A Randomized, Double Blind, Placebo-Controlled Single Center Phase 2 Pilot Study to Assess the Safety and Efficacy of Off-label Subcutaneous Administration of Erenumab-aooe in Patients With Temporomandibular Disorder
Phase: PHASE2
Conditions: Temporomandibular Disorder
Sponsor: Indiana University

Version Date: Amend 8- January 12, 2023 
 
Page 1 of 27 
 
RESEARCH PROTOCOL 
 
 
Study Number: 
 
 
 
Title: 
A Randomized, Double Blind, Placebo-Controlled Single 
Center Phase 2 Pilot Study to Assess the Safety and 
Efficacy of Off-label Subcutaneous Administration of 
Erenumab-aooe in Patients with Temporomandibular 
Disorder 
 
Sponsor: 
 
 
 
Indiana University* 
 
 
Investigation Site: 
 
 
Oral Health Research Institute 
 
 
 
 
 
Indiana University School of Dentistry 
 
Principal Investigator: 
 
Domenick T. Zero, DDS, MS,  
 
 
 
 
 
Oral Health Research Institute 
 
 
 
 
 
415 Lansing Street 
 
 
 
 
 
Indianapolis, IN 46202-2876  
 
 
 
 
 
Phone: 317-274-8822 
 
 
 
 
 
FAX: 317-274-5425 
 
 
 
 
 
Email: dzero@iu.edu 
 
Co-Principal Investigator:  
Harold C. Avila, DDS, MS 
Adjunct Clinical Assistant Professor 
Department of Oral Pathology, Medicine and Radiology 
Indiana University School of Dentistry 
 
Co-Investigator: 
 
 
Kurt Kroenke, MD, MACP 
Chancellor’s Professor, IUPUI 
General Internal Medicine 
Indiana University Center for Health Services/Outcomes 
Research, Regenstrief Institute 1101 W. 10th Street 
Indianapolis, IN 46202 
 
 
 
 
 
Study Dentist 
 
 
Ana Gossweiler, DDS, MSD 
 
 
 
 
 
Oral Health Research Institute 
 
Statistician:  
 
 
George Eckert, MAS 
 
 
 
 
 
Department of Biostatistics 
 
 
 
 
 
Indiana University School of Medicine 
 
Study Manager: 
 
 
 TBD 
 
Version:  
  
  
 
Final: Revised 01FEB2021 
 
 
 
 
 
Amendment 8: January 12, 2023 
 
* Funded by Amgen through Investigator Sponsored Studies (ISS) Program 
(CAMG334AUS01T) 

Version Date: Amend 8- January 12, 2023 
 
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Table of Contents 
List of Abbreviations ................................................................................................................... 3 
1. 
Background & Rationale ..................................................................................................... 4 
2. 
Study Objectives and Outcome Measures .......................................................................... 5 
2.1 
Primary Objective and Outcome Measure .................................................................... 5 
2.2 
Secondary Objective and Outcome Measures ............................................................. 5 
3. 
Study Design ...................................................................................................................... 5 
4. 
Study Population ................................................................................................................ 6 
4.1 
Inclusion Criteria .......................................................................................................... 6 
4.2 
Exclusion Criteria ......................................................................................................... 6 
4.3 
Enrollment Procedures ................................................................................................ 7 
5. 
Treatments ......................................................................................................................... 8 
5.1 
Study Treatments......................................................................................................... 8 
5.2 
Treatment Arms ........................................................................................................... 8 
5.3 
Treatment assignment and randomization ................................................................... 8 
5.4 
Treatment blinding ....................................................................................................... 8 
5.5 
Dispensing of study drug.............................................................................................. 8 
6. 
Visit Schedule and Assessments ........................................................................................ 9 
7. 
Safety Monitoring ..............................................................................................................11 
7.1 
Adverse Events ...........................................................................................................11 
7.2 
Serious Adverse Events ..............................................................................................11 
7.3 
Study Withdrawal/Discontinuation ...............................................................................12 
8. 
Data Analysis ....................................................................................................................12 
8.1 
Sample size calculations .............................................................................................12 
9. 
References ........................................................................................................................12 
10. 
Appendices ....................................................................................................................15 
Appendix A – TMD Symptoms ..............................................................................................15 
Appendix B – TMD Treatments .............................................................................................16 
Appendix C – Diagnostic Criteria for Temporomandibular Disorders Symptom Questionnaire
 ..............................................................................................................................................18 
Appendix D – Brief Pain Inventory (BPI) ................................................................................20 
Appendix E – PEG (Pain, Enjoyment, General Activity) Scale and Pain Medication 
Assessment ..........................................................................................................................22 
Appendix F – Patient Global Impression of Change (PGIC) ..................................................23 
Appendix G – Jaw Function Limitation Scale (JFLS-8) ..........................................................24 
Appendix H – Depressive and anxiety symptoms (PHQ-4) ....................................................25 
Appendix I – Somatic symptom severity as measured by the SSS-8 .....................................26 
11. 
Table 1 ...........................................................................................................................27 
 

