minus the weekly mean pain duration at V1. 
Quantitative sensory tests of 
sensitivity to experimental pain 
(QST form) 
For each visit when it was measured, Thermal Pain 
Tolerance, recorded in degrees Celsius, will be computed as 
the mean of 4 pain tolerance trials. 
For each visit when it was measured, Thermal Pain 
Threshold recorded in degrees Celsius, will be computed as 
the mean of 4 pain threshold trials. 
Pressure Pain Threshold 
(DC/TMD exam) 
For each visit when they were measured, five variables, 
recorded in kg, representing mean Pressure Pain Threshold 
at each of five anatomical locations: a) Temporalis muscle, 
b) Masseter muscle; c) TMJ; d) Trapezius muscle; and 
e) lateral epicondyle eminence (item 8 of DC/TMD Exam 
form).  At each site, the mean response to two trials, each 
performed bilaterally, will be computed.  For each trial, 
threshold is defined as the amount of pressure at which the 
participant first perceives the stimulus to be painful..  
Facial pain ratings (SF-McGill 
questionnaire) 
For each visit when it was administered, two subscales, each 
a continuous variable, will be computed from the Short Form 
McGill Pain Questionnaire: a) Affective component, and 
b) Sensory component. 
In addition, 4 variables assessing facial pain will be 
analyzed: a) Present Pain Intensity (Item II of the SF-
McGill); b) Weekly Pain Intensity (Item III of the SF-
McGill); c) Weekly Pain Duration (Item IV of the SF-
McGill); and d) Weekly Fatigue (Item V of the SF-McGill). 
Clinical measures of limitation in 
jaw function (DC/TMD Exam) 
For each visit when they were measured, the following 
clinical measures will be derived. 
Three measurements of range of jaw motion will be 
analyzed, each recorded in millimeters: a) Pain-free jaw 
opening; b) Maximum unassisted jaw opening; and 
c) Maximum assisted jaw opening (Item 4 of the DC/TMD 
form) 
The count of clinical pain masticatory structure locations 
will be computed (range=0 to 8) representing locations 
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Efficacy Variables 
Description and Derivation 
where pain is reported during the 30-day period prior to 
examination: temporalis muscles, masseter muscles, other 
masticatory muscles, and TMJs, each reported bilaterally 
(Item 1a of DC/TMD form). 
The count of examination hyperalgesia masticatory structure 
locations will be computed (range=0 to 8) representing 
places in which pain is elicited during jaw provocation 
during the examination: temporalis muscles, masseter 
muscles, other masticatory muscles, and TMJs, each reported 
bilaterally (Items 4, 5 and 6 of DC/TMD form). Jaw 
provocation includes jaw mobility maneuvers and 
standardized pressure palpation. 
The count of examination familiar pain masticatory structure 
locations will be computed (range=0 to 8) representing 
places in which pain is elicited during jaw provocation 
during the examination: temporalis muscles, masseter 
muscles, other masticatory muscles, and TMJs, each reported 
bilaterally, and confirmed by the subject to be familiar to 
pain experienced in the prior 30 days (Items 4, 5 and 6 of 
DC/TMD form). Jaw provocation includes jaw mobility 
maneuvers and standardized pressure palpation. 
Vital signs 
For each visit when it was measured, systolic and diastolic 
blood pressure (recorded in mmHg) and heart rate (recorded 
in beats per minute) will be computed, each as the mean of 
three repeated measurements taken 2 min apart and recorded 
as Vital Signs in RAVE. 
Subjective health status (SF-12v2 
questionnaire) 
For each visit when it was administered, published scoring 
algorithms will be used to compute two continuous variables 
from the SF-12v2 questionnaire: a) Physical Component 
Subscale and b) Mental Component Subscale (SF-12v2 
questionnaire). 
Headache Impact (HIT-6 
questionnaire) 
For each visit when it was administered, published scoring 
algorithms will be used to compute the Total Score for 
headache impact, a continuous variable. 
Graded chronic pain ratings 
(GCPS questionnaire) 
For each visit when it was administered, published scoring 
algorithms will be used to compute two continuous 
measurements (Characteristic Pain Intensity and Pain 
Interference) and one derived ordinal score (Grade of 
Chronic Pain) from the GCPS questionnaire. 
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Efficacy Variables 
Description and Derivation 
Anxiety and Depression (HADS 
questionnaire) 
For each visit when it was administered, published scoring 
algorithms will be used to compute two continuous 
measurements: Anxiety, and Depression scores. 
Patient global impression of 
change (PGIC questionnaire) 
The ordinal rating of change, measured at the subject’s  
visits 3 and 4, will be reported as two secondary outcome 
variables. 
Subjective measure of jaw 
functional limitation (JFLS 
questionnaire) 
For each visit when it was administered, published scoring 
algorithms will be used to compute four continuous scores of 
subjective jaw function from the JFLS questionnaire: 
a) Chewing Limitation b) Opening Limitation; c) Verbal & 
Emotional Expression Limitation; and d) Combined Global 
Measure. 
Psychological Stress (PSS 
questionnaire) 
For each visit when it was administered, published scoring 
algorithms will be used to compute a continuous summary 
score of psychological stress from the PSS questionnaire. 
Somatic symptoms (SCL-90R 
questionnaire) 
For each visit when it was administered, published scoring 
algorithms will be used to compute the Somatization Scale 
from the SCL-90R questionnaire. 
Sleep quality (PSQI 
questionnaire) 
For each visit when it was administered, published scoring 
algorithms will be used to compute the global measure of 
sleep quality from the PSQI questionnaire. 
 
