Erenumab as a Therapeutic Approach for the Management of Painful Chronic Temporomandibular Disorders (TMD)
Phase: PHASE2
Conditions: Temporomandibular Disorders
Sponsor: University of Maryland, Baltimore

Erenumab as a therapeutic approach for the management 
of painful chronic temporomandibular disorders (TMD) 
Protocol Number: HP-0093037 (UMB) 
Grant Number: Amgen ISS 20207211 
Principal Investigator: Marcela Romero Reyes DDS, PhD 
IND/IDE Sponsor: IND EXEMPT 
Draft or Version Number:  <1.2> 
REDACTED VERSION : 01/16/2024 
 
 

Erenumab as a therapeutic approach for the management of chronic TMD 
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 Erenumab as a therapeutic approach for the 
management of painful chronic 
temporomandibular disorders (TMD) 
Protocol Number: HP-0093037 (UMB) 
Grant Number: Amgen ISS 20207211 
Principal Investigator: Marcela Romero Reyes DDS, PhD 
IND/IDE Sponsor: IND EXEMPT 
Draft or Version Number:  <1.2> 
11 March 2022 
 
 
 
 
 

Erenumab as a therapeutic approach for the management of chronic TMD 
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STATEMENT OF COMPLIANCE 
   
The study will be conducted in accordance with the International Conference on 
Harmonisation guidelines for Good Clinical Practice (ICH E6), the Code of Federal 
Regulations on the Protection of Human Subjects (45 CFR Part 46), and the NIDCR 
Clinical Terms of Award. All personnel involved in the conduct of this study have 
completed human subjects protection training. 

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SIGNATURE PAGE 
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. 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date: 3/31/2022 
 
Name: Marcela Romero Reyes DDS,PhD 
 
Title: Clinical Associate Professor, Director, Brotman Facial Pain Clinic 
 
{For multi-site studies, 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.  
For a clinical trial involving an Investigational New Drug (IND), this is the individual who 
signs the Form FDA 1572 for a drug or the investigator agreement for a device.}0 
 

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TABLE OF CONTENTS 
{This table uses the Table of Contents function in Microsoft Word that will automatically 
update headings and page numbers used in the body of the report.  To update the 
Table of Contents and all cross-references in the document, press CTRL-A to select the 
entire document, then press F9.} 
PAGE 
STATEMENT OF COMPLIANCE ................................................................................................. I 
SIGNATURE PAGE .................................................................................................................... II 
TABLE OF CONTENTS ............................................................................................................. III 
LIST OF ABBREVIATIONS ....................................................................................................... VI 
PROTOCOL SUMMARY ......................................................................................................... VIII 
1 
KEY ROLES AND CONTACT INFORMATION ................................................................. 12 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ....... 14 
2.1 
Background Information ........................................................................................ 14 
2.2 
Rationale .............................................................................................................. 15 
2.3 
Potential Risks and Benefits ................................................................................. 16 
2.3.1 
Potential Risks .......................................................................................... 16 
2.3.2 
Potential Benefits ...................................................................................... 17 
3 
OBJECTIVES ................................................................................................................... 18 
3.1 
Study Objectives ................................................................................................... 18 
3.2 
Study Outcome Measures .................................................................................... 18 
3.2.1 
Primary ...................................................................................................... 18 
3.2.2 
Secondary ................................................................................................. 18 
4 
STUDY DESIGN .............................................................................................................. 20 
5 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................. 21 
5.1 
Subject Inclusion Criteria ...................................................................................... 21 
5.2 
Subject Exclusion Criteria ..................................................................................... 23 
5.3 
Strategies for Recruitment and Retention ............................................................. 24 
5.4 
Treatment Assignment Procedures ....................................................................... 25 
5.4.1 
Randomization Procedures (if applicable) ................................................. 25 
5.4.2 
Masking and Unbliniding Procedures (if applicable) .................................. 26 
5.5 
Subject Withdrawal ............................................................................................... 27 
5.5.1 
Reasons for Withdrawal ............................................................................ 27 
5.5.2 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention ............................................................................................... 27 
5.6 
Premature Termination or Suspension of Study .................................................... 28 
6 
STUDY INTERVENTION .................................................................................................. 29 
6.1 
Study Product Description .................................................................................... 29 
6.1.1 
Acquisition ................................................................................................. 29 
6.1.2 
Formulation, Packaging, and Labeling....................................................... 29 
6.1.3 
Product Storage and Stability .................................................................... 30 
6.2 
Dosage, Preparation and Administration of Study Product .................................... 30 

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6.3 
Modification of Study Product Administration for a Subject ................................... 31 
6.4 
Accountability Procedures for the Study Product .................................................. 32 
6.5 
Assessment of Subject Compliance with Study Product Administration ................ 32 
6.6 
Concomitant Medications/Treatments ................................................................... 32 
7 
STUDY SCHEDULE ......................................................................................................... 34 
7.1 
Pre-Screening ....................................................................................................... 34 
7.2 
Screening and Baseline Visit (Visit 0, 1-3 weeks period) ....................................... 34 
7.3 
Treatment Visits .................................................................................................... 35 
7.4 
Follow up and final Study Visit, Visit 5 (Day 120, 4 weeks after Visit 4 ) ................ 38 
7.5 
Withdrawal Visit .................................................................................................... 39 
7.6 
Unscheduled Visit ................................................................................................. 39 
8 
STUDY PROCEDURES /EVALUATIONS ........................................................................ 40 
8.1 
Study Procedures/Evaluations .............................................................................. 40 
8.2 
Laboratory Procedures/Evaluations ...................................................................... 42 
8.2.1 
Clinical Laboratory Evaluations ................................................................. 42 
8.2.2 
Special Assays or Procedures ................................................................... 42 
8.2.3 
Specimen Preparation, Handling, and Storage .......................................... 42 
8.2.4 
Specimen Shipment .................................................................................. 43 
9 
ASSESSMENT OF SAFETY ............................................................................................ 44 
9.1 
Specification of Safety Parameters ....................................................................... 44 
9.1.1 
Unanticipated Problems ............................................................................ 45 
9.1.2 
Adverse Events ......................................................................................... 45 
9.1.3 
Serious Adverse Events ............................................................................ 45 
9.2 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 46 
9.3 
Characteristics of an Adverse Event ..................................................................... 46 
9.3.1 
Relationship to Study Intervention ............................................................. 46 
9.3.2 
Expectedness of SAEs .............................................................................. 47 
9.3.3 
Severity of Event ....................................................................................... 47 
9.4 
Reporting Procedures ........................................................................................... 48 
9.4.1 
Unanticipated Problem Reporting to IRB and AMGEN .............................. 48 
9.4.2 
Serious Adverse Event Reporting to AMGEN Safety and UMB IRB .......... 49 
9.4.3 
Reporting of SAEs and AEs to FDA .......................................................... 53 
9.4.4 
Events of Special Interest (if applicable) .................................................... 53 
9.4.5 
Reporting of Pregnancy ............................................................................. 53 
9.5 
Halting Rules ........................................................................................................ 53 
10 
STUDY OVERSIGHT ....................................................................................................... 55 
11 
CLINICAL SITE MONITORING ........................................................................................ 56 
12 
STATISTICAL CONSIDERATIONS .................................................................................. 57 
12.1 
Study Hypotheses ................................................................................................. 57 
12.2 
Sample Size Considerations ................................................................................. 58 
12.3 
Planned Interim Analyses (if applicable) ............................................................... 58 
12.3.1 Safety Review ........................................................................................... 58 
12.3.2 Efficacy Review ......................................................................................... 58 

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12.4 
Final Analysis Plan ............................................................................................... 58 
13 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .................. 60 
14 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................................ 61 
15 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................. 62 
15.1 
Ethical Standard ................................................................................................... 62 
15.2 
Institutional Review Board .................................................................................... 62 
15.3 
Informed Consent Process ................................................................................... 62 
15.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 63 
15.5 
Subject Confidentiality .......................................................................................... 63 
15.6 
Future Use of Stored Specimens and Other Identifiable Data ............................... 63 
16 
DATA HANDLING AND RECORD KEEPING ................................................................... 64 
16.1 
Data Management Responsibilities ....................................................................... 64 
16.2 
Data Capture Methods .......................................................................................... 64 
16.3 
Types of Data ....................................................................................................... 64 
16.4 
Schedule and Content of Reports ......................................................................... 65 
16.5 
Study Records Retention ...................................................................................... 65 
16.6 
Protocol Deviations ............................................................................................... 65 
17 
PUBLICATION/DATA SHARING POLICY ........................................................................ 66 
18 
LITERATURE REFERENCES .......................................................................................... 67 
SUPPLEMENTAL MATERIALS ................................................................................................ 70 
APPENDICES ........................................................................................................................... 71 
APPENDIX A: SCHEDULE OF EVENTS .................................................................................. 72 
 

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LIST OF ABBREVIATIONS 
{Please add all disease or study-specific abbreviations/acronyms in this section. Modify 
this list as needed for your particular study and remove abbreviations that are not used 
in the document.} 
 
AE 
Adverse Event/Adverse Experience 
AMGEN 
AMGEN (AMGEN, biopharmaceutical company) 
CFR 
Code of Federal Regulations 
CGRP 
Calcitonin Gene Related Peptide 
CIOMS 
Council for International Organizations of Medical Sciences 
CIBR 
Center for Innovative Biomedical Resources 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSOC 
Clinical Study Oversight Committee 
DCC 
Data Coordinating Center 
DC/TMD 
Diagnostic Criteria/Temporomandibular Disorders  
DHHS 
Department of Health and Human Services 
DMFS 
Decayed, missing, and filled tooth surfaces 
DSD 
Daily Symptom Diary 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FFR 
Federal Financial Report 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ICTR 
Institute for Clinical & Translational Research  
IDE 
Investigational Device Exemption 
IDS 
Investigational Drug Services 

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IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NDA 
New Drug Application 
OCTOM 
Office of Clinical Trials Operations and Management, NIDCR, NIH 
OHRP 
Office for Human Research Protections 
OFP 
Orofacial Pain 
PHI 
Protected Health Information 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SC 
Subcutaneous ( as subcutaneous injection) 
SOP 
Standard Operating Procedure 
TMD 
Temporomandibular Disorders 
UMB 
University of Maryland 
UMBSOD 
University of Maryland, School of Dentistry  
UP 
Unanticipated Problem 
US 
United States 
WHO 
World Health Organization 
 

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PROTOCOL SUMMARY 
 
Title:                      
Erenumab as a therapeutic approach for the management 
of painful chronic temporomandibular disorders (TMD). 
Précis: 
A total of 60 patients (30 per each arm) aged 18-65 years old of 
either sex, and any race or ethnicity presenting chronic 
temporomandibular disorders (TMD) will be randomly assigned 
in a 1:1 parallel, double-blind clinical trial, to receive either 
Erenumab or placebo. Participants will attend 6 clinic visits (Visit 
0-Visit 5) over a period of 21 weeks.  
Potential participants will be pre-screened at the Brotman Facial 
Pain clinic and the Oral and Maxillofacial Surgery Clinic  both at 
the University of Maryland, School of Dentistry or by telephone; 
those willing to participate will be scheduled for a screening and 
baseline visit (Visit 0). During this visit potential participants will 
be evaluated for eligibility and written informed consent will be 
obtained. The screening and baseline procedures include 
medical history review, clinical examinations, tests and 
administration of questionnaires. Instructions will be given for 
the completion of a Daily Symptom Diary (DSD) and other 
questionnaires at home or online. Participants who show 80% 
compliance with the DSD and who meet the pain score 
(inclusion criteria) after Visit 0 (baseline period), will be randomly 
assigned to one of two groups either the investigational drug or 
placebo and will be scheduled for Visit 1.  
The study drug is Erenumab 70mg, SC injection. After 
randomization and on Visit 1, the participant will receive the drug 
or placebo. This same treatment will be administered once a 
month for 3 months (3 cycles/12 weeks). The primary end point 
will be a change in the average pain index score from baseline, 
representing the mean of daily average pain intensity score 
values (0-100 scale) derived from Daily Symptom Diaries for 12 
weeks (12 weeks treatment). 
Secondary end points will be participant ratings of other pain 
related outcomes, examiner assessment of pain, occurrence of 
symptoms and adverse events. 
Exploratory end points are change of pro-inflammatory and anti-
inflammatory cytokine profiles (Th1/Th2). 
 

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Objectives: 
 
Primary: To investigate the efficacy of Erenumab compared to 
placebo on the reduction of pain scores in patients with TMD 
during a 12-week treatment period.  
Secondary: To determine the efficacy of Erenumab on the 
proportion of subjects with at least 50% reduction from baseline 
in mean monthly TMD pain days and to determine the efficacy 
of Erenumab using functional measures namely, jaw functional 
limitation, pressure pain thresholds and oral behaviors disability, 
and emotional functioning. 
Exploratory: To investigate the efficacy of Erenumab in 
decreasing 
pro-inflammatory 
cytokine 
release 
(pro-
inflammatory/anti-inflammatory panel profile: (IL-6, TNF-α, IL1-, 
β/ IL-10, IL-4).  
 
 
 
 
 
Population: 
60 adults of either sex and any ethnicity between the ages of 18 
and 65 years with a diagnosis (According to the Diagnostic 
Criteria for Temporomandibular Disorders (DC/TMD) for Clinical 
and Research Applications) of chronic TMD (myalgia +/- 
arthralgia) and no contraindications for the use of Erenumab will 
be enrolled from the Brotman Facial Pain Clinic and the Oral and 
Maxillofacial Surgery clinic from the University of Maryland, 
School of Dentistry.  
Phase: 
 II 
Number of Sites: 
University of Maryland, School of Dentistry 
Description of  
Intervention: 
Study drug is Erenumab 70mg or an inert placebo will be 
administered by subcutaneous injection once a month (3 
cycles) over a 12-week period. 
  