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List of Abbreviations 
 
 
AE 
Adverse Event 
BPI 
Brief Pain Inventory 
CFR 
Code of Federal Regulations 
CGRP 
Calcitonin Gene Related Peptide 
CM 
Chronic Migraine 
COPCs 
Chronic Overlapping Pain Conditions COPCs 
CPAP 
Continuous Positive Airway Pressure 
CRF 
Case Report Form 
DC/TMD 
Diagnostic Criteria/Temporomandibular Disorder 
EREN 
Erenumab-aooe 
EREN-P 
Placebo  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IRB 
Institutional Review Board 
IUPUI 
Indiana University Purdue University Indianapolis 
IUSD 
Indiana University School of Dentistry 
JFLS 
Jaw Function Limitation Scale  
NIH/NIDCR National Institutes of Health/National Institutes of Dental and Craniofacial Research 
PEG 
Pain, Enjoyment, General Activity Scale 
PGIC 
Patient Global Impression of Change 
PHQ-4 
Patient Health Questionnaire  
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
s.c. 
Subcutaneous 
SOP 
Standard Operating Procedure 
SSS-8 
Somatic Symptom Scale  
TGV 
Trigeminovascular Pathway 
TMD 
Temporomandibular Disorder 
UmMa(s) 
Human Monoclonal Antibody(s) 

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1. 
Background & Rationale 
Aimovig® [erenumab (EREN)] is a first in class FDA-approved human monoclonal antibody 
(UmAb) for the prevention of migraine in adults. It selectively targets and blocks the calcitonin 
gene-related peptide (CGRP) receptor, disrupting a key component of migraine pathophysiology 
(Hargreaves & Olesen, 2019). Several studies have provided evidence of the safety and efficacy 
of Aimovig® in reducing the frequency of migraine compared to placebo (Goadsby et al., 2017; 
Tepper et al., 2017). Furthermore, an open-label longer-term study found that Aimovig® was safe 
and well-tolerated with a safety profile consistent with shorter-term placebo-controlled studies 
(Ashina et al., 2020), through 5-years of treatment. Aimovig® has rapidly become a widely 
accepted prescription drug for the prevention of migraines, including episodic migraine and 
chronic migraine (CM) along with other anti-CGRP monoclonal antibody-based therapies (Yuan 
et al., 2019).  
Temporomandibular Disorders (TMD) are known to be co-morbid with the medical diagnosis of 
CM (Speciali, 2015). TMD symptoms are numerous and chronic in nature (see appendix A) and 
TMD treatments are more numerous than symptoms and are predictable only in their 
unpredictability (see Appendix B). Most patients experiencing TMD find it to be a chronic, 
untreatable condition. In the US alone, TMDs are the second most commonly occurring 
musculoskeletal conditions resulting in pain and disability (after chronic low back pain), affecting 
approximately 5 to 12% of the population, with an annual cost estimated at $4 billion (NIH/NIDCR). 
There is increasing interest in the concept of Chronic Overlapping Pain Conditions (COPCs), 
which 
include 
TMD, 
fibromyalgia, 
irritable 
bowel 
syndrome, 
vulvodynia, 
myalgic 
encephalomyelitis/chronic fatigue syndrome, interstitial cystitis/painful bladder syndrome, 
endometriosis, chronic tension-type headache, migraine headache, and chronic lower back pain 
that may have common biopsychosocial factors (Maixner et al., 2016). 
Co-Principal Investigator, Dr. Harold C. Avila, has treated several patients that presented with 
chronic TMD pain and a history of migraines headaches, which have responded positively to off-
label administration of Aimovig®. Anecdotally, five of Dr. Avila’s TMD patients were treated with 
Aimovig® along with his standard therapy. Of these, three patients experienced substantial life-
changing relief of TMD pain symptoms. Another patient initially experienced substantial pain relief, 
which declined slightly over two months. The last patient stopped taking Aimovig® due to elevated 
blood pressure, which is not an adverse event associated with Aimovig® in the published clinical 
trials (Goadsby et al., 2017; Tepper et al., 2017); however, the development of hypertension and 
worsening of pre-existing hypertension have been reported following the use of AIMOVIG in the 
postmarketing setting (FDA-approved Patient Labeling). 
   
CM is thought to originate within the trigeminovascular pathway (TGV) (Noseda & Burstein, 2013). 
TMD is also considered to originate within the TGV (de Leeuw, 2018). Thus, our working 
hypothesis is that a CGRP receptor antagonist for treatment of CM will also be effective in 
reducing TMD pain and related symptoms. To test this hypothesis, we applied several validated 
measures: Brief Pain Inventory (BPI) (Kean et al., 2016); PEG (Pain, Enjoyment, General Activity) 
Scale (Krebs et al., 2009); an assessment of daily pain medication; Patient Global Impression of 
Change (PGIC) (Kroenke et al., 2018); Jaw Function Limitation Scale (JFLS) (Ohrbach et al., 
2008); Patient Health Questionnaire (PHQ-4) (Kroenke et al., 2009); and Somatic Symptom Scale 
(SSS-8) (Toussaint et al., 2017). 
 