8.3 Analysis Methods 
The ITT population will be used in all analyses unless otherwise stated. The alpha level for 
determining significance will be set to 0.05 for all inference tests. The mixed models analyses 
described below automatically adjust for missing values; there will be no further imputation or 
adjustments for missing values.  During the analysis of the primary hypothesis, treatment 
allocation will be masked (i.e., groups will be labeled A and B) during the statistical 
programming and unmasked only after the statistical programming code has been finalized.  
8.3.1 Primary Efficacy Analyses 
The primary statistical analysis to evaluate the primary hypothesis will use all data from the ITT 
analytical sample in a linear mixed model.  Mixed models will be used to analyze the treatment 
effect at V4 (Proc Mixed, SAS, version 9.4 or greater, SAS Institute, Inc., Cary, North Carolina). 
The mixed model will include the net change in the mean pain index as the dependent variable. 
The model’s independent variables will include fixed effects for site, sex, race-ethnicity, the 
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mean pain index at V1 (as a baseline covariate), visit (V2, V3 and V4), treatment allocation 
(active versus placebo), and a visit by treatment interaction. Participants will be included as a 
random effect in the mixed model. The mixed model will be run twice assuming either a 
compound symmetry or an unstructured variance structure.  The mixed model achieving the 
lowest Akaike information criterion will be selected as the best model and used for reporting of 
results. The model’s denominator degrees of freedom will be adjusted for any possible effects of 
sample imbalances due to any missing values using Kenward Roger’s method in SAS. For 
descriptive purposes (and regardless of the P-value for efficacy at Visit 4), efficacy estimates at 
each visit (2, 3 and 4) will be described in terms of adjusted means and 95% confidence 
intervals. 
If there is a treatment effect, then “responder analyses” will be performed to compare the 
responder status of the treatment allocation groups. Participants will have their binomial 
responder status classified at both the 30% and 50% response threshold levels. The odds ratios of 
treatment group allocation on the responder status of participants at both the 30% and 50% 
threshold levels will be estimated using logistic regression with covariate adjustments for site 
and V1 weekly mean pain index. The odds ratio for the effect of treatment allocation on 
responder status for both the 30% and 50% threshold levels will be reported with their 95% 
confidence limits and their associated P-values. 
As secondary efficacy analyses, the above primary hypothesis analyses will be repeated on the 
PP population. The results of the ITT and PP population based analyses will be reported 
separately. If it appears reasonable to assume that the results of the primary hypothesis are 
independent of choice of the analysis population (ITT or PP), then all subsequent analyses will 
be performed on the ITT population only. Stratified analysis will estimate ITT treatment effects 
separately for the two sexes and for the main racial-ethnic groups. The analysis will be 
descriptive, reporting means and 95% confidence intervals. There will be no hypothesis tests of 
efficacy within demographic subgroups because of the expected small numbers of males and 
minorities.  
 