Study Duration: 
36 months 

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Subject 
Participation 
Duration: 
21 weeks 
Estimated Time to 
Complete 
Enrollment: 
Approximately 2.5 years (30 months) 

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Schematic of Study Design: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 300:  Obtain verbal consent to pre-screen by phone or in person in clinic for potential eligibility. Explain study 
purpose and design.  For potential participants, contact information collected; schedule Visit 0  
Randomize 
Arm 2: PLACEBO 
N=30 participants 
Arm 1: ERENUMAB 
N=30 participants 
Screen 60 participants. Obtain written consent. Obtain med hx, height, weight, vitals, demographics, concomitant 
meds/therapies, collect blood (cytokine release) and urine for pregnancy. Perform DC-TMD, PPT. Administered pain 
questionnaires; instruct completing at home questionnaires and Daily Symptom diary (DSD). 
Review DSD and pain score. If still eligible proceed to randomize and Schedule Visit 1 
Day 14 Telephone check in: Review medication tolerance/AE 
Review DSD, concomitant meds/therapies, AEs, questionnaires from V1. Collect weight, vitals., urine pregnancy test, review 
eligibility. Perform DC-TMD, PPT; Administered pain questionnaires; instruct completing DSD and at home questionnaires; 
Perform s.c. injection of Study drug/placebo. Schedule visit 3. 
Day 42 Telephone check in: Review medication tolerance/AE 
Review DSD, concomitant meds/therapies, AEs, questionnaires from V2. Collect weight, vitals., urine pregnancy test, review 
eligibility. Perform DC-TMD, PPT; Administered pain questionnaires; instruct completing DSD and at home questionnaires; 
Perform s.c. injection of Study drug/placebo. Schedule visit 4. 
Day 70 Telephone check in: Review medication tolerance/AE 
Review DSD, concomitant meds/therapies, AEs, questionnaires from V2. Collect weight, vitals., urine pregnancy test, review 
eligibility collect blood (cytokine release). Perform DC-TMD, PPT; Administered pain questionnaires; instruct completing DSD 
and at home questionnaires. Schedule final visit/follow up visit 5  
Day 98 Telephone check in: Review medication tolerance/AE 
Review DSD, concomitant meds/therapies, AEs, questionnaires from V2. Collect weight, vitals., urine pregnancy test. Perform 
DC-TMD, PPT; Administered pain questionnaires; Provide final instructions. Complete disposition form. 
Pre-enrollment/pre-
screening (0-2 weeks) 
Visit 0: Screening and 
Baseline (4 weeks)   
Randomization (7 
days after baseline 
phase Visit 0) 
Visit 2: Treatment  
Day 28 
Visit 3: Treatment  
Day 56 
Visit 4: End of cycle 
Day 84 
Visit 5: Follow 
up/final visit  
Day 112 
Visit 1: Treatment. 
Day 0 
Review DSD and at home questionnaires from Visit 0, concomitant meds/therapies/AEs. Collect weight, vitals, urine 
pregnancy test. Administered pain questionnaires; review eligibility criteria, instruct completing DSD and at-home 
questionnaires. Perform s.c. injection of Study drug/placebo. Schedule Visit 2  

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1 KEY ROLES AND CONTACT INFORMATION 
 
Principal 
Investigator:   
Marcela Romero Reyes DDS, PhD 
Clinical Associate Professor, Clinical Director, Brotman Facial 
Pain Clinic 
Department of Neural and Pain Sciences 
University of Maryland, Baltimore 
School of Dentistry 
650 W. Baltimore St, Room 8253 
Baltimore, MD 21201 
Phone: 410-706-7168 
FAX: 410-706-086  
 
Medical Monitor: 
DSMB 
Program Official:   
 
Other Key 
Personnel: 
Jane L Phillips RDH MS 
Faculty Research Assistant/Study Coordinator 
Department of Neural and Pain Sciences 
University of Maryland, Baltimore 
School of Dentistry 
650 W. Baltimore St, Room 4307 
Baltimore, MD 21201 
Phone: 410 706 63454 
 
 
Gary Warburton MD, DDS  
Associate Professor in Oral and Maxillofacial Surgery 
Department of Oral and Maxillofacial Surgery 
University of Maryland, Baltimore 

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School of Dentistry  
650 W. Baltimore St, Room 1201 
Baltimore, MD 21201 
Phone: 410 706 7060 
 
  

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2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
2.1 
Background Information 
Temporomandibular disorders (TMD) are a group of related heterogenous 
musculoskeletal disorders that affect the temporomandibular joint (TMJ), masticatory 
muscles, and associated structures [1]. TMD pain commonly can be localized in the 
muscles of mastication, along the mandible, the pre-auricular area, the ear, the temple 
area as well as associated with TMJ biomechanics, such as mandibular movements, 
including chewing, talking, yawing and mouth opening[2]. 
Pain associated with TMD is one of the most common complaints in the craniofacial and 
cervical area and the most common non-dental reason why patients seek treatment in 
the dental office [3, 4].  TMD have an overall prevalence estimated between 5% and 12% 
[5] and are more prevalent in women [5, 6]. TMD include myalgia, arthralgia, intra-articular 
disorders and degenerative joint diseases [7]. TMD exert a significant burden on the 
population affecting the productivity and quality of life [8] and it can also be present with 
other pain conditions such as lower back pain, fibromyalgia and headache[9, 10]. 
For some patients, TMD has a tendency to remit or improve pain symptomatology over 
time [11, 12] but for others, TMD have the potential to become chronic and to lead to 
persistent dysfunction [13-15]. TMD management should be conservative, reversible and 
based in evidence based therapeutics [16, 17] and includes a combination of home self-
care, physical therapy, pharmacotherapy, oral appliance therapy, and behavioral 
interventions [2, 18]. Pharmacotherapy includes non-steroidal anti-inflammatory drugs 
(NSAIDs), corticosteroids, muscle relaxants, benzodiazepines, and some anticonvulsants 
and antidepressants [18] but clear evidence establishing their efficacy is limited. 
Gabapentin, and anti-epileptic medication have shown to be superior than placebo in 
reducing myalgia [19] but dizziness and sedation, often present in this drug class with 
other important side effects, have been reported with its use [20]. Recently propanonol, 
a non-selective beta adrenergic receptor antagonist, was shown to reduce TMD myalgia 
when compared to placebo [21]. However, no medical treatment exists that is approved 
by the Food and Drug Administration (FDA) specifically for the management of TMD. 
Therefore, safer, and novel pharmacological therapy protocols are urgently needed to 
address this unmet medical need with significant social and psychological implications. 
The calcitonin gene-related peptide (CGRP) is a pro-inflammatory vasodilating 
neuropeptide involved in migraine pathophysiology in where CGRP levels increase during 
a migraine attack [22]. Targeting the CGRP receptor pathway has proven to be effective 
in migraine therapeutics. Erenumab is a fully human monoclonal antibody that inhibits 
CGRP pathway and is the first in its class to be FDA approved for the management of  
migraine as a migraine preventive[23]. 
TMD and migraine are often co-morbid. The presence of TMD significantly increases the 
likelihood of any form of headache, particularly migraine and can exacerbate its disability 

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impact [10, 24-26]. We and others have shown that CGRP is also involved in TMD 
pathophysiology [27] and we demonstrated that blocking CGRP with a CGRP receptor 
antagonist in a pre-clinical model of TMD, significantly decreased nociception[28]. The 
management of chronic TMD inhibiting CGRP pathway with an FDA approved medication 
that has been proved safe for another indication such as migraine which shares CGRP 
as a molecular link, would be very promising. Therefore, we have hypothesized that 
Erenumab - a monoclonal antibody that inhibits CGRP receptor- reduces pain and 
restores function in patients suffering of chronic TMD. This proposed clinical trial is the 
first study of this nature, looking at Erenumab as a new pharmacological therapy for 
patients suffering of chronic TMD. 
The study will be a randomized, double blind, placebo-controlled trial comparing 
Erenumab vs Placebo. Participants will be evaluated for TMD and have other related 
assessments; blood samples will be collected, and they will need to answer some 
questionnaires. We are going to assess changes in pain intensity and other pain 
outcomes related to TMD. 
 
2.2 
Rationale 
Chronic TMD is a considerable burden and affects significantly the quality of life of the 
sufferer [8]. Medications such as gabapentin and propranolol have indicated to be 
beneficial in clinical studies [19, 21], but tolerability and side effects may be present for 
some patients. Furthermore, the indications of these drugs are for other disorders, so it 
is unclear their mechanism of action in TMD pathophysiology. Currently there is no 
medication specifically indicated for the management of TMD based on its molecular 
pathophysiology. However, there is evidence showing that CGRP has a role in TMD 
pathophysiology [27] and we demonstrated that targeting CGRP in a preclinical model of 
TMD decreased nociception [28].  
CGRP is a key molecule in migraine pathophysiology. Erenumab is the first antibody 
therapeutic targeting the CGRP receptor with FDA approval [23]. It has shown efficacy, 
to be well tolerated and with a safety profile similar to placebo for the prevention of chronic 
migraine in adults [29-31]. Erenumab is also approved in the prevention of episodic 
migraine  in adults demonstrating its efficacy in randomized controlled clinical trials and  
has been shown promising for the management post-traumatic headache attributed to 
brain injury [32, 33]. Migraine and TMD share CGRP as a molecular link [26]. Therefore, 
the scientific premise for this study is that inhibiting CGRP in chronic TMD will decrease 
pain, pain related outcomes and improve TMJ biomechanics (function) in a safe and well 
tolerated manner for this patient population. 
 

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2.3 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
Use of Erenumab: Erenumab is a fully human monoclonal antibody that inhibits CGRP 
receptor and is FDA approved for the preventive treatment of migraine in adults.  As of 
16 May 2020, approximately 6,550 people have received erenumab in research studies. 
Since it was first approved for sale on 17 May 2018, approximately 423,800 people have 
been prescribed erenumab (Aimovig®) for treatment as of 16 May 2020. 
The safety profile of erenumab has been favorable in clinical trials and in the post-
marketing setting. A limited number of adverse drug reactions (injection site reactions, 
constipation, muscle spasm, and pruritus) have been identified at low frequencies (< 5%) 
in clinical trials. In the long-term use of erenumab, the safety profile remained consistent 
through 5 years of open-label treatment. In post-marketing settings, hypersensitivity 
reactions (including rash, angioedema and anaphylactoid reactions) and constipation with 
serious complications have been reported. In addition, oral sores (eg, stomatitis, mouth 
ulceration, oral mucosal blistering), alopecia and rash (eg, rash papular, exfoliative rash, 
rash erythematous, urticaria, blister) have been observed in post-marketing surveillance 
 
Serious constipation has been reported in patients prescribed erenumab. In some cases, 
hospitalization or surgery was required. Constipation and the use of medications that 
decrease gastric motility are in our exclusion criteria, however if a new onset of 
constipation occurs, the participant will be withdrawn of the study and will be referred to 
an appropriate practitioner for continued care (see section 9.2). 
 
Hypertension or worsening of high blood pressure can happen after receiving Erenumab.  
Hypertension is in our exclusion criteria, however if a new onset of hypertension occurs, 
the participant will be withdrawn of the study and will be the participant will be referred to 
an appropriate practitioner for continued care (see section 9.2) 
 
After taking erenumab, antibodies against erenumab may be produced; this has been 
observed in clinical studies. No side effects associated with these antibodies were 
observed.  
 
Side effects of the use of erenumab in combination with other drugs are unknown at this 
time.  
 
There are no adequate data on the developmental risk associated with the use of 
erenumab in pregnant women or breastfed babies. There are no data on the presence of 
erenumab in human milk, or on milk production. Pregnant women, breastfeeding women 
and women planning to become pregnant will be excluded from this study. If a participant 
gets pregnant, decides to breastfeed her baby or father a child while taking erenumab will 
be withdrawn from the study and will be monitored and referred to an appropriate 
practitioner for continued care (see section 9.2 and 9.4.1). 

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Participants will be closely monitored for any AEs, during the clinic visit and between visits 
by telephone. Potential risks and discomforts will be clearly stated in the ICF. 
TMD examination and pressure pain threshold testing (PPT): A TMD examination will 
assess muscles of mastication and TMJ sensitivity to manual palpation. The PPT will 
assess pain applying pressure with the use of an algometer in muscles and the TMJs. 
Both assessments will be performed on 4 clinic visits. It is expected that these 
assessments will evoke brief pain or discomfort within a range that is acceptable for the 
participant. Transient redness or tenderness of the skin may appear after these 
assessments but none of them is expected to result in lasting discomfort or tissue 
damage. In addition, the participants may request to stop the examination/test at any time. 
These assessments will end upon the completion of the modality or upon the participant’s 
request, whichever comes first. 
Self-care: It is possible that some participants may feel frustrated if they are unable to 
incorporate and to understand some self-management approaches.   
Questionnaires: It is possible that some participants may experience discomfort 
associated with answering several questionnaires as well as with being asked personal 
questions about his/her emotional state and feelings, health history or symptomatology. 
The participants will be informed that they can choose not to answer any question for any 
reason. 
Blood collection: Participants may find the blood draw unpleasant and there is a possibility 
of mild pain and bruising associated with it. Trained personnel will perform the blood draw 
using standard procedures. If for any reason the blood draw is being difficult (i.e. finding 
a vein) and the subject/patient is uncomfortable, the blood draw will be stopped 
immediately. The participants will be informed that they can choose to stop the blood 
collection for any reason. 
2.3.2 
Potential Benefits 
Participants may or may not receive benefit from the use of Erenumab in pain reduction 
and improved function. Additionally, if Erenumab proves to be effective, this will be the 
first pharmacological approach specifically indicated for TMD with a clear mechanism of 
action and will provide a novel therapeutic approach to fulfill this highly unmet medical 
need, changing current management paradigms for the patients suffering of chronic TMD. 
 