The purpose of this proof of concept study was to evaluate the safety and efficacy of the off-label 
use of Aimovig® (EREN) in reducing Temporomandibular Disorder (TMD) pain compared to 
placebo.  
 

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2. 
Study Objectives and Outcome Measures 
2.1 
Primary Objective and Outcome Measure 
To assess the effects of Aimovig® (EREN) compared to placebo (EREN-P) based on the change 
in mean between-group difference in pain using the Brief Pain Inventory (BPI) 4-item pain 
severity/intensity scale during the 20-week trial. The BPI is a validated and widely used outcome 
measures in chronic pain trials (Kean et al., 2016; Kroenke et al., 2019). We postulated that 
Aimovig® will be superior to placebo in reducing pain intensity/severity over 20 weeks. 
 
2.2 
Secondary Objective and Outcome Measures 
To assess the effects of Aimovig® (EREN) compared to placebo (EREN-P) based on the change 
in mean between-group difference in secondary outcomes during the 20-week trial and after 24 
weeks (two months after the last treatment). The outcome measures are based on consensus 
recommendations for research assessments in chronic pain and TMD research (Ohrbach et al., 
2016; Kroenke et al., 2019). We postulated that Aimovig® will be superior to placebo in improving 
several secondary outcomes including: 
a) Pain interference as measured by the BPI interference scale 
b) Trajectory of pain improvement based on changes in daily reporting of pain using the PEG 
(Pain, Enjoyment, General Activity) Scale as measured using an app downloaded on the 
subject’s smartphone or for individuals without smartphones at baseline and every 4 
weeks over the 24-week study period 
c) Days of use of TMD pain-specific medication per month 
d) Global improvement in pain as measured by the Patient Global Impression of Change 
(PGIC) 
e) Jaw function as measured by the Jaw Function Limitation Scale (JFLS-8) 
f) Depressive and anxiety symptoms as measured by the Patient Health Questionnaire 
(PHQ-4) 
g) Somatic symptom severity as measured by the Somatic Symptoms Scale (SSS-8) 
h) Safety and tolerance as measured by incidence of AEs and SAEs 
 
3. 
Study Design 
This was a 24-week, randomized, double-blinded, placebo-controlled, parallel group proof-of-
concept study with two arms (active and placebo). The plan was to enroll 30 subjects. There was 
a four-week screening period to identify subjects that meet the diagnostic criteria (DC/TMD) for 
“myalgia”, recommended by the International RDC/TMD Consortium Network and Orofacial Pain 
Special Interest Group (Schiffman et al., 2014). The Diagnostic Criteria for Temporomandibular 
Disorders Symptom Questionnaire and DC/TMD Examination Form (Ohrbach, 2016) was used 
during Screening and Baseline visits to confirm the TMD diagnosis and determine whether 
subjects met the inclusion/exclusion criteria.  
Subjects attended a Screening visit followed by Baseline visit to randomize eligible subjects to 
active (EREN) or placebo (EREN-P). During the Baseline visit and Wks 4, 8, 12, and 16, subjects 
received treatment with either 140 mg of EREN or Placebo administered by subcutaneous 
injection. At Baseline and Wks 4, 8, 12, 16, 20, and 24 subjects were instructed to complete the 
Brief Pain Inventory (BPI) (Kean et al., 2016); PEG (Pain, Enjoyment, General Activity) Scale 
(Krebs et al., 2009); pain mediation assessment; Patient Global Impression of Change (PGIC) 

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(Kroenke et al., 2018) (except for Baseline visit); Jaw Function Limitation Scale (JFLS) (Ohrbach 
et al., 2008); Patient Health Questionnaire (PHQ-4) (Kroenke et al., 2009); and Somatic Symptom 
Scale (SSS-8) (Toussaint et al., 2017). These visits also included review of continuance criteria 
and adverse event collection.  
At the Screening and Baseline visits the subjects were instructed on how to use the PEG Scale 
and pain use assessment app, which was downloaded on their smartphone, to provide a daily 
assessment of their pain intensity and interference with enjoyment and general activity (PEG) and 
their daily used of pain medications. Subjects who did not own a smartphone or were unwilling to 
use the app on a daily basis only completed the PEG and pain medication assessment at the 
Baseline visit and all subsequent visits using the app onsite.  
4. 
Study Population 
The study population consisted of male and female subjects diagnosed as having pain-related 
TMD using the diagnostic criteria (DC/TMD) for “myalgia”, recommended by the International 
RDC/TMD Consortium Network and Orofacial Pain Special Interest Group (Schiffman et al., 
2014). The goal was to recruit 30 subjects that fulfill the inclusion and exclusion criteria. It was 
anticipated that 24 subjects (12 in each treatment group) will complete all aspects of the study.  
 