8.3.2 Secondary Efficacy Analyses 
For secondary efficacy measures that are continuous variables or counts (Table 8-1), the effect of 
treatment arm on the net change in the secondary efficacy measures will be analyzed using the 
same statistical model as in the primary efficacy analyses but with derived scores for each 
measure used as the dependent variables. In summary, data from all applicable visits will be 
analyzed with linear mixed models as described for the primary hypothesis. For most secondary 
efficacy measures, the data were collected at V1, V3 and V4, although the schedule differed for a 
few data forms as shown in Appendix A. Outcomes will be reported at each study visit using 
number of subjects, the mean ± standard error, and 95% confidence limits of the mean, median, 
min, and max. Tests for significance of treatment group differences in the change from V1 to V4 
will be evaluated with linear mixed models as described for the primary hypothesis. P-value 
testing for the main effects of treatment allocation will be reported for overall treatment effect 
and for the treatment effects at each study visit.  
 
For secondary efficacy variables measured on an ordinal scale, the non-parametric signed-rank 
Wilcoxon test will instead be used to test for change between visits within each treatment group, 
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and there will be no adjustment for covariates.  Patients’ Global Impression of Change is the one 
secondary-efficacy measure that was not measured at V0 or V1, so the test for treatment group 
differences in that outcome will be evaluated using the Wilcoxon rank sum. 
  
To test the secondary hypothesis of gene-by-treatment interaction, the linear mixed model 
described for the primary analysis will be extended by adding three sets of predictor variables: 
(1) the number of COMT LPS haplotypes (0, 1, or 2) will be modeled as a fixed effect (both as a 
continuous variable and as a categorical variable); (2) two-way interactions between haplotype 
effect and treatment allocation and between haplotype effect and visit sequence; and (3) a three-
way interaction term between the haplotype effect, treatment allocation, and visit sequence. The 
gene-by-treatment interaction at V4 is the interaction of interest.  A contrast statement within the 
mixed model will test for a gene-by-treatment interaction at V4 with a P-value ≤ 0.05 considered 
statistically significant. Both an unstructured and compound symmetry variance structure, as 
well as, fitting the haplotype variable as a continuous (linear) and a categorical variable will be 
tested.  The statistical model with the lowest Akaike information criterion will consider the best 
model and used for inference testing.  Residual analysis will be used to confirm that there are no 
major violations of model assumptions.  Model adjusted means will be reported with their 95% 
confidence intervals.  For descriptive purposes, a second set of secondary analyses will be 
performed on the valine allele of the COMT gene using valine allele (Val/Met allele) counts in an 
identical manner as for the LPS haplotype counts described.  A third set of secondary analyses 
will adapt the approach for analysis of the LPS haplotype, restricting the model to non-Hispanic 
whites.  This is consistent with the approach of some genetic researchers who advocate racial-
group restriction as a preferable analytic method to control for population stratification. 
 
The participants’ use of rescue medications for TMD pain as well as over-the-counter analgesics 
(namely, NSAIDs, acetaminophen, and aspirin) for the treatment of any type of pain during a 
period from V1 to V4 will be summarized by treatment group, both overall and by study visit.  
The number of days on over-the counter analgesics and the number of days on over-the counter 
analgesics as a ratio of days on study drug will be summarized (n, mean and standard error) by 
treatment group, both overall and by study visit.  Log-transformed linear regression models will 
test for treatment group effects on the total number of days a participant is on rescue medications 
for the treatment of TMD-related pain and (in a separate analysis) for over-the-counter 
analgesics for the treatment of any pain.  The days on rescue medications (or over-the-counter 
analgesics for any pain) will be log-transformed and used as the dependent variable.  If there are 
some participants with 0 days on rescue medications (or over-the-counter analgesics), then a 
log(x+1) transformation of days will be used to prevent log(0) values.  Study site, mean pain 
index at V1, and days on study (log-scale) will be used as covariates in the statistical models.  
Adjusted mean estimates and their 95% confidence intervals of the model adjusted days on 
rescue medications (or analgesics for any pain) will be reported with their treatment group effect 
p-values.  If residual analysis suggests that model assumptions are unreasonable, then the 
following alternative model will be used to test for treatment group effects on the use of rescue 
medications (or over-the-counter analgesics for any pain).  This alternative model will be a 
generalized linear mixed model using a negative binomial link with days on rescue medications 
(or over-the-counter analgesics for any pain) as the dependent variable and covariates for study 
site, mean pain index at V1, and for days on study.    
 