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3 OBJECTIVES 
3.1 
Study Objectives 
Primary Objective 
To investigate the efficacy of Erenumab compared to placebo in the reduction of pain 
scores in participants with chronic TMD during a 12-week treatment period. 
Secondary Objectives 
To determine the efficacy of Erenumab on the proportion of subjects with at least 50% 
reduction from baseline in mean monthly TMD pain days. 
To determine the efficacy of Erenumab using functional measures and pain related 
behaviors: Jaw function, Pressure Pain Thresholds, Oral Behaviors, changes in pain 
intensity and pain related disability, perspective of pain improvement, and anxiety and 
depression.  
Exploratory Objectives 
To explore changes in pro-inflammatory and anti-inflammatory cytokines from 
plasma/serum. 
 
3.2 
Study Outcome Measures 
3.2.1 
Primary 
The primary endpoint will be a monthly mean pain intensity score change from baseline, 
representing the arithmetic mean of daily average pain intensity score values. The daily 
average pain intensity score will be measured on a 0-100 numeric rating scale (NRS) and 
reported in the Daily Symptom Diary (DSD). The monthly mean pain intensity score will 
be determined from baseline, for each month/cycle (4 weeks/28 days) during the 12 
weeks (3 cycles) of treatment and the last month prior last visit (Follow up). 
The monthly mean pain intensity score will be calculated if a participant has at least 80% 
compliance with the DSD. 
3.2.2 
Secondary 
Efficacy will be investigated further using secondary outcomes: 
TMD pain days: Percentage of participants with at least a 50% reduction from baseline in 
monthly TMD pain days. Time Frame: Baseline phase, the 12 weeks of management and 
until Visit 4. 

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Definition of TMD pain day: A TMD pain day was any calendar day in which the participant 
experienced pain, stiffness, soreness, tenderness, in the jaw or temple area or either side 
being brief or continuous; and/or pain with TMJ biomechanics (chewing, mouth opening 
or any jaw movement; and/or pain with jaw activities (yawning, kissing, talking); and/or 
pain with jaw habits (chewing gum, clenching, grinding). 
At least a 50% reduction from baseline in monthly TMD days will be determined if the 
change in monthly TMD days from baseline phase through the 12 weeks treatment phase 
(3 cycles) * 100 / baseline monthly TMD days less than or equal to -50%. 
Functional measures related to TMJ biomechanics and pain related behaviors:  
TMD examination and Jaw functional limitation Scale: Change related to TMJ 
biomechanics/Jaw function and symptomatology in response to TMD examination.  
Oral Behaviors (OBC): Changes in parafunctional behaviors 
Pressure Pain Thresholds: Changes in myalgia and arthralgia 
Graded Chronic Pain Scale (GCPS): Changes in pain intensity and pain related disability 
Patient Global Impression of Change (PGIC): Assesses patient perspective of pain 
improvement 
Hospital Anxiety and Depression Scale: Evaluation of Anxiety and depression  
 
Exploratory Endpoint 
To investigate the efficacy of Erenumab in decreasing pro-inflammatory cytokine release 
(pro-inflammatory/anti-inflammatory panel profile: IL-6, TNF-α, IL1-β/IL-10, IL-4).  
 
 

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4 STUDY DESIGN 
60 patients (30 per each arm) aged 18-65 years old of either sex, and any race or ethnicity 
presenting chronic painful temporomandibular disorders (TMD) will be randomly assigned 
in a 1:1 parallel, double-blind, phase 2 single center clinical trial, to receive either 
Erenumab or placebo. Participants will attend 6 clinic visits (Visit 0-Visit 5) over a period 
of 21 weeks. The study should be completed over a period of 3 years, with an estimated 
duration of recruitment of 2.5 years. 
Participants will be pre-screened in person at the Brotman Facial Pain clinic, the Oral and 
Maxillofacial Surgery Clinic both at the University of Maryland, School of Dentistry or by 
telephone. Potentially eligible and interested participants will be scheduled for a 
Screening and Baseline Visit (Visit 0). During Visit 0, participants will provide informed 
consent and be evaluated for eligibility; information including demographics, medical 
history, concomitant medications, and therapies will be collected. In addition, participants 
will be assessed for pain level, pain symptoms, jaw function, health status, among other 
measures and a blood sample will be collected. 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). 
Participants who show compliance with the Daily Symptom Diary of at least 80% and who 
meet the pain score (inclusion criteria) for 28 days/4 weeks (baseline period) after Visit 0, 
will be randomly assigned to one of two groups (Erenumab or placebo) and will be 
scheduled for Visit 1 within a week of randomization. 
At Visit 1, randomized participants will receive the 1st cycle of management and begin a 
12-week drug treatment/placebo phase that will be divided into once a month 
injection/cycle for a total of 3 cycles. During that period, Visits 2-4 will take place, and 
many of the baseline assessments will be repeated. Between visits, communication will 
be conducted by telephone. The final study visit, visit 5, will occur 4 weeks after the last 
assessment (visit 4) and 8 weeks after the last dosage of drug treatment (Visit 3).   
The primary endpoint will be the change in a monthly mean pain intensity score derived 
from the Daily Symptom Diary. Efficacy will be evaluated as the difference between 
Erenumab arm and the placebo arm in the monthly pain intensity score (on a 0-100 scale) 
during the 12 week treatment period.  

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5 STUDY ENROLLMENT AND WITHDRAWAL 
The study is planning to enroll a total of 60 subjects that will be randomly assigned to one 
of the two study groups. It is anticipated that a total of 300 subjects will be screened in 
order to meet recruitment goals. 
Vulnerable subjects: No specific vulnerable populations are being targeted for recruitment 
for this study. 
 
5.1 
Subject Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the 
following criteria: 
1. Provide 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: Myalgia with or without arthralgia 
• The participant must meet 2 criteria relating: 1) reported pain, ache or 
tenderness in the face, jaw/mandible, pre-auricular area, inside the ear or 
temple that it is modified by TMJ biomechanics. 2) finding(s) of TMD 
myalgia according to the classification DC/TMD criteria. 
4. Has experienced facial pain and/or pain with TMJ biomechanics for the last 3 
months episodically or unremitting   
5. Has experienced facial pain for at least 10 days of the last 30 days prior to 
Baseline Visit (Visit 0)  
 
6. Prior to randomization, has been compliant 80% with the entries in the Daily 
Symptom Diary within the baseline period and reported an average pain level 
≥30 on a numerical rating scale (0-100) in the DSD, or has experienced a pain 
level ≥30 on the same scale for at least 3 days in the week prior to Visit 1.  
 
7. If taking a prescription medication daily for the management of pain (taken for at 
least 30 days before baseline), agrees to continue the daily use of the medication 
throughout the study at the same dosage.  
 

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8. If taking prescription medication, opioid medication or OTC medications as 
needed or episodically for the management of TMD pain agrees to discontinue its 
use prior to the Screening and Baseline Visit.  
• Rescue medications will be defined as allowable over-the-counter 
analgesics used for treatment of TMD pain. In case a patient presents pain 
during the study, only it is allowed the use of OTC medications as a “rescue” 
and as described on section 6.6.3: Participants use of short-acting non-
prescription analgesics such as NSAIDs, acetaminophen or aspirin during 
the study, will be recorded and quantified at each visit, and the usage will 
be classified as either episodic or daily. Episodic use of non-prescription 
analgesics will be defined as use for no more than 2 consecutive days and 
for no more than 18 days from baseline to visit 4.  
• This type of analgesics should not be used for more than 2 days a week 
prior to Baseline and a week prior to visit 4, when the exploratory outcome 
is assessed (cytokine release assay). 
9. If taking OTC pain medications daily agrees to continue its daily use at the same 
dosage throughout the study. 
 
• If a participant is taking an over-the-counter medication daily for 
management of other type of pain or for prophylaxis of myocardial 
infarction or stroke, the participant will be encouraged to continue the 
same usage of that medication throughout the study. 
 
10. Agrees to not start any new prescription medication for the management of pain 
throughout the study  
11. Agrees to not start any injection therapy for the management of TMD (trigger 
point injections, steroid injections, Botox) during the course of the study  
12. Agrees to not use acupuncture for the management of pain during the course of 
the study  
13. Agrees to not have Physical therapy for the management of TMD during the 
course of the study.  
14. Agrees to not start intraoral appliance therapy during the course of the study. If 
the patient has used a nightguard for more than one month before the study, 
agrees to continue use it only at night. 

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15. Females of childbearing potential agree to use one of the following methods of 
contraception throughout the study: licensed hormonal method, intrauterine 
device, female or male condoms with contraceptive foam, abstinence, bilateral 
tubal ligation/occlusion, or vasectomy in partner (if postmenopausal, must not 
have menstruated for at least 12 consecutive months)  
16. Willing and able to understand and comply with all study procedures and be 
available for the duration of the study  
 
5.2 
Subject Exclusion Criteria 
1. Participants with a history of congestive heart failure, rheumatoid arthritis or 
uncontrolled diabetes. 
2. Participants with serious hepatic, respiratory, hematologic or immunologic illnesses, an 
unstable cardiovascular disease, or any other severe acute or chronic medical or 
psychiatric condition or laboratory abnormality that may increase the risk associated with 
trial participation or Erenumab or may interfere with the interpretation of trial results and, 
in the judgment of the investigator, would make the participant inappropriate for entry into 
this trial  
3. Participants with high blood pressure, history of abnormal electrocardiograms, history 
of heart conductance defects, malignant disease, chronic constipation, IBSc or any other 
severe acute or chronic medical or psychiatric condition or laboratory finding that may 
increase the risk associated with trial participation with Erenumab  
4. Participants with active malignancy of any type or a history a malignancy (with 
exception of participants with malignancy surgically removed with no evidence of 
recurrence within 5 years before enrollment.  
5. History of facial trauma or orofacial or orthognathic surgery within the previous 6 
months  
6. Patients with dental pain  
7. Patients with trigeminal neuralgia or other neuropathic pain in the craniofacial area  
8. Patients with rheumatoid arthritis or any systemic arthritis  
9. Patients with chronic migraine with and w/o aura following the ICHD-3 criteria treated 
or not treated with medication 
• Without excluding headache attributed to TMD   
 

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10. Participants currently taking or have previously taken Erenumab or other CGRP 
monoclonal antibody (mAmb) or currently taking a CGRP-Receptor antagonist (gepants) 
for migraine prevention. CGRP-Receptor antagonist (gepants) for acute use for migraine 
are allowed. 
11. Patients with hypersensitivity to Erenumab 
12. Patients who have received the Botox injection protocol in the masseters and/or 
Migraine protocol within 3 months prior screening and baseline visit.  
13. Used injections for management of TMD (trigger point injections, steroid injections) 
within 2 weeks prior to the Screening and Baseline Visit  
14. Has commenced a new daily prescription medication for the management of pain 
within 30 days prior to the Screening and Baseline Visit  
15. Has commenced intraoral appliance therapy for the management of facial pain within 
30 days prior to the Screening and Baseline Visit  
16. Patient currently undergoing active orthodontic treatment (passive retainers are 
permitted)  
17. Treatment for drug or alcohol abuse within the last year  
18. Has been treated with another investigational drug or treatment within 30 days prior 
to the Screening and Baseline Visit  
19. Patients sensitive to Latex 
20.Patient is pregnant, planning to become pregnant or breastfeeding  
21. Anything that, in the opinion of the investigator, would place the participant at 
increased risk or impede the participant’s full compliance with or completion of the study.  
 
5.3 
Strategies for Recruitment and Retention 
 
Participants will be recruited from direct contact with patients who have relevant 
diagnoses recorded in electronic health records or patient registries at the Brotman Facial 
Pain Clinic and from the Clinic of Oral and Maxillofacial Surgery at the University of 
Maryland, School of Dentistry.  Providers at these clinics will be made aware of the study 
and asked to inform their patients about the study and to provide them with study contact 
information. Previous study participants who gave prior permission may be contacted. 
Participants may be also recruited through advertisements, websites, print, and electronic 

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media. All recruitment materials will be submitted to the IRB for review and approval prior 
to their use. 
 
Participants will be contacted to be reminded of each upcoming visit by telephone, text 
message, email, or letter. Participants will be informed about the importance of keeping 
each scheduled appointment, and they will be instructed to contact the study staff as soon 
as possible in case they are unable to attend a scheduled appointment. Participants who 
miss a scheduled visit without notifying the study staff will be contacted by telephone, text 
message, email, or letter to encourage their 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 7.6). 
 
Participants will be compensated for their participation in the study in an amount stated 
in the informed consent form. In some cases, the participant may be eligible for 
reimbursement of travel expenses. 
 
5.4 
Treatment Assignment Procedures 
This will be a conventional factorial design, randomized, double-blinded clinical trial with 
two parallel arms to evaluate efficacy of Erenumab: 
 
• Erenumab, a monoclonal antibody medication that inhibits the CGRP pathway, 
which is FDA-approved for the prevention of migraine in adults. The comparison 
will be to placebo. 
 
5.4.1 
Randomization Procedures (if applicable) 
 
Extensive screening procedures of potential participants to determine their eligibility 
based on the inclusion and exclusion criteria will be carried out prior randomization. 
Participants who do not meet these criteria will not be enrolled in the study. 
 