4.1 
Inclusion Criteria 
Subjects eligible for inclusion in the study must have met all of the following criteria: 
 
 
1. Signed the informed consent; 
2. Have a history of head, face, neck and/or shoulder pain for longer than 3 months; 
3. Have a diagnosis of myalgia based on clinical examination using DC/TMD criteria; 
4. Age 18 years and younger than 60 years; 
5. Have a good knowledge of the English language; 
6. Able to understand and comply with the study requirements; and  
7. If taking prescription pain medications, the dose regimen must be stable for at least 2 
months prior to the screening visit. 
 
4.2 
Exclusion Criteria 
Subjects that met any of the following criteria were not eligible for inclusion: 
 
1. Lacking stable bilateral posterior occlusion; 
2. Currently uses a complete maxillary or mandibular prosthetic denture; 
3. Currently pregnant or plan to become pregnant; 
4. Breastfeeding or plan to breastfeed; 
5. Allergic to erenumab-aooe or any of the ingredients in Aimovig® (acetate, polysorbate 
80, and sucrose); 
6. Allergic to rubber or latex; 
7. Currently undergoing TMD treatment elsewhere. Exception: patients undergoing TMD 
treatment involving the use of oral orthotics for a minimum of 3 months prior to Screening 
can be considered eligible for the study; 

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8. Started orthodontic treatment during the 3 months prior to Screening; 
9. Currently included in other experimental protocols within the last 30 days or 5 half-lives 
before enrollment; 
10. Having 8 or more migraine days during the past 4 weeks; 
11. Started receiving massage, acupuncture or physical therapy treatment of the head, neck 
or shoulders during the previous 3 months prior to Screening; 
12. History of unstable or acute severe non-head, neck or shoulder pain; 
13. History of traumatic brain injury; 
14. History of surgical treatment or recommended surgical treatment for TMD; 
15. History of ongoing, unresolved disability litigation; 
16. History of drug abuse; 
17. Started treatment for moderate to severe sleep apnea requiring CPAP or oral mandibular 
repositioning appliance during the previous 3 months prior to Screening;  
18. Anything that would place the subjects at increased risk or preclude the individual's full 
compliance with or completion of the study (e.g., medical condition, laboratory finding, 
physical exam finding logistical complication); 
19. History of previously receiving erenumab-aooe or other anti-CGRP pathway therapies, 
including anti-CGRP and anti-CGRP receptor monoclonal antibodies and small molecule 
CGRP receptor antagonists (gepants); 
20. History of chronic constipation and/or using medication associated with decreased 
gastrointestinal motility; and 
21. History of uncontrolled hypertension or risk factors for hypertension. 
 
4.3 
Enrollment Procedures 
Subjects were recruited using fliers and advertisements placed in the Indiana University (IU) 
School of Dentistry (IUSD) and other locations on the Indiana University Purdue University 
Indianapolis (IUPUI) campus including IU Health facilities. Fliers may also be posted on 
Facebook.  
 Dr. Avila may send approved study information to persons who may have TMD and he may also 
mention the study during planned radio interviews about TMD.  Dr. Avila’s website will not mention 
research. 
Persons responding to an advertisement will be given a brief description of the study and asked 
a series of questions related to the inclusion/exclusion criteria using an IRB approved phone 
script. Those who are interested and appear to meet the study requirements will be scheduled for 
a screening visit at the Oral Health Research Institute (OHRI). 
 
Additionally, contact information was obtained from Regenstrief for IU Health patients who have 
indicated they have TMJ problems and are willing to be contacted for future studies. Once 
contact information was obtained, the OH study coordinator contacted the potential subjects by 
telephone to see if they were interested in attending a screening visit. 
 

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5. 
Treatments 
5.1 
Study Treatments 
Investigational drug: erenumab-aooe (EREN) 140 mg, for s.c. injections, provided by Amgen 
 
Placebo: liquid placebo (EREN-P), for s.c. injections provided by Amgen  
Amgen provided the active and placebo free of charge through the Investigator Sponsored 
Studies (ISS) Program (CAMG334AUS01T). 
 
5.2 
Treatment Arms 
Subjects were assigned at baseline to one of the two treatment arms: 
 
• 
Arm A: erenumab-aooe (EREN) 140 mg s.c. administered every four weeks for a total of 
five treatments 
• 
Arm B: placebo (EREN-P) s.c. administered every four weeks for a total of five treatments 
 
5.3 
Treatment assignment and randomization 
Subjects were randomized and stratified based on gender into two groups using block 
randomization based on a schedule provided by the study statistician, George Eckert, Indiana 
University School of Medicine Department of Biostatistics.  
 
The randomization code was provided to Amgen as part of the ISS contract agreement.  
 
5.4 
Treatment blinding 
Subjects, investigators and study staff will remain blind to the identity of the treatment from the 
time of randomization until database lock. The randomization code will be kept strictly confidential 
and the identity of the study drug treatments will be concealed using identical packaging and 
labeling. The blind will only be broken in an emergency where it is essential to know which 
treatment a subject received in order to give the appropriate medical care. 
 