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There are approximately 20 participants that were enrolled early at UB who did not have the 
“type of pain” documented when taking over-the-counter analgesics. It cannot be known whether 
the over-the-counter analgesics were taken due to TMD pain (i.e., rescue medications) and thus 
these 20 participants will be excluded from the above treatment group effects on the rescue 
medication use analysis.  These subjects will be included in the use of over-the-counter 
analgesics for any pain. 
 
All of the above secondary efficacy analyses are secondary to and supportive of the primary 
hypothesis analysis, and thus no statistical corrections will be made for multiplicity for any of the 
secondary analyses. P-values ≤ 0.05 will be considered statistically significant.   
Additional secondary analyses of the incidence of adverse events are described in Section 9. 
8.3.3 Exploratory Efficacy Analyses 
The mixed model described for the secondary hypothesis of the LPS and Val/Met haplotypes 
will be modified by specifying genetic variants for the COMT promoter, ADRB2 gene, and 
ADRB3 gene. Other genetic variants may also be included in the mixed model. The only 
difference in these mixed model analyses is that the ADRB2 and ADRB3 gene types will be 
included as categorical fixed effects rather than the linear continuous fixed effects in the LPS and 
Val/Met haplotype mixed models. 
Other stratum-specific estimates of treatment effect will be explored in an analogous manner, 
namely through the use of mixed models in which the stratification variable is a categorical fixed 
effect. Each stratum will be a mutually exclusive category of study participants, classified 
according to the following characteristics assessed either at V0 or V1:  
• Body Mass Index, computed from measurements recorded at V1, will be used to create 
two strata, with the dichotomy based on one of two established thresholds ≥25 or ≥30. 
The decision as to which threshold will be made after inspecting the distribution of BMI, 
and select the threshold that is closest to the median. 
• Smoking status, assessed using the Smoking questionnaire completed at V0, will be used 
to create two strata: current tobacco smokers or not (the latter therefore including former 
smokers and never smokers).  Smokeless tobacco and other sources of nicotine will not 
be used for this classification. 
• Migraine headache will be classified using responses to the headache questionnaire 
(HAQ) administered at V1. Two strata will be created, classified according to presence or 
absence of one or more of four types of migraine sub-types (Migraine without aura, 
Migraine with aura, Chronic migraine, or Probable migraine without aura).   
• Degree of examiner-assessed tenderness to body palpation, recorded at Item 4 of the 
Fibromyalgia Questionnaire at V0, will be used to create two strata, based as closely as 
possible on a median split of the total number of tender points. 
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• Published scoring algorithms will be used to compute the catastrophizing subscale of the 
revised Coping Strategies Questionnaire (CSQ-R) measured at V1. The two strata will be 
based as closely as possible on a median split of the subscale score. 
• Self-rated general health at V1, reported at item 1 of the SF-12v2 questionnaire, will be 
used to create two strata based as closely as possible on a median split of the ordinal 
rating (high, low). 
• Anxiety and depression as measured using the two subscales of the Hospital Anxiety and 
Depression Scale (HADS) administered at V1.  Two strata will be created based as 
closely as possible on a median split of each of the subscale scores  (high, low). 
• Sleep quality, as measured using the Global Score of the Pittsburgh Sleep Quality Index 
(PSQI) administered at V1.  Two strata will created based as closely as possible on a 
median split of Global Score  (high, low).  
• Subjects’ rating of confidence in treatment outcome reported at V1 will be used to create 
two strata based as closely as possible on a median split of the ordinal rating (high, low). 
Exploratory analyses of the incidence of adverse events are described in Section 9. 
9. SAFETY EVALUATION 
9.1 Overview of Safety Analysis Methods 
All safety analyses will be carried out using the Safety population. The following assessments 
will be used to evaluate the safety of propranolol for participants with TMD: 
• Adverse events (AEs) 
• Vital signs 
• Unanticipated Problems 
 