Randomization visit will be within 7 days after Visit 0, eligibility will be further confirmed 
based on completion of Daily Symptom Diaries and pain intensity score. Qualified 
participants will be randomly assigned to one of the two arms of the study in a 1:1 ratio:  
 
1) Investigational arm: Erenumab: N= 30 participants 
2) Placebo: N=30 participants 
 
Randomization 
Subjects will be randomized to the investigational treatment group (Erenumab) or the 
placebo group using a blocked randomization scheme. The examiners and patients will 
be blind to the group assignment. Randomization will be done by Investigational Drug 
Services (IDS/Research pharmacy). There will be a 1:1 ratio of treatment to placebo 
participants.  

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Blinding 
Blinding will be done by Investigational Drug Services (IDS). The PI and study staff will 
be blind to what the participant is receiving.  
 
Treatment/randomization codes 
IDS will be responsible for randomization of participant assignment to either the study 
medication or placebo groups.  IDS will use a random number generation program to 
determine assignment.  
 
 
5.4.2 
Masking and Unbliniding Procedures (if applicable) 
 
All study staff, including investigators, study care providers, study clinician, study 
coordinators, and research assistants, will remain blinded to the participants' medication 
assignments throughout the study. Erenumab and Placebo will be packaged in identical 
vials and stored. Only IDS, the research pharmacy will be unblinded. If the 
IRB and/or Data and/or the Safety Monitoring Board (DSMB) request an unblinded data 
report during the data collection period, an unblinded biostatistician will generate the 
report.  
 
Unmasking/unblinding prior to study completion will occur only if there is evidence that a 
participant's health or safety is threatened and therefore, knowledge of treatment 
assignment is necessary to protect the participant.  
 
Except in extreme medical emergencies, before a participant's treatment assignment is 
revealed, the investigator must confer the request for unmasking with the IDS. For a 
medical emergency that occurs during business hours, the site investigator will contact 
the IDS to determine the participant's treatment assignment; for a medical emergency 
that occurs outside of business hours, medical personnel will contact the IDS pharmacy 
to determine the treatment assignment.  
 
An event is considered an extreme medical emergency when medical management of a 
participant requires the knowledge of the treatment assignment. Study participants will be 
provided with instructions and contact information for emergency situations. Emergency 
unmasking will be recorded and reported to the PI, and the medical monitor as soon as 
possible, with a full accounting of the event, date and time of occurrence, the reason for 
unmasking, and names of all individuals who were notified of the emergency. Unblinding 
will be reported to the Data Safety Monitoring Board (DSMB) and IRB according to the 
University of Maryland policies and guidelines. 
 

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5.5 
Subject Withdrawal 
Subjects may withdraw voluntarily from the study or the investigator may terminate a 
subject's participation at any time. 
 
5.5.1 
Reasons for Withdrawal 
Participants are free to withdraw from participation in the study at any time, for any 
reason, with no explanation upon request. This decision will not interfere or alter in any 
way their following treatments and pain management if they are patients of the dental 
school, the Brotman Facial Pain Clinic or the Oral and Maxillofacial Surgery Clinic. 
 
If a participant does not return for a scheduled visit, every effort will be made to contact 
the participant and to document the outcome. If a participant withdraws 
consent and refuses to come to an Early Termination Visit, no further evaluations will be 
performed, and no attempts will be made to collect additional data. 
 
Investigators may withdraw a participant for any of the following reasons: 
 
• Withdrawal of consent 
• The participant does not meet eligibility criteria for randomization. 
• Any clinical adverse event (AE), laboratory abnormality, or other medical 
condition or situation occurs such that continued participation in the study would 
not be in the best interest of the participant. 
• The subject meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation. 
• Pregnancy 
• At Investigator discretion 
 
5.5.2 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention 
 
Participants withdrawn after randomization will not be replaced. Participants who are 
withdrawn voluntarily or by the investigator will be discontinued from the study.  
Study staff will complete a study disposition form in the eCRF, indicating the reason for 
discontinuation.  
 
If the patient is a patient from the school and/or is interested in following TMD care at the 
Brotman Facial Pain clinic, will be referred to the faculty practice clinic front desk for 
information and to schedule an appointment if wants to.  
 
Unblinding, if required, will be carried out according to the procedures described in 

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Section 5.4.2. A participant who has an AE at the time of discontinuation will be followed 
until the event returns to baseline, resolves, or is stabilized. If the AE does not meet one 
of these outcomes within 30 days after discontinuation or the end of the study, the 
participant will be referred to an appropriate provider for continued medical care (See 
section 9.2). 
 
5.6 
Premature Termination or Suspension of Study 
This study may be suspended or prematurely terminated if there is sufficient reasonable 
cause as determined by the sponsor, the PI, medical monitor, DSMB, or IRB. Written 
notification, documenting the reason for study suspension or termination, will be provided 
by the suspending, or terminating party. If the study is prematurely terminated or 
suspended, the principal investigator will promptly inform the IRB and will provide the 
reason(s) for suspension or termination. 
Circumstances that may warrant termination include, but are not limited to: 
 
• Determination of unexpected, significant, or unacceptable risk to subjects. 
• Insufficient adherence to protocol requirements. 
• Data that are not sufficiently complete and/or evaluable. 
• Determination of futility. 

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6 STUDY INTERVENTION 
6.1 
Study Product Description 
The investigational drug is Erenumab-aooe (Aimovig), an FDA approved medication for 
the prevention   migraine in adults. Erenumab-aooe is a fully human monoclonal antibody 
IgG2 that binds in a competitive and reversible manner to the Calcitonin Gene Related 
Peptide (CGRP) receptor with greater selectivity. It is available as a subcutaneous 
injection only and it is used once a month.  
Erenumab injection is a sterile, preservative-free, clear to opalescent, colorless to light 
yellow solution for subcutaneous administration. The needle shield of the prefilled 
syringes contain dry natural rubber (a derivative of latex). The  syringe is a prefilled  glass 
syringe with a  stainless-steel needle and delivers 1 mL of 70 mg/mL. Each 1 mL 70 mg 
single-dose prefilled glass syringe contains 70 mg erenumab-aooe, acetate (1.5 mg), 
polysorbate 80 (0.10 mg), and sucrose (73 mg). 
The placebo injection is a sterile solution. The syringe is a 1 mL prefilled glass syringe of 
10 mM Sodium Acetate, 9% (w/v) Sucrose, 0.004% (w/v) polysorbate 20, pH 5.2 
 
6.1.1 
Acquisition 
Our study will use Erenumab at the dosage of 70 mg once monthly. The drug will be 
acquired from AMGEN, the manufacturer, and shipped to the research pharmacy at the 
University of Maryland. The research pharmacy will release the drug to study personnel, 
who will dispense it to the participants at study visits.  The placebo will be also acquired 
from AMGEN and will be packaged, labeled, dispensed, and administered in the same 
manner as described above for the active drug. Placebo ingredients are 10 mM Sodium 
Acetate, 9% (w/v) Sucrose, 0.004% (w/v) polysorbate 20, pH 5.2. Storage requirements 
for the placebo are the same as for the active drug.   
 
6.1.2 
Formulation, Packaging, and Labeling 
An Erenumab 70 mg/mL, 1 mL prefilled glass syringe (15mM sodium acetate, 8.5% (w/v) 
sucrose, 0.010% (w/v) polysorbate 80, pH 5.2)  will be used. The placebo will be Placebo 
1 mL in a prefilled glass syringe consisting of of 10 mM Sodium Acetate, 9% (w/v) 
Sucrose, 0.004% (w/v) polysorbate 20, pH 5.2. Neither study personnel nor study 
participants will be able to differentiate the study drug from placebo by appearance alone.  
The research pharmacy will label and dispense the autoinjectors in individual cartons. 
The cartons 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 “Erenumab or placebo” to protect the blinding 
• Strength of the drug or placebo (70mg/ml). Dispense 1 
• Name of the prescribing clinician 
• Instructions for use 
• Participant name and clinic record number 
• Date dispensed 
• The following statement: “Limited by Federal Law to Investigational Use Only” 
 
6.1.3 
Product Storage and Stability 
Erenumab will be stored following the instructions of the manufacturer. Erenumab needs 
to be stored refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from 
light until time of use.  
• If removed from the refrigerator, Erenumab should be kept at room temperature (up to 
25°C [77°F]) in the original carton and must be used within 7 days. It will be thrown away 
if it has been left at room temperature for more than 7 days. It should not be freeze or 
shaken. 
Study personnel will pick up the study product from the research pharmacy the day prior 
or the same day that will be administered to participants. If picked up a day before to be 
administered, the study product will be storage in an allocated refrigerator specifically for 
its storage at the Brotman Facial Pain Clinic. 
6.2 
Dosage, Preparation and Administration of Study Product 
Erenumab 70 mg/mL or placebo prefilled glass syringe will be administered 
subcutaneously once monthly.  
Erenumab or placebo will be administered by the study personnel who will be trained in 
how to administer it using the single-dose prefilled syringe, including aseptic technique 
and according to the instructions of the manufacturer. 
• Prior to subcutaneous administration, allow Erenumab or placebo to sit at room 
temperature for at least 30 minutes protected from direct sunlight. 
• Do not warm by using a heat source such as hot water or a microwave. 
• Do not shake the product. 

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• Inspect visually for particulate matter and discoloration prior to administration [see 
Dosage 
• Do not use if the solution is cloudy or discolored or contains flakes or particles. 
• Erenumab or placebo will be administered in the abdomen, thigh, or upper arm 
subcutaneously.  
• It will not be injected into areas where the skin is tender, bruised, red, or hard. 
• Both prefilled autoinjector and prefilled syringe are single-dose and deliver the 
entire contents. 
Erenumab or placebo administration to participants will be once a month for 3 months on 
Visits 1-3. The study personnel will explain the participant how it will be injected. 
Participants will receive the first dose on Visit 1. The second dose a month after on Visit 
2 and the third and last dose a month after the second dose on Visit 3 for a total of 3 
cycles.   
Erenumab or placebo is for subcutaneous use only. The needle shields of erenumab and 
placebo prefilled syringe contain dry natural rubber (a derivative of latex),which may 
cause allergic reactions in individuals sensitive to latex. Sensitivity to latex is included in 
the exclusion criteria (See 5.2) 
 
6.3 
Modification of Study Product Administration for a Subject 
If a dose of Erenumab is missed, will be administered as soon as possible. Thereafter, 
Erenumab will be scheduled monthly from the date of the last dose. 
The safety profile of erenumab has been favorable in clinical trials and in the post-
marketing setting. A limited number of adverse drug reactions (injection site reactions, 
constipation, muscle spasm, and pruritus) have been identified at low frequencies (< 5%) 
in clinical trials. In the long-term use of erenumab, the safety profile remained consistent 
through 5 years of open-label treatment. In post-marketing settings, hypersensitivity 
reactions (including rash, angioedema and anaphylactoid reactions) and constipation with 
serious complications have been reported. In addition, oral sores (eg, stomatitis, mouth 
ulceration, oral mucosal blistering), alopecia and rash (eg, rash papular, exfoliative rash, 
rash erythematous, urticaria, blister) have been observed in post-marketing surveillance. 
Hypertension or worsening of high blood pressure can happen after receiving 
Erenumab.  Hypertension is in our exclusion criteria, however if a new onset of 
hypertension occurs, the participant will be withdrawn of the study and will be the 
participant will be referred to an appropriate practitioner for continued care (see section 
9.2). 

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Participants will be closely monitored for any of these AEs, during the clinic visit and 
between visits by telephone. Potential risks and discomforts will be clearly stated in the 
ICF. Exclusion criteria includes medical history of constipation or taking medications 
associated with decrease of G.I motility as well as pre-existent hypertension (See 5.2).  
If the participant reports a hypersensitivity reaction (rash, angioedema, anaphylaxis), 
new onset constipation or new onset of hypertension or any of the reactions described 
above, if there is worsening of TMD signs and symptoms during the 18 weeks of 
participation or if the participant decides against using Erenumab, he/she will be 
discontinued from the study (See 2.3.1 and 5.5.2).  
The following expected events will not be considered reportable AEs:   
• 
Temporary injection site reactions such as pain, erythema, pruritus after the 
injection of Erenumab 
• 
Minor bleeding or bruising resulting from the blood draw 
• 
Temporary pain or temporary increases in existing pain prompted during the 
TMD clinical examination or PPT. 
 
6.4 
Accountability Procedures for the Study Product 
The research pharmacy will be responsible for maintaining logs (paper or electronic) to 
document the acquisition and dispensing of Erenumab and placebo. The pharmacy will 
also be responsible for maintaining and monitoring storage conditions. The logs and 
records of storage conditions will be reviewed by the study clinical monitor during periodic 
monitoring visits. 
 
6.5 
Assessment of Subject Compliance with Study Product Administration 
 
Participants will receive the medication or placebo injection by a trained study staff 
member once a month on Visits 1, 2 and 3.  
Between visits, study personnel will contact participants by telephone to assess study 
drug tolerance (AEs), and to remind them when they are scheduled for another dosage.   
 
6.6 
Concomitant Medications/Treatments 
 
At the Screening and Baseline Visit (Visit 0), information concerning prior and 
concomitant medications for the previous 30 days will be collected, including name(s) of 
medication(s), total daily dose, start date, stop date (if applicable), and primary reason 
for use. Similarly, information about prior and concomitant therapies, including injection 
therapy, acupuncture, physical therapy, and intraoral appliance therapy, will also be 
collected for all participants for the 30 days prior to the Screening and Baseline Visit. The 

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concomitant medication/therapy information will also be updated at subsequent study 
visits (Visits1-5). 
 
6.6.1 Allowable Pain Medication 
 
6.6.2 Prescription medications 
 
Participants who enter the study already on a daily regimen of a prescription medication 
for pain management will be encouraged to continue that regimen throughout the study 
and should not be modified. The usage of all prescription medications for pain during the 
study will be recorded and quantified at each visit. 
 