5.5 
Dispensing of study drug  
The investigational products (EREN and EREN-P) supplied in prefilled syringes will be shipped 
by Amgen to the attention of the unblinded IU Health Investigational Drug Services Pharmacy. 
The IU Health Pharmacy will dispense the investigational products according to a randomization 
schedule provided by the study statistician, George Eckert. A written prescription order form will 
be completed by the licensed study dentist and submitted to the pharmacy each time study drug 
is requested for a subject. Doses will be administered in the upper arm, thigh, or abdomen by a 
study dentist qualified in s.c. drug administration.  
Study product will be stored and handled according to labeling instructions: store refrigerated at 
2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use; do not freeze; 
and do not shake; leave the prefilled syringe at room temperature for at least 30 minutes before 
injecting. The investigational products will be stored in a secured area of the IU Health 
Investigation Drug Services Pharmacy to which only the pharmacy staff have access.  
The IU Health pharmacy will maintain adequate records documenting the receipt, use, loss, or 
other disposition of the products on the electronic Investigational Agent Accountability Record. 
The log will identify the products and account for the disposition including specific dates and 

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quantities used/dispensed and returned, as applicable. The log will capture the electronic 
signatures of the site designees who dispensed and verified the products. 
The clinical site, OHRI, working with the pharmacy will also maintain a Drug Administration Form 
documenting the date and time of transport to the blinded site staff, the date and signature of the 
blinded site staff receiving the study drug, the date and time the study drug was received from the 
pharmacy, the date and time the study drug was administered, and the injection site body location. 
 
 
 
 
 
6. 
Visit Schedule and Assessments 
Study Schedule 
 
 
Screening Visit: Subjects will complete the informed consent process, being given ample time 
to review the consent and to ask any questions they have before deciding if they wish to 
participate. Those interested will sign and date their informed consent and the consent will also 
Period 
Screening 
Treatment Period 
Post-
Treatment 
Visit Name 
Screening 
Baseline Wk 4 
Wk 8 
Wk 12 Wk 16 Wk 20 
Wk 24 
Days 
-28 to -1 
1 
29 
57 
85 
113 
141 
169 
Weeks 
-4 to -1 
0 
4 
8 
12 
16 
20 
24 
Informed consent 
X 
Randomization 
X 
Study drug 
administration 
 
X 
X 
X 
X 
X 
Inclusion / Exclusion 
criteria 
X 
Demography 
X 
Medical history/current 
medical conditions 
X 
Prior therapy for TMD 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Familiarize with PEG App 
X 
X 
 
 
 
 
 
 
BPI, PEG and pain 
medication assessment 
(daily), JFLS-8, PHQ-4, 
SSS-8 
 
X 
X 
X 
X 
X 
X 
X 
PGIC 
 
 
X 
X 
X 
X 
X 
X 

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be signed and dated by the person reviewing the consent process with them. Subjects will receive 
a signed copy of their consent before leaving this visit. A Study Dentist qualified to diagnosis TMD 
will review the potential subject’s health history, medications and TMD history for the inclusion 
and exclusion criteria. 
The Diagnostic Criteria for Temporomandibular Disorders Symptom Questionnaire (Appendix C) 
and DC/TMD Examination Form (Ohrbach, 2016) will be used to confirm the TMD diagnosis and 
determine whether subjects meet the inclusion/exclusion criteria. To meet the diagnostic criteria 
for TMD Myalgia (IDC-9 729; ICD-10 M79.1) (Schiffman et al., 2014), subjects must have a history 
of pain of muscle origin that is affected by jaw movement, function, or parafunction, and 
demonstrate replication of this pain with provocation testing of the masticatory muscles. The 
specific criteria (Schiffman et al., 2014) include having a positive history for both pain in the jaw, 
temple, in the ear, or in front of ear and pain modified with jaw movement, function or parafunction. 
During clinical examination, subjects must have a confirmation of pain in the temporalis or 
masseter muscle(s) and report familiar pain in the temporalis or masseter muscle(s) with at least 
one of the following provocation tests: palpation of the temporalis or masseter muscle(s) or 
maximum unassisted or assisted opening movement(s).  
Subjects with smartphones will be asked to download the MyCap app and will then be trained on 
completing the PEG Scale and the pain medication assessment questions using their 
smartphone. The subject will be scheduled to return to the study site for their Baseline visit.  
 