9.2 Adverse Events 
All AEs will be coded to a system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 18.0. All tabular AE summaries will be 
for treatment-emergent AEs (TEAEs). TEAEs will be defined as those AEs with an onset on or 
after the date of first dose of study drug (study visit 1: V1). If an AE was recorded prior to the 
first dose of study drug and there was an increase in its severity, the AE will be considered a 
TEAE. All other AEs will be classified as non-treatment-emergent. Non-treatment-emergent AEs 
will be flagged in all AE data listings. 
An overall summary table will be developed to report the number of events and the incidence of 
participants having at least one event in the following categories:  
• TEAEs 
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• TEAEs indicated as serious (SAEs) 
• TEAEs that lead to study drug discontinuation 
• TEAEs with an outcome of death 
• TEAEs that were reported as having a definite, probable, or possible relation to  study 
drug 
• TEAEs reported as having a severity rating of severe 
In addition, a summary table of TEAEs classified by system organ class (SOC) and preferred 
term (PT) will be provided for each of the following: 
• TEAEs 
• TEAEs by maximum severity  
• TEAEs by relationship to study drug 
• TEAEs by week of treatment 
The summary of all TEAEs will present both the number of TEAEs and the incidence of TEAEs 
by severity, and relationship to study drug. When reporting the number of TEAEs, if the same 
TEAE occurs for a patient on multiple occasions, the event will be counted once for each 
occurrence. When reporting the incidence, a patient will only be counted once if they ever 
experience an event within the SOC and ever experience the individual PT. 
If for any TEAE (system organ class or preferred term) the incidence rate is 5% or more in either 
treatment arm then a logistic regression will be performed and descriptive p-values of treatment 
arm differences will be reported.   
For the summary of TEAEs by severity, if the severity of the TEAE is not reported, then the 
severity of the AE will be counted as severe. If the same TEAE occurs for a patient on multiple 
occasions, the TEAE will be categorized according to the highest severity rating for that TEAE 
in that patient. For the summary of TEAEs by relationship to study drug, if the relationship is 
missing, it will be counted as definite/certain. If the same TEAE occurs for a patient on multiple 
occasions, the TEAE will be categorized according to the closest relationship to study drug 
reported for that TEAE in that patient. 
9.3 Deaths, Serious Adverse Events, and Other Significant Adverse Events 
In addition to these summary tables, the incidence of adverse events leading to death, the 
incidence of SAEs, and incidence of TEAEs that led to study drug being discontinued will be 
presented in summary tables and listings. The summary listings will provide all of the 
information reported for that AE and will include the number of days from date of first dose to 
date of the occurrence of the AE. 
9.4 Vital Signs and Other Observations Related to Safety 
Listings will include all participant vital signs and any other comments as provided by the 
examining clinician. Vital signs statistics  will be summarized in table form by treatment group 
and study visit. These tables will include summary statistics appropriate for variable type as 
listed in Section 3.  
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9.5 Unanticipated Problems 
Unanticipated problems will be included in the listings. 
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10. INTERIM ANALYSES AND DATA MONITORING 
No interim analyses have been planned. 
11. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
No changes to the analyses planned in the protocol have been made. 
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12. 
APPENDICES 
12.1 Study Schematic 
 
 
 
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12.2 Schedule of Events 
 
Study Phase: 
Pre-screeninga 
Screening 
and 
Baseline 
Randomization and Treatment 
(1 week titration, 8 weeks maintenance, and 
1 week taper) 
Follow-Up 
Clinic Visit: 
 
V0 
V1b 
V2 
V3 
V4 
V5 
 
                    Study Day: ≤ 28 days prior to
V0 
7 to 21 days 
prior to V1  
0 
7 (+ 3) 
35 (± 7) 
63 (+ 6) 
77 (+ 7) 
Procedure 
 
 
 
 
 
 
 
Contact Information 
x 
 
 
 
 
 
 
Prescreening Interview Script 
x 
 
 
 
 
 
 
Informed Consentc 
 
x 
 
 
 
 
 
Eligibility Review 
x 
x 
x 
 
 
 
 
AUDIT Questionnaire 
 
x 
 
 
 
 
 
Smoking Questionnaire 
 
x 
 
 
 
 
x 
Alcohol Consumption per week  
 
 
x 
x 
x 
x 
x 
Demographic Information 
 
x 
 
 
 
 
 