Rescue medications will be defined as allowed over-the-counter analgesics used for 
treatment of TMD pain. In case a patient presents pain, the medications described below 
may be used: 
 
6.6.3 Over-the-counter medications 
 
 
NSAIDs are very often used to manage pain in TMD patients and for other pain 
conditions. Participants use of short-acting non-prescription analgesics such as NSAIDs, 
acetaminophen or aspirin during the study, will be recorded and quantified at each visit, 
and the usage will be classified as either episodic or daily. 
 Episodic use of non-prescription analgesics will be defined as use for no more than 2 
consecutive days and for no more than 18 days from baseline to visit 4. This type of 
analgesics should not be used for more than 2 days a week prior to Baseline and a week 
prior to V4, when the exploratory outcome is assessed. 
 
If a participant is taking an over-the-counter medication daily for management of any type 
of pain or for prophylaxis of myocardial infarction or stroke, the participant will be 
encouraged to continue the same usage of that medication throughout the study.  
 
6.6.4 Nonpharmacologic Therapy 
 
During the course of the study, participants will not be restricted in the use of non-
pharmacological therapies, with the exception of acupuncture, physical therapy and splint 
therapy. If a participant starts these therapies for the management of pain during the 
study, the use of these therapies will be recorded in the eCRF and the patient will need 
to be withdrawn of the study. The use of intraoral appliances at night only is allowed if 
was started at least 30 days prior to Screening and Baseline V0. 
 
 
 
 

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7 STUDY SCHEDULE 
7.1 
Pre-Screening 
Pre-screening (0-2 weeks, Day -15 to -1) 
Potential participants may be contacted by telephone or in person for pre-screening; in 
some instances, it may also be conducted simultaneous with the Screening and Baseline 
Visit (Visit 0) or during a scheduled visit to the Brotman Facial Pain Clinic or Oral Surgery 
Clinic.  
After contacting potentially eligible participants and after obtaining their verbal consent 
we will proceed to conduct a pre-screening interview with questions designed to identify 
participants with a high probability of meeting inclusion criteria. This interview will be 
conducted by trained study staff using a standard script. For the potential participants 
who express interest in the study, documentation of verbal consent, the pre-screening 
date, and screening ID will be recorded. In addition, an in-clinic Screening and Baseline 
Visit (Visit 0), will be scheduled after 0-2 weeks from the date of the pre-screening 
interview. 
 
7.2 
Screening and Baseline Visit (Visit 0, 4 weeks baseline period) 
• Obtain and document consent from subject participation in the study. 
• Obtain signed Health Insurance Portability and Accountability Act (HIPAA) 
     Authorization 
• Review medical/dental history to determine eligibility based on inclusion/exclusion 
criteria. 
• Take blood pressure and collect weight and height. 
• Review medications history to determine eligibility based on inclusion/exclusion 
criteria. 
o Record concomitant medications and therapies 
• Administer Symptom Inventory 
• Perform TMD examination (Including Panoramic X-Ray). 
• Perform Pressure Pain examination 

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• Collect blood for Cytokine release assay 
• Perform urine pregnancy test (in women with childbearing potential) 
• Provide instruction to complete 6 outcome measure questionnaires in paper or 
electronically for review next visit 
• Provide instruction to complete Daily Symptom Diaries electronically or in paper 
dispense forms. 
 
7.2.1  Randomization  
Prior randomization, the participant to be eligible is required to have 80% compliance with 
the Daily Symptom Diary for the baseline period after visit 0 and reported an average pain 
level ≥30 on a numerical rating scale (0-100) or had experienced a pain level ≥30 on the 
same scale for at least 3 days the week before randomization. Participants then will be 
randomly assigned to one of two groups (Erenumab or placebo) and will be scheduled 
for Visit 1. Visit 1 should be scheduled within a week after randomization 
 
7.3 
Treatment Visits 
Visits 1-4  
Participants will be receiving 3 cycles of either erenumab or placebo in visits 1-3. On visit 
4, treatment will not be delivered but assessments will be performed. 
7.3.1  First treatment cycle (Visit 1, Day 0) 
• Review Daily Symptom Diaries in eCRF or collect and review it in paper forms 
• Review medical history 
• Record concomitant medications and therapies 
• Take blood pressure and collect weight 
• Administer the Symptom Inventory 
• Assess and record adverse events (AEs) 
• Perform TMD examination 
• Perform Pressure Pain examination 

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• Perform urine pregnancy test (in women of childbearing potential) 
• Review 5 questionnaires from Visit 0 in eCRF or collect and review the paper forms 
• Provide instruction to complete 6 new outcome measure questionnaires in paper 
or electronically for review at Visit 2. 
• Provide instruction to complete Daily Symptom Diaries electronically or provide 
them in paper forms 
• Deliver the injection of the study drug or placebo 
• Schedule next visit 
 
7.3.2 Visit 2, 2nd  treatment/cycle ( Day 28/ 4 weeks after Visit 1) 
• Review Daily Symptom Diaries in eCRF or collect and review it in paper forms 
• Assess compliance with Daily Symptom Diaries 
• Review medical history  
• Record concomitant medications and therapies 
• Take blood pressure and collect weight 
• Administer the Symptom Inventory 
• Assess and record adverse events (AEs) 
• Perform TMD examination 
• Perform Pressure Pain examination 
• Perform urine pregnancy test (in women of childbearing potential) 
• Review 6 questionnaires from Visit 1 in eCRF or collect and review the paper forms 
• Provide instruction to complete 6 new outcome measure questionnaires in paper 
or electronically for review at Visit 3. 

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• Provide instruction to complete Daily Symptom Diaries electronically or provide 
them in paper forms 
• Deliver the injection of the study drug or placebo 
• Schedule next visit 
 
7.3.3 Visit 3, 3rd and final treatment cycle (Day 56/ after 4 weeks from Visit 2) 
• Review Daily Symptom Diaries in eCRF or collect and review it in paper forms 
• Assess compliance with Daily Symptom Diaries 
• Review medical history  
• Record concomitant medications and therapies 
• Take blood pressure and collect weight 
• Administer the Symptom Inventory 
• Assess and record adverse events (AEs) 
• Perform TMD examination 
• Perform Pressure Pain examination 
• Perform urine pregnancy test (in women of childbearing potential) 
• Review 5 questionnaires from Visit 2 in eCRF or collect and review the paper forms 
• Provide instruction to complete 6 new outcome measure questionnaires in paper 
or electronically for review at Visit 4. 
• Provide instruction to complete Daily Symptom Diaries electronically or provide 
them in paper forms 
• Deliver the injection of the study drug or placebo 
• Schedule next visit 
 
7.3.4 Visit 4, assessment of last treatment cycle (Day 84/4 weeks after Visit 3 ) 

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• Review Daily Symptom Diaries in eCRF or collect and review it in paper forms 
• Assess compliance with Daily Symptom Diaries 
• Review medical history  
• Record concomitant medications and therapies 
• Take blood pressure and collect weight 
• Administer the Symptom Inventory 
• Assess and record adverse events (AEs) 
• Perform TMD examination 
• Perform Pressure Pain examination 
• Collect blood for Cytokine release assay 
• Perform urine pregnancy test (in women of childbearing potential) 
• Review 5 questionnaires from Visit 3 in eCRF or collect and review the paper forms 
• Schedule next visit 
• Administer the <intervention>. 
• Record subject’s compliance with <intervention>. 
• Following administration of <intervention> 
o Assess vital signs 
o Administer Symptoms Questionnaire 
 
7.4 
Follow up and final Study Visit, Visit 5 (Day 112/ 4 weeks after Visit 4 ) 
• Review Daily Symptom Diaries in eCRF or collect and review it in paper forms 
• Assess compliance with Daily Symptom Diaries 
• Review medical history  
• Record concomitant medications and therapies 

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• Take blood pressure and collect weight 
• Administer the Symptom Inventory 
• Assess and record adverse events (AEs) 
• Perform TMD examination 
• Perform Pressure Pain examination 
• Perform urine pregnancy test (in women of childbearing potential) 
• Review 5 questionnaires from Visit 4 in eCRF or collect and review the paper 
forms 
• Provide final instructions to subject (in case of AE showing later)  
• Complete a disposition form 
 
7.5 
Withdrawal Visit 
An early termination visit will be performed if a participant is suspended before the 
completion of the study, prior to withdrawal of consent and with the participant’s 
permission. This could happen during a scheduled or unscheduled visit. The investigator, 
study coordinator or research staff will discuss with the participant to contact the research 
team in case AE arise after the withdrawal visit. The assessment and procedures of Visit 
4 will be conducted at this visit.  
7.6 
Unscheduled Visit 
These visits may occur at the discretion of the investigator. Reasons may include but not 
limited: The need for withdrawal of the study; the participant is not able to attend a 
scheduled visit on a specific date; inability to collect the blood sample at the scheduled 
visit and in case of an Adverse Effect. 
 
 

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8 STUDY PROCEDURES /EVALUATIONS 
8.1 
Study Procedures/Evaluations 
 
• Medical History 
The medical history will be taking by trained personnel during the interview and will be 
entered into the eCRF and will be updated each visit. As a part of the medical history, the 
study staff will administer a symptom inventory to assess/screen for possible AEs 
anticipated with the use of Erenumab throughout the study (V1-V5). Staff will record and 
evaluate new or worsened symptoms as possible AEs   
   
• Medications and other therapies 
Pharmacological therapies such as prescription and OTC medications and non-
pharmacological therapies used in the last 30 days prior Visit 0 will be recorded by trained 
personnel in the eCRF and will be updated in each visit. 
 
• Vital Signs and weight collection 
After the medical history is taken, trained personnel will take the blood pressure and 
collect height and weight. Weight collection and blood pressure reading will be 
performed in each visit.  
 
• Pregnancy Test 
Erenumab is not recommended to use during pregnancy, therefore female participants 
of childbearing potential will be screened for pregnancy with a urine test (instant type) 
that will be performed at every study visit. The results will be read by the study staff. 
The urine will be discarded after the test. 
 
• Blood Collection 
A blood sample will be collected at Visits 0 and 4 by staff trained in phlebotomy. Blood 
samples will be evaluated then for the presence of proinflammatory (TNFα, IL1β) and 
anti-inflammatory (IL10, IL4) cytokines by Luminex assay.  
 
• TMD Examination 
The TMD examination will be performed according the Diagnostic Criteria for 
Temporomandibular Disorders (DC-TMD) [7] by trained and calibrated staff.  The 
examination consists of bilateral digital palpation of masticatory muscles (masseter and 
temporalis) as well as the palpation of the temporomandibular joint (TMJ) and the 
manipulation of the jaw to assess if these elicit pain in these structures.  
The participant must meet 2 of the criteria for TMD listed in the inclusion criteria: 1) 
reported pain or ache in the face, jaw/mandible, pre-auricular area, inside the ear or 
temple that it is modified by jaw function. 2) finding(s) of TMD myalgia according to the 
classification DC-TMD criteria. 
 
• Pressure Pain Thresholds 

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The Pressure Pain Threshold (PPT) will be defined as the amount of pressure at which 
the participant first perceives pressure to be painful. The PPT measurements will be 
performed by trained staff using a pressure algometer (Wagner, Greenwich, CT). 
Calibrated pressured will applied bilaterally over the masseter, temporalis, upper 
trapezius, the TMJs, and the lateral epicondyles. One pre-trial assessment will be 
performed at each anatomic structure 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 [34, 35]. 
 
• Daily Symptom Diary 
Participants will be asked to complete the Daily Symptom Diary at the end of each day 
during the baseline phase and during the study (visits 1-5). 
Participants should have at least 80 % compliance with the DSD. 
 
The diary collects the participant’s pain intensity (reported on a 0-100 numeric rating 
scale) and duration (reported on a 0-100 percentage scale), pain days and use of pain 
medication. Participants are required to complete a Daily Symptom Diary electronically or 
on paper and a new form will be used for each month of the study. These forms may be 
returned in person at study visits.  
 
 
Outcome Measure Questionnaires 
Listed in the Schedule of Events (Appendix A). Questionnaire forms on paper will be 
provided to the participants if an electronic form is not feasible.  
Some questionnaires are self-administered, and others will be administered by trained 
study staff.  
 
 
• Jaw Functional Limitation Scale. This is a 20-item instrument that measures 
limitations across 3 domains related to TMJ biomechanics: masticatory function (6 
items), vertical jaw mobility/jaw opening (4 items), and verbal and emotional 
expression (8 items). 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”)[36, 37]. 
 
• Oral Behaviors Checklist (OBC). Evaluates parafunctional behaviors and 
generates a single scale representing the frequency of 21 activities such as 
clenching, chewing gum, and holding objects between teeth, yawn [38, 39]. 
 
• Graded Chronic Pain Scale (GCPS). The GCPS includes 7 items and assesses 2 
dimensions of pain: pain intensity and pain-related disability [40]. 

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• Patient Global Impression of Change (PGIC). This instrument 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 [41, 42]. 
 
• Hospital Anxiety and Depression Scale. Evaluates anxiety and depression with a 
14-item instrument [43]. 
 
8.2 
Laboratory Procedures/Evaluations 
8.2.1 
Clinical Laboratory Evaluations 
 
• Pregnancy test: Female participants of childbearing potential will be screened for 
pregnancy with a urine test (instant type) that will be performed at every study visit. 
The results will be read by the study staff. The urine will be discarded after the test. 
8.2.2 
Special Assays or Procedures 
 
Blood Collection to evaluate cytokine profile 
 
• A blood sample will be collected at Visits 0 and 4 by staff trained in phlebotomy. 
Blood samples will be evaluated then for the presence of pro-inflammatory (IL-6, 
TNFα, IL1β) and anti-inflammatory (IL10, IL4) cytokines by Luminex assay.  
• Pre-collection preparation – participants do not require any special preparation for 
the sample collection.  
• Mode of collection – A blood sample will be taken by a blood draw.  
• Amount, frequency, and quality of specimen collection – The blood sample will 
consist of 10-15 ml this will be for each subject and will be taking on visits 1 and 
4 
• Specimen collection duration – We estimate that the collection procedure will have 
a duration of 15 minutes. 
 