Baseline, Wk 4, 8, 12, and 16 Visits: The subject’s medical history, medications and continuance 
criteria will be reviewed to assure the subject still qualifies to participate in the study. The 
Diagnostic Criteria for Temporomandibular Disorders Symptom Questionnaire (Appendix C) and 
DC/TMD Examination Form will be used to confirm the TMD diagnosis and determine whether 
subjects meet the inclusion/exclusion criteria. In addition, the subjects will be assessed using the 
Brief Pain Inventory (BPI) (Appendix D), PEG (Pain, Enjoyment, General Activity) Scale and pain 
medication assessment (Appendix E), Jaw Function Limitation Scale (JFLS) (Appendix G), 
Patient Health Questionnaire (PHQ-4) (Appendix H), and Somatic Symptom Scale (SSS-8) 
(Appendix I). Starting at week 4 the subjects will also be assessed using global improvement in 
pain as measured by the Patient Global Impression of Change (PGIC) (Appendix F). 
The subject will receive their assigned treatment (EREN or EREN-P) based on the randomization 
scheme at baseline and Wk 4, 8, 12, and 16.  
The procedure for texting each day will be reviewed with the subject and a practice text will be 
sent to assure communication is accurate. Subjects without smartphones will only be required 
complete the PEG Scale and pain medication assessment questions using the app onsite at 
Baseline and at all subsequent study visits. 
Adverse events will be assessed and documented, and the subjects will be schedule for their next 
visit. 
 
Wk 20 End of Treatment Period Visit: Subjects will be assessed using the BPI, PEG and pain 
medication assessment (app), PGIC, JFLS, PHQ-4, and SSS-8. Adverse events will be assessed 
and documented, and the subjects will be schedule for their next visit. 
  
 
Wk 24 Post-Treatment Follow-up Visit: Subjects will return for follow-up examination and 
assessed using the BPI, PEG and pain medication assessment (app), PGIC, JFLS, PHQ-4, and 
SSS-8. Adverse events will be assessed and documented. 
 

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7. 
Safety Monitoring 
This study will be conducted in compliance with the US Code of Federal Regulations (CRF) 
governing informed consent (21 CFR 50), Institutional Review Board (IRB) (21 CFR 56), and with 
applicable regulations governing Investigator conduct (21 CFR 312). 
This study will be performed according to GCPs. SOPs for all procedures are on file with the 
Quality Assurance staff of the Oral Health Research Institute. 
 
All study staff who have direct subject contact will be required to review the WARNINGS AND 
PRECAUTIONS for Hypersensitivity Reactions, Constipation with Serious Complications and 
Hypertension found in Section 5 of the US Prescribing Information (USPI) for Aimovig®.  
https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-
com/aimovig/aimovig_pi_hcp_english.ashx 
 
7.1 
Adverse Events  
Subjects will be questioned regarding any general health or oral complaints and symptoms they 
have experienced during each visit. Any findings will be documented on the AE CRF. In the event 
of subjects reporting AEs outside the scheduled clinical visit, the Investigator will assess them at 
the earliest opportunity. 
All AEs, regardless of severity or relationship to the treatments, will be recorded. Serious AEs 
include any events resulting in death, decreased life expectancy, life-threatening situations, 
persistent or permanent disability/incapacity, hospitalization, or congenital anomaly/birth defect. 
In addition, other important medical events that are deemed clinically important/serious based on 
PI judgement will be recorded as AEs. Within 24 hours, the Investigator will submit a written report 
to Amgen documenting the circumstances of the serious AE. 
 
7.2 
Serious Adverse Events  
Safety monitoring for this study will focus on adverse events related to treatment use and 
unanticipated problems involving risks to participants, including unanticipated problems that meet 
the definition of a serious adverse event. At each visit, subjects will be queried about any adverse 
events that may have occurred since their last visit, regardless of direct relationship to treatment 
use. Adverse events will be recorded on an Adverse Event form. Abnormalities, or worsening of 
pre-existing conditions, observed by the examiner or reported by the subject that occur at any 
visit will be recorded on the AE CRF. All AEs will be transcribed onto a log, which will be monitored 
by the PI to determine if the nature, frequency, or severity of an event meets the criteria for prompt 
reporting. All adverse events will be reported to the IRB during annual review. 
The PI will be notified immediately if a serious adverse event occurs. All serious adverse events 
that meet the prompt reporting requirements will be reported to the IRB within 5 business days. 
Serious adverse events include: any event resulting in death, is life-threatening, requires 
hospitalization, results in disability/permanent damage, congenital anomaly/birth defect, or 
requires intervention to prevent permanent impairment or damage, and/or other medical events. 
The study site will be responsible for reporting SAEs to Amgen in accordance with the Amgen 
ISS Program contract requirements.  
The study site will be responsible for reporting all safety information to Amgen in accordance with 
their reporting requirements (Table 1). 
 

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7.3 
Study Withdrawal/Discontinuation 
Subjects may withdrawal or discontinue from the clinical trial at any time without penalty or loss. 
Subjects will be advised at the start of the trial that they may withdraw from the trial at any time, 
without giving a reason. Subjects may be withdrawn by the Principal Investigator for the 
following reasons: 
 
• 
the volunteer wishes to withdraw; 
• 
if, in the opinion of the Investigator, it is in the best interests of the subject; 
• 
if serious adverse reactions occur; 
• 
inter-current illness occurs; 
• 
there is a significant violation of the prohibitions and restrictions; 
• 
development of an exclusion criterion. 
 