Medical History and Review 
x 
x 
x 
x 
x 
x 
x 
Concomitant Medications 
 
x 
x 
x 
x 
x 
x 
Concomitant Therapies 
 
x 
x 
x 
x 
x 
x 
Dispense New Daily Symptom Diaries 
 
x 
x 
x 
x 
x 
 
Adverse Event Review 
 
 
x 
x 
x 
x 
x 
Collect Daily Symptom Diaries 
 
 
x 
x 
x 
x 
x 
Assess Compliance with Daily Symptom Diaries 
 
 
x 
x 
x 
x 
x 
Collect Confidence in Treatment Outcome 
 
 
x 
 
 
 
 
Randomization 
 
 
x 
 
 
 
 
Dispense Study Drug 
 
 
xd 
x 
x 
x 
 
Collect Study Drug Container(s) 
 
 
 
x 
x 
x 
x 
Assess Compliance with Study Drug 
 
 
 
x 
x 
x 
x 
Clinical Examinations and Tests 
 
 
 
 
 
 
 
Physical Measurements 
 
x 
 
 
 
 
 
Version 3.0 
 
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SOPPRANO 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. 14-067-E 
21 Feb 2018 
Study Phase: 
Pre-screeninga 
Screening 
and 
Baseline 
Randomization and Treatment 
(1 week titration, 8 weeks maintenance, and 
1 week taper) 
Follow-Up 
Clinic Visit: 
 
V0 
V1b 
V2 
V3 
V4 
V5 
 
                    Study Day: ≤ 28 days prior to
V0 
7 to 21 days 
prior to V1  
0 
7 (+ 3) 
35 (± 7) 
63 (+ 6) 
77 (+ 7) 
Vital Signs 
 
x 
x 
x 
x 
x 
x 
Urine Pregnancy Test (females) 
 
x 
x 
x 
x 
x 
x 
Manual Tender Point Exam 
 
x 
 
 
 
 
 
TMD Examination 
 
x 
 
 
x 
x 
 
Heat and Pressure Pain Tests  
 
x 
 
 
x 
x 
 
12-Lead ECG 
 
x 
 
 
 
 
 
Blood Draw 
 
 
x 
 
 
x 
 
Schedule Next Visit 
x 
x 
x 
x 
x 
x 
 
Outcome Measure Questionnaires 
 
 
 
 
 
 
 
Symptom Inventory 
 
x 
x 
x 
x 
x 
x 
Fibromyalgia Questionnaire 
 
x 
 
 
 
 
 
Headache Questionnairee 
 
 
x 
 
 
 
 
SF-McGill Pain Questionnaire 
 
x 
 
x 
x 
x 
x 
Graded Chronic Pain Scalee 
 
 
x 
 
x 
x 
 
SF-12 Health Survey v2e 
 
 
x 
 
x 
x 
 
Jaw Functional Limitation Scalee 
 
 
x 
 
x 
x 
 
Perceived Stress Scalee 
 
 
x 
 
x 
x 
 
Hospital Anxiety and Depression Scalee 
 
 
x 
 
x 
x 
 
Pittsburgh Sleep Quality Indexe 
 
 
x 
 
x 
x 
 
Headache Impact Test (HIT-6) e 
 
 
x 
 
x 
x 
 
SCL-90R Somatization Scalee 
 
 
x 
 
x 
x 
 
Coping Strategies Questionnaire-Revisede 
 
 
x 
 
 
 
 
Patient Global Impression of Changee 
 
 
 
 
x 
x 
 
AUDIT = Alcohol Use Disorders Identification Test; ECG = electrocardiogram; SCL-90 = Symptom Checklist -90R; SF = Short Form; V = Visit 
a May occur by phone or at a clinic visit, and may be combined with the Screening and Baseline Visit (Visit 0). 
Version 3.0 
Page 24 of 25 


SOPPRANO 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. 14-067-E 
21 Feb 2018 
b If Visit 1 cannot occur within 3 weeks of Visit 0 and the participant is to remain in the study, then Visit 0 will be repeated as an unscheduled visit. The timing of 
Visits 3-6 and their windows are established from the date of Visit 1. 
c Includes consent for study participation, consent to store biological specimens for future studies, and Health Insurance Portability and Accountability Act 
statement, if applicable. 
d The first dose of study drug should be taken in the evening of the Day 1. 
e Questionnaires will be distributed at Visit 0 and the participant will return completed questionnaires at Visit 1. 
Version 3.0 
Page 25 of 25