8.2.3 
Specimen Preparation, Handling, and Storage 
Collection of blood will be performed at the school of Dentistry and serum/plasma 
isolation and storage will be held at the same facility. The samples will be labeled with 
the same unique identification number provided for the participant at the moment of 
enrollment in our study and randomization. Peripheral blood leukocytes (PBLs) and 
plasma will be isolated from 10-15 ml of the subjects’ blood and stored at -80°C. The 
plasma fraction will be  used  for  analysis  of  the presence of soluble cytokines, 

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proinflammatory (IL-6, TNFα, IL1β and anti-inflammatory (IL10, IL-4) cytokines by 
Luminex assay. At the end of the sample analysis, any remaining sample will be 
discarded.  
 
8.2.4 
Specimen Shipment 
The analysis of the specimens will be performed by the Cytokine Core Laboratory (CCL). 

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9 ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
 
This study involves the use of Erenumab, a fully human monoclonal antibody that is a 
CGRP receptor antagonist FDA approved for the prevention of migraine in adults   
 
The participants of this study will be closely monitored and follow up in their clinic visits 
and between visits with telephone calls. As part of the study outcomes, the study staff will 
record information regarding AEs. Overall health parameters will be captured on case 
report forms. These will be completed at every visit and data will be compiled for review 
by the IRB. 
 
The description of potential risks is described in 2.3 and 6.3. The most common side 
effects of the use of Erenumab are: 
• Injection site reactions: which may include tenderness, pain, redness, itching, 
bruising, firmness, or hypersensitivity 
• Constipation 
• Muscle spasms/cramps 
• Itching (pruritus) 
 
Allergic reactions can happen within hours to days after using erenumab. Therefore, after 
the injection is administered, the participant will wait in the room for  20 minutes and the 
evening of the treatment visit, the participant will receive a follow up phone call and the 
information will be recorded.  
 
If the participant reports a hypersensitivity reaction (rash, angioedema, anaphylaxis), new 
onset constipation or new onset of hypertension or any of the reactions described above, 
if there is worsening of TMD signs and symptoms during the 18 weeks of participation or 
if the participant decides against using Erenumab, he/she will be discontinued from the 
study (See 2.3.1 and 5.5.2).  
 
 
The following expected events will not be considered reportable AEs: 
 
• Temporary injection site reactions such as pain, erythema, pruritus after the 
injection of Erenumab 
• Minor bleeding or bruising resulting from the blood draw 
• Temporary pain or temporary increases in existing pain prompted during the TMD 
clinical examination or PPT. 
 
 
 
 
 

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9.1.1 
Unanticipated Problems 
The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to subjects 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 subject population being studied; 
• Related or possibly related to participation in the research (“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); and 
• Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
9.1.2 
Adverse Events 
An adverse event is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the 
research, whether or not considered related to the subject’s participation in the research. 
9.1.3 
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 subject 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 subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. 

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• Severe allergic reactions due to Erenumab: Severe skin reactions, difficulty 
breathing or swallowing.  
• Severe constipation that may need hospitalization. 
 
9.2 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 and staff personnel will record all reportable events with start dates occurring any 
time after informed consent is obtained until 30 days after the last day of study 
participation.  At each study visit, the study staff will inquire about the occurrence of 
AE/SAEs since the last visit.  Events will be followed for outcome information until 
resolution, returns to baseline or stabilizes. If the AE does not meet these outcomes within 
30 days after discontinuation of Erenumab or the end of the study, the participant will be 
referred to an appropriate practitioner for continued care. 
 
9.3 Characteristics of an Adverse Event 
9.3.1 
Relationship to Study Intervention 
To assess relationship of an event to study intervention, the following guidelines are 
used: 
1. Related (Possible, Probable, Definite) 
a. The event is known to occur with the study intervention. 
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. 
 

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9.3.2 
Expectedness of SAEs 
AMGEN and the Study PI will be responsible for determining whether an AE/SAE is 
expected or unexpected.  
The most common adverse reactions (incidence ≥ 3% and more often than placebo) in 
the migraine studies were injection site reactions and constipation. Common side effects 
that may affect between 1 and 10 people in every 100: 
• Injection site reactions: which may include tenderness, pain, redness, itching, 
bruising, firmness, or hypersensitivity 
• Constipation 
• Muscle spasms/cramps 
• Itching (pruritus) 
 
Since erenumab was approved in May 2018, the following events have been reported in 
patient’s exposed to erenumab in the  post-marketing setting:  
 
1)Severe allergic reactions such as rash, swelling and difficulty breathing, or swallowing.  
2) Mouth/lip sores (e.g., stomatitis, mouth ulcerations, and oral mucosal blistering)  
3) Skin and subcutaneous tissue disorders  
o Alopecia (loss of hair)  
o Rash (e.g., papular rash [small raised red rash], exfoliative rash [redness and/or peeling 
of skin], erythematous rash [red rash], urticaria [hives], and blisters) 
4)Constipation and the use of medications that decrease gastric motility are in our 
exclusion criteria, however if a new onset of constipation occurs, the participant will be 
withdrawn of the study and will be referred to an appropriate practitioner for continued 
care (see section 9.2). 
5) Hypertension or worsening of high blood pressure can happen after receiving 
Erenumab.  Hypertension is in our exclusion criteria, however if a new onset of 
hypertension occurs, the participant will be withdrawn of the study and will be the 
participant will be referred to an appropriate practitioner for continued care (see section 
9.2) 
An adverse event (AE) will be considered unexpected if the nature, severity, or frequency 
of the event is not consistent with the risk information previously described for the 
intervention, protocol, investigator’s brochure and/or informed consent document. 
9.3.3 
Severity of Event 
Severity grades will be based on the Common Terminology Criteria for Adverse Events 
(CTCAE) 
grade 1 = mild; grade 2 = moderate; grade 3 = severe or medically significant; grade 4 = 
life-threatening consequences; and grade 5 = death. 

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9.4 
Reporting Procedures 
9.4.1 
Unanticipated Problem Reporting to IRB and AMGEN 
 
Incidents or events that meet the OHRP criteria for unanticipated problems require the 
creation and completion of an unanticipated problem report form within the Electronic 
Data Capture (EDC) system.  Following OHRP recommendations the investigators will 
include the following information when reporting an adverse event, or any other incident, 
experience, or outcome as an unanticipated problem to the IRB and AMGEN Safety: 
• 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 serious adverse events will be reported to the IRB 
and to AMGEN Safety within 1 week (5 days)  of the investigator becoming aware 
of the event.  
• Pregancy/lactation exposure and any associated reports/outcomes (i.e. 
unexpected pregnancy, pregnancy of partner, spontaneous abortion, congenital 
anomaly etc.) will be reported within 1 business day of sponsor/PI awareness, for 
reports meeting serious criteria and not to exceed 15 calendar days of sponsor 
awareness, for non-serious reports to IRB and AMGEN Safety.  
• Any other unanticipated problem will be reported to the IRB and to AMGEN safety 
within 2 weeks of the investigator becoming aware of the problem.  
• All unanticipated problems will 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 reported to AMGEN Safety via email by the investigator. 
These reports will be reviewed by the IRB.  

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Amgen Global Safety 
Fax:Toll-free #:1-888-814-8653 
For countries where the U.S. toll-free # cannot be used: +44-20-7136-1046 
Email :svc-ags-in-us@amgen.com 
 
9.4.2 
Serious Adverse Event Reporting to AMGEN Safety and UMB IRB  
 
Safety Data 
Timeframe for submission to 
Amgen 
Send to 
Suspected Unexpected 
Serious Adverse Reaction 
(SUSARs) 
At time of regulatory submission 
Amgen Safety 
Pregnancy/Lactation 
exposure and any 
associated 
reports/outcomes (i.e. 
unexpected pregnancy, 
pregnancy of partner, 
spontaneous abortion, 
congenital anomaly etc.) 
Within 1 business day of Sponsor 
awareness, for reports meeting 
serious criteria 
Not to exceed 15 calendar days of 
Sponsor awareness, for non-serious 
reports 
Amgen Safety 
*Table 2 IIS Time frames for Submission of Safety To AMGEN. Specific requirements are to be 
outlined in the Research Agreement. 
 
Any AE meeting the specified Serious Adverse Event criteria will be submitted on an 
SAE form to the IRB and AMGEN Safety. This report may be sent by fax or email. 
Once submitted, Amgen Safety will send a confirmation email to the investigator within 
1 business day. The investigator should contact Amgen Safety if this confirmation is 
not received. This process applies to both initial and follow-up SAE reports. 
SAE Reporting Contact Information: 
Amgen Global Safety 
Fax:Toll-free #:1-888-814-8653 

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For countries where the U.S. toll-free # cannot be used: +44-20-7136-1046 
Email : svc-ags-in-us@amgen.com 
For Adverse Device Effectsab for studies using AMGEN-marketed devices and device 
constituents in combination products and Products complaints: 
Safety Data 
Timeframe for submission to 
Amgen 
Send to 
Unanticipated 
Serious 
Adverse Device Effects, 
(USADEs), 
Serious 
Adverse Device Effects 
(SADEs) 
 
and 
Non-
serious Adverse Device 
Effect 
(Non-serious 
ADEs) 
Within 
1 
business 
day 
of 
Sponsor awareness  
Amgen Safety 
Product Complaintsc 
Within 24 hours of Sponsor 
awareness 
Amgen Quality 
*Table 4. ISS for Submission of Safety Data to AMGEN. Specific requirements are to be outlined in the Research 
Agreement. 
aAmgen combination products and devices that are marketed anywhere in the world 
(regardless of the status of the combination product/device in the country where the study 
is carried out). 
bAdverse device effect (ADE) is: any adverse effect caused by or associated with the use 
of a device constituent of a combination product or medical device. Adverse device effects 
include, but are not limited to, adverse effects resulting from insufficient or inadequate 
instructions for use, any malfunction of the device, or use error or intentional misuse of 
the device.  
Unanticipated serious adverse device effect (USADE)  
• 
ISO14155/MEDDEV2.7.3 definition: Serious adverse device effect which by its 
nature, incidence, severity or outcome has not been identified in the current version of 
the risk analysis report 
o 
Note: The ‘risk analysis report’ refers to the most current risk documents for a given 
investigational device. The essence of the risk documents is captured under the Risk 
Assessment section of the device IB or the device section of a combination product IB. 

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• 
US FDA definition (Unanticipated adverse device effect (UADE)): Any serious 
adverse effect on health or safety, any life-threatening problem or death caused by, or 
associated with a device, if that effect, problem, or death was not previously identified in 
nature, severity, or degree of incidence in the application; or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. 
cProduct Complaint is: Any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product, or device after it is released for distribution 
to market or clinic by either: (1) Amgen or (2) distributors or partners for whom Amgen 
manufactures the material.  This includes all components distributed with the drug, such 
as packaging, drug containers, delivery system, labelling, and inserts. Examples include: 
• 
Device that is damaged or broken 
• 
Bent or blunt needles 
• 
Missing or illegible labeling 
• 
Inability of customer to administer the product 
• 
Product with an unexpected color, appearance, or particles 
• 
Use error (i.e, an act or omission of an act that results in a different combination 
product or medical device response than intended by the manufacturer or expected by 
the user, where the user attempted to use the combination product or medical device in 
good faith and experienced difficulty or deficiency administering the product). 
Reports of misuse of a combination product or medical device (i.e, the intentional and 
improper use of a combination product or medical device not in accordance with the 
authorized product information) are not considered Product Complaints. 
 
 
 
 
 
 
 

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For aggregate reports: 
Safety Data 
Timeframe 
for 
submission 
to 
Amgen 
Send to 
Listing 
for 
Safety 
data 
reconciliationa 
Once per year and at the end of the 
study 
NASCR 
Manager 
Annual Safety Report 
(eg, 
EU 
Clinical 
Trial 
Directive DSUR and US IND 
Annual Report) 
 
Annually 
 
NASCR 
Manager 
Other aggregate analyses 
(any report containing Safety 
data generated during the 
course of the study) 
At the time of Sponsor submission to 
any body governing research conduct 
(eg. RA, IRB etc.) 
NASCR 
Manager 
Final (End of Study Report, 
including): 
• Unblinding data for 
blinded studies 
• Reports 
of 
unauthorized use of a 
marketed product 
 
At the time of Sponsor submission to 
any body governing research conduct 
(eg. RA, IRB etc.) but no later than 1 
calendar year of study completion 
 
NASCR 
Manager 
*Table 5. ISS Timeframes for Submission of Safety Data to AMGEN. Specific requirements are to be outlined 
in the Research Agreement. 
a Listing for reconciliation should include all ICSRs submitted to Amgen Safety per contract ( SUSARs, 
pregnancy and lactation exposure (and any associated reports/outcomes), USADEs, SADEs and non-
serious ADEs. 
 
 
 
 
 

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The PI will complete a Serious Adverse Event Form and submit via fax or email within the 
following timelines:   
• All deaths and immediately life-threatening events, whether related or unrelated, 
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, will be reported by fax within 72 hours of site awareness.  
All SAEs will be followed until resolution or stabilization.  
 