Withdrawals due to non-attendance must be followed up to attempt to obtain the reason that the 
subject is ‘lost to follow up’. Subjects who are lost to follow up will be encouraged to return to 
the site for an exit visit. Subjects withdrawn for medical reasons will be referred to a physician 
/dentist. Their condition will be monitored until it is resolved or clinically non-significant. All 
withdrawals and the reason for withdrawal will be documented. Withdrawn subjects will not be 
replaced. 
 
8. 
Data Analysis 
Mixed model repeated measures (MMRM) analysis will be used to evaluate changes over time in 
the BPI pain severity/intensity scale and BPI total score, PEG Scale total score and daily pain, 
days of use of pain medication and TMD pain-specific medication per month, JFLS-8, PHQ-4 
anxiety and depression, SSS-8 Scale, and PGIC pain change within and between treatment 
groups. The MMRM will include factors for treatment group, time, and their interaction. Time will 
be repeated within subject. The MMRM will also include gender as a covariate due to stratification 
by gender in the randomization. The distribution of the outcomes will be examined and a 
transformation of the data will be used if necessary. A two-sided 5% significance level will be used 
for all tests without multiplicity adjustment between multiple endpoints. 
 
8.1 
Sample size calculations 
A sample size of 12 subjects per group has been suggested for pilot studies to evaluate feasibility 
and to estimate group means and standard deviations for future study planning (Julious, 2005). 
Based on two-sided paired t-tests and two-sample t-tests, all conducted at a 5% significance level, 
this pilot study will have 80% power to detect effect sizes of 0.9 for changes over time within 
groups and effect sizes of 1.2 for differences between groups. To account for dropout, the study 
will enroll 15 subjects per group, 30 total subjects. 
 
9. 
References 
Ashina M, Goadsby PJ, Reuter U, Silberstein S, Dodick DW, Xue F, Zhang F, Paiva da Silva Lima 
G, Cheng S, Mikol DD. Long-term efficacy and safety of erenumab in migraine prevention: Results 
from a 5-year, open-label treatment phase of a randomized clinical trial. Eur J Neurol. 2021 
May;28(5):1716-1725. doi: 10.1111/ene.14715. Epub 2021 Jan 20. PMID: 33400330; PMCID: 
PMC8248354. 

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de Leeuw, R, Editor, Orofacial Pain: Guidelines for Assessment, Diagnosis, and Management, 
The American Academy of Orofacial Pain, Sixth Edition, Hanover Park, IL: Quintessence 
Publishing Co, Inc., 2018, 1-25. 
Edvinsson L, The CGRP Pathway in Migraine as a Viable Target for Therapies. Headache 
2018;58:33-47. 
Goadsby PJ, Reuter U, Hallstrom Y, Broessner G, Bonner JH, Zhang F, Sapra S, Picard H, Mikol 
DD, Lenz RA. A controlled trial of erenumab for episodic migraine. N Engl J Med. 
2017;377(22):2123–2132. 
Hargreaves R, Olesen J. Calcitonin Gene-Related Peptide Modulators - The History and 
Renaissance 
of 
a 
New 
Migraine 
Drug 
Class. 
Headache 
2019;59(6):951-970. 
doi: 
10.1111/head.13510. 
https://www.nidcr.nih.gov/research/data-statistics/facial-pain, July 2018. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761077s007lbl.pdf 
Headache Classification Committee of the International Headache Society (IHS), The 
International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38(1): 1-211. 
doi: 10.1177/0333102417738202. PMID: 29368949. 
Julious SA. Sample size of 12 per group rule of thumb for a pilot study. Pharmaceutical statistics. 
2005;4:287-291. 
Kean J, Monahan PO, Kroenke K, Wu J, Yu Z, Stump TE, Krebs EE. Comparative 
Responsiveness of the PROMIS Pain Interference Short Forms, Brief Pain Inventory, PEG, and 
SF-36 Bodily Pain Subscale. Med Care. 2016 Apr;54(4):414-21.  
doi: 10.1097/MLR.0000000000000497. 
Krebs EE, Lorenz KA, Bair MJ, Damush TM, Wu J, Sutherland JM, Asch S, Kroenke K. (2009). 
Development and Initial Validation of the PEG, a Three-item Scale Assessing Pain Intensity and 
Interference. 
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Internal 
Medicine, 
24(6), 
733–738. 
http://doi.org/10.1007/s11606-009-0981-1 
Kroenke K, Evans E, Weitlauf S, McCalley S, Porter B, Williams T, Baye F, Lourens SG, Matthias 
MS, Bair MJ. Comprehensive vs. Assisted Management of Mood & Pain Symptoms (CAMMPS) 
trial: study design and sample characteristics. Contemporary Clin Trials 2018;64:179-187. 
Kroenke K, Krebs EE, Turk D, Von Korff M, Bair MJ, Allen KD, Sandbrink F, Cheville AL, DeBar 
L, Lorenz KA, Kerns RD. Core outcome measures for chronic musculoskeletal pain research: 
recommendations from a Veterans Health Administration work group. Pain Med 2019;20(8):1500-
1508. 
Kroenke K, Spitzer RL, Williams JBW, Löwe B. An ultra-brief screening scale for anxiety and 
depression: the PHQ-4 Psychosomatics 2009;50:613-621. 
Maixner W, Fillingim RB, Williams DA, Smith SB, Slade GD. Overlapping Chronic Pain 
Conditions: Implications for Diagnosis and Classification. J Pain. 2016 Sep;17(9 Suppl):T93-
T107. doi: 10.1016/j.jpain.2016.06.002. 
Noseda R, Burstein R. Migraine pathophysiology: Anatomy of the trigeminovascular pathway and 
associated neurological symptoms, CSD, sensitization and modulation of pain. Pain. 
2013;154(Suppl. 1):S44-S53. 
Ohrbach, R, editor. Diagnostic Criteria for Temporomandibular Disorders Assessment 
Instruments. Version 15May2016. www.rdc-tmdinternational.org Accessed on 23Sep2019 