9.4.3 
Reporting of SAEs and AEs to FDA 
 FDA reporting is not applicable. 
9.4.4 
Events of Special Interest (if applicable) 
 
Any clinically significant finding of worsening of a medical condition other than TMD 
established at baseline/Visit 0 or the development of any new clinically significant medical 
condition throughout the study will be considered an AE and will be reported as described 
previously. 
9.4.5 
Reporting of Pregnancy 
Pregnancy will be considered a SAE. If a participant becomes pregnant at any time during 
the study, it will be recorded on a case report form within the EDC system. 
Pregnancy/lactation exposure and any associated reports/outcomes (i.e. unexpected 
pregnancy, pregnancy of partner, spontaneous abortion, congenital anomaly etc.) will be 
reported within 1 business day of sponsor/PI awareness, for reports meeting serious 
criteria and not to exceed 15 calendar days of sponsor awareness, for non-serious reports 
to IRB and AMGEN Safety (As mentioned on 9.4.2 Table 2). 
Participants who become pregnant while participating in the study will be withdrawn 
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. 
 
9.5 
Halting Rules 
 
This is addressed in Section 5.6. Based on the findings of a (scheduled or ad-hoc) 
safety review, the study may be temporarily suspended to enrollment (or to an 

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intervention), or it may be prematurely terminated. 
 
Depending on the findings of a safety review, the medical monitor, UMB (sponsor) IRB, 
or the DSMB will determine whether the study: should continue per protocol; proceed with 
caution; be further investigated; be modified; or be terminated. 
 
Some types of events that might trigger a safety review are: number of SAEs overall; 
prevalence of a specific SAE; number/type of severe AEs; or increased frequency of AEs. 
 

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10 STUDY OVERSIGHT 
In addition to the PI’s responsibility for oversight, study oversight will be under the 
direction of a Data and Safety Monitoring Board (DSMB) composed of members with 
expertise in pain management and TMD management at the sponsor site. The PI and 
DSMB will meet on a predetermined schedule to assess safety and efficacy data, study 
progress, and data integrity for the study.   

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11 CLINICAL SITE MONITORING 
Clinical site monitoring is conducted to ensure that the rights of human subjects 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 the IRB UMB. The 
monitor will evaluate study processes and documentation based on IRB UMB standards 
and the International Conference on Harmonisation (ICH), E6: Good Clinical Practice 
guidelines (GCP). 
. 
 

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12 STATISTICAL CONSIDERATIONS 
12.1 
Study Hypotheses 
The main objective of the statistical analysis is to estimate change in study endpoints and 
evaluate the efficacy of Erenumab by testing a priori hypothesis concerning the 
differences between treatment and placebo.  
Erenumab reduces pain and restores function in patients suffering of TMD. 
The primary efficacy hypothesis is that Erenumab produces greater change in average 
pain score (0-100 scale) from Visit 1 to Visit 4 than placebo.   
The secondary efficacy hypothesis is that Erenumab produces a greater proportion of 
patients reaching at least a 50% reduction from baseline in monthly TMD pain days 
compared to placebo. This will be determined as a change from baseline phase (4 weeks)  
through the 12 weeks treatment phase (3 cycles) until Visit 4.  
Functional measures related to TMJ biomechanics and pain related behaviors:  
There is a greater proportion of patients achieving >=30% decrease (score) in limitation 
of jaw function with the use of erenumab after 12 weeks of treatment compared to 
placebo. 
There is a greater proportion of patients achieving >=30% decrease (score) in oral 
behaviors with the use of erenumab after 12 weeks of treatment compared to placebo. 
There is a greater proportion of patients achieving >=30% increase in value in pressure 
pain thresholds in temporalis, masseter, trapezius muscles, TMJs and epicondyles with 
the use of erenumab after 12 weeks of treatment compared to placebo. 
There is a greater proportion of patients achieving >=30% decrease in intensity and 
pain related disability (GCPS) with the use of erenumab after 12 weeks of treatment 
compared to placebo. 
There is a greater proportion of patients achieving >=30% increase in score (impression 
of improvement/ impression of change/PGIC) with the use of erenumab after 12 weeks 
of treatment compared to placebo.  
There is a greater proportion of patients achieving >=30% decrease (score) in anxiety 
and depression (change in HADS) with the use of erenumab after 12 Weeks of 
treatment compared to placebo. 
 

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The exploratory hypothesis is that Erenumab decreases pain and the presence of pro-
inflammatory cytokines (TNF-α, IL-6 and IL-1β) and increases anti-inflammatory 
cytokines (IL-10 and IL-4) from blood samples. 
12.2 
Sample Size Considerations 
The proposed sample size of 60 randomized patients split into two independent groups 
is based on a 30-50% reduction in TMD pain scores at follow-up, assuming a power of 
90%, alpha = 0.05, assuming  a 0.5 (medium) effect size. This was calculated using 
GPower software. This sample size is also based on the conservative assumption of a 
15% patient drop out at follow up.  
12.3 
Planned Interim Analyses (if applicable) 
If any interim analyses are to be conducted this will take place without unblinding. 
12.3.1 Safety Review 
Analysis of adverse events will use the safety sample, defined as all randomized 
participants who received at least one cycle of study medication.  
12.3.2 Efficacy Review 
The study’s primary aim is to evaluate the effects of Erenumab in reducing pain level and 
secondary outcomes in participants with chronic TMD. The primary 
endpoint is change from Visit 0 to Visit 4 in average pain level (0-100) calculated in the 
month prior to the visit. Secondary outcomes are TMD pain days, jaw function, pain-
related disability, and other pain related outcomes. 
 
12.4 
Final Analysis Plan 
The main goal of the statistical analyses is to estimate change in study primary and 
secondary endpoints to evaluate efficacy of Erenumab. Intention to treat analysis will be 
performed using a within-subjects student’s pair t-test or repeated measures ANOVA (if 
more than two time points) to determine significant reduction in pain after drug 
intervention in each patient. Subsequently, a between-subjects unpaired t-test or two-way 
mixed designed ANOVA (if more than two time points) will be performed to determine 
difference between the placebo and erenumab groups. Post-hoc analysis will only be 
conducted following a significant ANOVA test, to protect from Type I errors. We will use 
a 2-way between subject’s repeated measure ANOVA design to determine difference 
between the Erenumab group and placebo group, or a between-subjects unpaired t-test 
if two groups only. We will also use student’s paired t-test to determine time points of 
significance. 50% reduction in pain days will be determined as a function of baseline pain 
days. Where, appropriate similar statistical procedures will be used for secondary 
endpoints.   
Descriptive statistics for safety measures will also be calculated.  

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We will collect the following data for descriptive purposes and, if necessary, to use as 
covariates:  Demographic information (age and race/ethnicity), rescue medication history, 
psychological factors and perceived change in overall status (PGIC).  

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13 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
All information collected considered to be source of that data such as original records of 
clinical findings, observations, participant self-reported information, hospital and 
pharmacy records, medical records, laboratory and diagnostic reports, notes to file, and 
all other information that is necessary to reconstruct and evaluate this clinical trial, will be 
kept. Clinical examination, daily symptom diary, and questionnaire data will be recorded 
directly from the participant onto eCRFs, with the eCRFs being the source document. 
Study staff will have access to the records in accordance with their assigned 
responsibilities outlined in the Delegation of Responsibility Log. 
 
Study staff will maintain appropriate medical and research records for this study, in 
compliance with ICH E6, Section 4.9 and regulatory and institutional requirements for the 
protection of confidentiality of subjects. Study staff will permit authorized representatives 
of UMB, clinical monitors, and regulatory agencies to examine (and when required by 
applicable law, to copy) research records for the purposes of quality assurance reviews, 
audits, and evaluation of the study safety progress and data validity. 
 

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14 QUALITY CONTROL AND QUALITY ASSURANCE 
Quality control is the ongoing, concurrent review of data collection forms for completion 
and logic/consistency. Quality assurance is the comprehensive, retrospective review of 
all components of research records to assess adherence to the protocol, standard 
operation procedures, and regulatory requirements, and to evaluate the accuracy of the 
records. Quality management is the overall process of assessing the quality of 
processes, data, and documentation associated with clinical research activities. It 
encompasses both quality control and quality assurance. 
 
The quality management program will include but will not be limited to, the 
following: 
 
• Training of staff on the protocol, study procedures, data collection forms, and 
data entry methods 
• Documentation and tracking of training for each staff member 
• A Quality Management Plan that describes processes and activities to be used to 
ensure compliance with the study protocol and accuracy in relation to source 
documents and data entry 
• A Data Management Plan that describes procedures for collecting and entering 
data, storing data securely, and integrating data quality control and validation 
• A Clinical Monitoring Plan that describes the periodic site visits to be made by 
study monitors to insure that human subjects are protected, that the study has 
been implemented in accordance with the protocol  and that study data are 
current, complete, and are securely stored. 

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15 ETHICS/PROTECTION OF HUMAN SUBJECTS 
15.1 
Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the 
principles set forth in The Belmont Report: Ethical Principles and Guidelines for the 
Protection of Human Subjects of Research, as drafted by the US National Commission 
for the Protection of Human Subjects of Biomedical and Behavioral Research (April 18, 
1979) and codified in 45 CFR Part 46 and/or the ICH E6.  
15.2 
Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all subject materials 
will be submitted to the IRB for review and approval.  Approval of both the protocol and 
the consent form must be obtained before any subject is enrolled.  Any amendment to the 
protocol will require review and approval from the IRB before the changes are 
implemented in the study.   
15.3 
Informed Consent Process 
Potential participants may be contacted by telephone or in person for pre-screening; in 
some instances, it may also be conducted simultaneous with the Screening and Baseline 
Visit (Visit 0) or during a scheduled visit to the Brotman Facial Pain Clinic or Oral Surgery 
Clinic. Written informed consent will be obtained at Visit 0 in where will be evaluated 
eligibility, obtain demographics, medical history, medication information, and perform 
evaluations and provide the daily symptoms diaries and then schedule visit 1.  
Informed consent is a process that is initiated prior to the individual agreeing to participate 
in the study and continues throughout study participation.  Extensive discussion of risks 
and possible benefits of study participation will be provided to subjects and their families, 
if applicable.  A consent form describing in detail the study procedures and risks will be 
given to the subject.  Consent forms will be approved by the sponsor (UMB) IRB, and the 
subject is required to read and review the document or have the document read to him or 
her.   
The investigator or designee will explain the research study to the subject and answer 
any questions that may arise.  The subject will sign the informed consent document prior 
to any study-related assessments or procedures.  Participants will be given the 
opportunity to discuss the study with their surrogates or think about it prior to agreeing to 
participate.  They may withdraw consent at any time throughout the course of the study.  
A copy of the signed informed consent document will be given to subjects for their records.  
The rights and welfare of the subjects will be protected by emphasizing to them that the 
quality of their clinical care will not be adversely affected if they decline to participate in 
this study. 
The consent process will be documented in the clinical or research record.   

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15.4 
Exclusion of Women, Minorities, and Children (Special Populations) 
 
There are no exclusions based on gender or racial/ethnic groups. The age range for 
participation is 18-65 years old, to assure that participants have the cognitive acuity to 
understand and adhere to the study procedures. Persons over 65 y/o and children will not 
be included in the study since Erenumab has not been validated in older patients and 
children and because TMD rarely occurs in children.   
 
15.5 
Subject Confidentiality 
Participant confidentiality is strictly held in trust by the investigators, study staff, and the 
sponsor(s) and their agents.  This confidentiality is extended to cover testing of biological 
samples in addition to any study information relating to the 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 sponsor. 
The study safety monitor, or other authorized representatives of the sponsor may inspect 
all study documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) for the study subjects.  The 
clinical study site (UMB School of Dentistry) will permit access to such records. 
Research data from participants will be collected on either paper or electronic forms. Only 
a unique study identification number will appear on such forms; therefore, no information 
that could be used to individually identify a participant will be displayed. 
 
Only study staff will be given access to the key that links name and identification number. 
All paper records and study-related information will be kept under lock and key in a 
private, locked research office. Electronic records will be stored according to UMB 
requirements for research data security. 
 
15.6 
Future Use of Stored Specimens and Other Identifiable Data 
Blood samples will be stored until analysis. At the end of the sample analysis, any 
remaining sample will be discarded. 
 

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16 DATA HANDLING AND RECORD KEEPING 
Participant’s research data will be collected on either paper or electronic forms. Only a 
unique study identification number will appear on such forms; therefore, no information 
that could be used to individually identify a participant will be displayed. 
Only a minimum number of study staff will be given access to the key that links name and 
identification number and will be strictly controlled. Individual identifiers will never appear 
on data forms. All paper records and study-related information will be kept under lock and 
key in a private, locked research office. Electronic records will be stored according to 
UMB requirements for research data security. 
 
Participants can complete the questionnaires and diaries at home or at the research study 
site. A private (locking) room will be provided for data collected at the study site. All data 
entry, transfer, and storage will be accomplished in strict accordance with all regulations 
and UMB requirements for data security. 
The investigators are responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported.  All source documents should be completed in a neat, 
legible manner to ensure accurate interpretation of data. When making corrections, the 
original entry will be crossed out with a single line and the correction will be entered and 
dated.  The investigators will maintain adequate case histories of study subjects, including 
accurate case report forms (CRFs), and source documentation. 
16.1 
Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study staff under 
the supervision of the investigator.  All source documents and laboratory reports must be 
reviewed by the study team and data entry staff, who will ensure that they are accurate 
and complete.  Unanticipated problems and adverse events must be reviewed by the 
investigator or designee.   
16.2 
Data Capture Methods 
Study staff will complete case report forms online via a password-protected, web-based 
EDC system that has been validated and is compliant with Title 21 CFR Part 11. Data 
quality will be continuously monitored, with real-time detection and correction of errors. 
This system will incorporate an audit trail, such that all elements of data entry (date, time, 
name of person performing data entry, verbatim alpha/numeric responses) can be 
retrained and reviewed as needed, in accordance with federal regulations.  
16.3 
Types of Data 
Demographic and medical history data, concomitant medication information, clinical 
examination information, psychosocial and clinical questionnaire information, pressure 
pain threshold testing information, laboratory test results and serum/plasma cytokines will 
be collected in the study. 

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16.4 
Schedule and Content of Reports 
The study coordinator will continuously monitor data collection. It will post study 
progress reports (numbers screened, screen failures, enrolled, and randomized) to the 
study website monthly throughout the study period, as directed by the IRB and the PI. It 
will also post data management reports that contain measures of data quality (i.e., 
number of outstanding data queries and data completion rates). Study reports will be 
provided to the DSMB according to an established schedule, and the DSMB report will 
be submitted to the UMB IRB as part of the study’s annual renewal. 
16.5 
Study Records Retention 
Study documents should be retained for a minimum of 2 years after the last approval of 
a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  These 
documents should be retained for a longer period, however, if required by local 
regulations. It is the responsibility of the sponsor to inform the investigator when these 
documents no longer need to be retained. 
16.6 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol, Good Clinical 
Practice, or Manual of Procedures requirements.  The noncompliance may be on the part 
of the participant, the investigator, or study staff.  As a result of deviations, corrective 
actions are to be developed by the study staff and implemented promptly. 
These practices are consistent with investigator and sponsor obligations in ICH E6: 
• Compliance with Protocol, Sections 4.5.1, 4.5.2, 4.5.3, and 4.5.4. 
• Quality Assurance and Quality Control, Section 5.1.1 
• Noncompliance, Sections 5.20.1 and 5.20.2. 
All deviations from the protocol must be addressed in study participant source documents 
and promptly reported to the IRB and AMGEN according to their requirements.   
 
 

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17 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. 
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 subjects 
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 
adverse events. 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. 
The study will comply with AMGEN requirements and will provide AMGEN the pre-
publication / presentation, abstract for review in their specific timelines. Amgen may 
request sponsors to withhold any publication or presentation an additional period upon 
request. The sponsor is expected to keep study results confidential until publication and 
must acknowledge Amgen's support in all publications. Sponsor to grant Amgen, subject 
to publisher's rights, a license to distribute copies of any publication / presentation within 
Amgen and to licensees, licensors, affiliates, and authorized representatives and to 
prepare derivative works of any publication. 
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 Devices: Controlled trials with health outcomes of a product subject to FDA 
regulation (other than small feasibility studies) and pediatric postmarket surveillance 
studies. 
 

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18 LITERATURE REFERENCES 
 
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2. 
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3. 
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Johansson, A., et al., Gender difference in symptoms related to 
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Schiffman, E., et al., Diagnostic Criteria for Temporomandibular Disorders 
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Dahlstrom, L. and G.E. Carlsson, Temporomandibular disorders and oral health-
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Fillingim, R.B., et al., Long-term changes in biopsychosocial characteristics 
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Manfredini, D., et al., Natural course of temporomandibular disorders with low 
pain-related impairment: a 2-to-3-year follow-up study. J Oral Rehabil, 2013. 
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Fricton JR and S. EL, Epidemiology of temporomandibular disorders.     , in 
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Press: New York. p. 1-14. 
16. 
Greene, C.S. and R. American Association for Dental, Diagnosis and treatment 
of temporomandibular disorders: emergence of a new care guidelines statement. 
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Ohrbach, R., AADR TMD statement is timely and necessary. Oral Surg Oral Med 
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Klasser, R.d.L.a.G.D., Orofacial Pain. Guidelines for Assessment, Diagnosis, and 
Managment. Sixth Edition ed. The American Academy of Orofacial Pain. 2018, 
Chicago , IL: Quintessence Books. 
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Kimos, P., et al., Analgesic action of gabapentin on chronic pain in the 
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Mersfelder, T.L. and W.H. Nichols, Gabapentin: Abuse, Dependence, and 
Withdrawal. Ann Pharmacother, 2016. 50(3): p. 229-33. 
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Tchivileva, I.E., et al., Efficacy and safety of propranolol for treatment of 
temporomandibular disorder pain: a randomized, placebo-controlled clinical trial. 
PAIN, 2020. 161(8). 
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Lars, E., The CGRP Pathway in Migraine as a Viable Target for Therapies. 
Headache: The Journal of Head and Face Pain, 2018. 58(S1): p. 33-47. 
23. 
King, C.T., et al., Discovery of the Migraine Prevention Therapeutic Aimovig 
(Erenumab), the First FDA-Approved Antibody against a G-Protein-Coupled 
Receptor. ACS Pharmacol Transl Sci, 2019. 2(6): p. 485-490. 
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Goncalves, D.A., et al., Headache and symptoms of temporomandibular 
disorder: an epidemiological study. Headache, 2010. 50(2): p. 231-41. 
25. 
Goncalves, D.A., et al., Temporomandibular symptoms, migraine, and chronic 
daily headaches in the population. Neurology, 2009. 73(8): p. 645-6. 
26. 
Akerman, S. and M. Romero-Reyes, Preclinical studies to dissect the neural 
mechanism for the comorbidity of migraine and temporomandibular disorders 
(TMD): the role of CGRP. Br J Pharmacol, 2020. 
27. 
Cady, R., et al., Calcitonin gene-related peptide promotes cellular changes in 
trigeminal neurons and glia implicated in peripheral and central sensitization. 
Molecular Pain, 2011. 7(1): p. 94. 
28. 
Romero-Reyes, M., V. Pardi, and S. Akerman, A potent and selective calcitonin 
gene-related peptide (CGRP) receptor antagonist, MK-8825, inhibits responses 
to nociceptive trigeminal activation: Role of CGRP in orofacial pain. Experimental 
Neurology, 2015. 271: p. 95-103. 
29. 
Tepper, S., et al., Safety and efficacy of erenumab for preventive treatment of 
chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. 
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30. 
Lattanzi, S., et al., Erenumab for Preventive Treatment of Migraine: A Systematic 
Review and Meta-Analysis of Efficacy and Safety. Drugs, 2019. 79(4): p. 417-
431. 
31. 
Ashina, M., et al., Efficacy and safety of erenumab (AMG334) in chronic migraine 
patients with prior preventive treatment failure: A subgroup analysis of a 
randomized, double-blind, placebo-controlled study. Cephalalgia, 2018. 38(10): 
p. 1611-1621. 
32. 
Reuter, U., et al., Efficacy and tolerability of erenumab in patients with episodic 
migraine in whom two-to-four previous preventive treatments were unsuccessful: 
a randomised, double-blind, placebo-controlled, phase 3b study. Lancet, 2018. 
392(10161): p. 2280-2287. 
33. 
Ashina, H., et al., Efficacy, tolerability, and safety of erenumab for the preventive 
treatment of persistent post-traumatic headache attributed to mild traumatic brain 
injury: an open-label study. J Headache Pain, 2020. 21(1): p. 62. 
34. 
Slade, G.D., et al., Summary of findings from the OPPERA prospective cohort 
study of incidence of first-onset temporomandibular disorder: implications and 
future directions. The journal of pain : official journal of the American Pain 
Society, 2013. 14(12 Suppl): p. T116-T124. 
35. 
Ohrbach, R. and E.N. Gale, Pressure pain thresholds, clinical assessment, and 
differential diagnosis: reliability and validity in patients with myogenic pain. Pain, 
1989. 39(2): p. 157-169. 
36. 
Ohrbach, R., et al., Preliminary development and validation of the Jaw Functional 
Limitation Scale. Community Dent Oral Epidemiol, 2008. 36(3): p. 228-36. 
37. 
Ohrbach, R., P. Larsson, and T. List, The jaw functional limitation scale: 
development, reliability, and validity of 8-item and 20-item versions. J Orofac 
Pain, 2008. 22(3): p. 219-30. 
38. 
Markiewicz, M.R., R. Ohrbach, and W.D. McCall, Jr., Oral behaviors checklist: 
reliability of performance in targeted waking-state behaviors. J Orofac Pain, 
2006. 20(4): p. 306-16. 
39. 
Ohrbach, R., Assessment and further development of RDC/TMD Axis II 
biobehavioural instruments: a research programme progress report. J Oral 
Rehabil, 2010. 37(10): p. 784-98. 
40. 
Von Korff, M., et al., Grading the severity of chronic pain. Pain, 1992. 50(2): p. 
133-49. 
41. 
Perrot, S. and M. Lantéri-Minet, Patients' Global Impression of Change in the 
management of peripheral neuropathic pain: Clinical relevance and correlations 
in daily practice. Eur J Pain, 2019. 23(6): p. 1117-1128. 
42. 
Hurst, H. and J. Bolton, Assessing the clinical significance of change scores 
recorded on subjective outcome measures. J Manipulative Physiol Ther, 2004. 
27(1): p. 26-35. 
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SUPPLEMENTAL MATERIALS 
These documents are relevant to the protocol, but they are not considered part of the 
protocol.  They are stored and modified separately. As such, modifications to these 
documents do not require protocol amendments. 
• Site Roster 
• Manual of Procedures 
• Laboratory Handling (if applicable) 
• Case report forms 
• Quality Management Plan 
• Data Management Plan 
• Clinical Monitoring Plan 
• Statistical Analysis Plan 
• DSMB or Oversight Committee Charter 
 

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APPENDICES 
 
• Key Study Questionnaires are attached separately 
• Consent Form is attached separately 
 

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APPENDIX A: SCHEDULE OF EVENTS 
Study Phase 
Pre-
screeningA 
Screening 
and 
Baseline 
Randomization and Treatment 
(12 weeks of treatment/3 cycles 
of Erenumab) 
Follow 
Up 
Early 
termination 
Clinic Visit 
 
V0 
V1B 
V2 
V3 
V4 
V5 
ET 
Study Day/ 
0-4 weeks 
prior to V0 
1-3 weeks 
prior V1 
Day 0 
Day 
28 
Day 
56 
Day 
84 
Day 
112 
 
Procedures 
 
 
 
 
 
 
 
 
Contact 
Information 
X 
 
 
 
 
 
 
 
Pre-screening 
interview Script 
X 
 
 
 
 
 
 
 
Informed 
consentC 
 
X 
 
 
 
 
 
 
Eligibility 
Review 
X 
X 
 
 
 
 
 
 
Demographic 
information 
 
X 
 
 
 
 
 
 
Medical history 
and Review 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
therapies  
 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Review 
 
 
X 
X 
X 
X 
X 
X 
Dispense Daily 
Symptom 
Diaries D 
 
X 
X 
X 
X 
X 
 
 
Collect Daily 
Symptom 
Diaries D 
 
 
X 
X 
X 
X 
X 
 
Assess 
compliance 
with Daily 
Symptom 
Diaries  
 
 
X 
X 
X 
X 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Provide study 
drug injectionE 
 
 
X 
X 
X 
 
 
 
 
 
 

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Study Phase 
Pre-
screeningA 
Screening 
and 
Baseline 
Randomization and Treatment 
(12 weeks of treatment/3 cycles 
of Erenumab) 
Follow 
Up 
Early 
termination 
Clinic Visit 
 
V0 
V1B 
V2 
V3 
V4 
V5 
ET 
Study Day 
0-4 weeks 
prior to V0 
1-3 weeks 
prior V1 
Day 0 
Day 
30 
Day 
60 
Day 
90 
Day 
120 
 
Clinical 
Examination 
and Tests  
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
Urine 
pregnancy test 
 
X 
X 
X 
X 
X 
X 
X 
TMD 
Examination 
 
X 
X 
X 
X 
X 
X 
 
Pressure Pain 
Threshold 
Examination 
 
X 
X 
X 
X 
X 
X 
 
Schedule next 
visit 
X 
X 
X 
X 
X 
X 
 
 
Laboratory 
 
 
 
 
 
 
 
 
Blood draw for 
Cytokine 
release assay 
 
X 
 
 
 
X 
 
 
Questionnaires 
 
 
 
 
 
 
 
 
Symptom 
Inventory 
 
X 
X 
X 
X 
X 
X 
X 
Graded Chronic 
Pain ScaleF 
 
 
X 
X 
X 
X 
X 
X 
Jaw functional 
Limitation 
ScaleF 
 
 
X 
X 
X 
X 
X 
X 
Oral Behaviors 
ChecklistF 
 
 
X 
X 
X 
X 
X 
X 
Hospital Anxiety 
and Depression 
IndexF 
 
 
X 
X 
X 
X 
X 
X 
 
Study Phase 
Pre-
screeningA 
Screening 
and 
Baseline 
Randomization and 
Treatment 
(12 weeks of treatment/3 
cycles of Erenumab/placebo) 
Follow 
Up 
Early 
termination 

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Clinic Visit 
 
V0 
V1B 
V2 
V3 
V4 
V5 
ET 
Study Day 
0-4 weeks 
prior to V0 
1-3 weeks 
prior V1 
Day 
0 
Day 
30 
Day 
60 
Day 
90 
Day 
120 
 
Patient 
Global 
Impression of 
ChangeF  
 
 
X 
X 
X 
X 
X 
X 
 
A Pre-screening can happen by phone or at clinic visit. It may be combined with screening visit 
and baseline visit (Visit 0). 
B In the case Visit 1 cannot occur after one week of Visit 0, and the participant is to remain in the 
study; Visit 0 will be repeated as an unscheduled visit. The timing of visits 2-5 and their windows 
are established from the date of Visit 1. 
C Includes consent to participate in the study and HIPPA 
D Diary symptom diaries are completed electronically but if a participant opted the paper form, 
they will be dispensed and collected. 
E The study drug will be administered (S.C.) on Visit 1, Visit 2 and Visit 3. 
F Questionnaires will be completed electronically a day prior to the scheduled visit or distributed 
on paper format a previous visit to be returned at the scheduled visit.