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Ohrbach R, Granger C, List T, Dworkin S. Preliminary development and validation of the Jaw 
Functional Limitation Scale. Community Dent Oral Epidemiol. 2008 Jun;36(3):228-36. doi: 
10.1111/j.1600-0528.2007.00397.x. 
Popko L. Some notes on papyrus ebers, ancient egyptian treatments of migraine, and a crocodile 
on the patient’s head. Bull Hist Med. 2018;92(2):352-366 
Schiffman E, Ohrbach R, Truelove E, Look J, Anderson G, Goulet JP, List T, Svensson P, 
Gonzalez Y, Lobbezoo F, Michelotti A, Brooks SL, Ceusters W, Drangsholt M, Ettlin D, Gaul C, 
Goldberg LJ, Haythornthwaite JA, Hollender L, Jensen R, John MT, De Laat A, de Leeuw R, 
Maixner W, van der Meulen M, Murray GM, Nixdorf DR, Palla S, Petersson A, Pionchon P, Smith 
B, Visscher CM, Zakrzewska J, Dworkin SF; International RDC/TMD Consortium Network, 
International association for Dental Research; Orofacial Pain Special Interest Group, International 
Association for the Study of Pain. Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) 
for Clinical and Research Applications: recommendations of the International RDC/TMD 
Consortium Network* and Orofacial Pain Special Interest Group. J Oral Facial Pain Headache. 
2014 Winter;28(1):6-27. doi: 10.11607/jop.1151. 
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2015;55;S1:72-83. 
Tepper SJ. History and Review of anti-Calcitonin Gene-Related Peptide (CGRP) Therapies: From 
Translational Research to Treatment. Headache 2018;58:238-275. doi: 10.1111/head.13379. 
Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of 
chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 
2017;16(6):425–434. 
Toussaint A, Kroenke K, Baye F, Lourens S. Comparing the Patient Health Questionnaire - 15 
and the Somatic Symptom Scale - 8 as measures of somatic symptom burden. J Psychosom Res. 
2017 Oct;101:44-50. doi: 10.1016/j.jpsychores.2017.08.002. 
Yuan H, Spare NM, Silberstein SD. Targeting CGRP for the Prevention of Migraine and Cluster 
Headache: A Narrative Review. Headache. 2019 Jul;59 Suppl 2:20-32. doi: 10.1111/head.13583. 
 
 

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Page 15 of 27 
 
10. 
Appendices 
 
Appendix A – TMD Symptoms 
 
Symptoms of TMD: 
Jaw pain 
Headache 
Earache 
Joint noise 
Limited range of motion 
Neck pain 
Toothache 
Shoulder pain 
Dizziness 
Changing bite 
Ringing in the ear 
Nausea 
TemporoMandibular Joint pain 
Locked shut 
Locked open 
Light sensitivity 
Sound sensitivity 
Hyper-sensitive facial skin 
Hyper-sensitive oral mucosa 
Sinus pain 
Arm pain 
Chest pain 
 
 
(TMD symptoms mask, mimic and distort other diagnoses.) 
 
 
 
 
 
 
 

Version Date: Amend 8- January 12, 2023 
 
Page 16 of 27 
 
Appendix B – TMD Treatments 
 
Multiple types of Orthotic appliances 
 Hard acrylic 
 Soft vinyl 
 Accentuated posterior stop 
 Accentuated anterior stop 
 Boil and Bite 
  
Multiple types of Occlusal rehabilitation 
 Full mouth reconstruction 
 Occlusal adjustment(s) 
 Orthodontics 
 
Multiple types of medicinal regimen 
 Muscle relaxants 
 Over-the-counter NSAIDS 
 Amitriptyline 
 Sumatriptan 
 
Multiple types of injections 
 TM joint injections – intracapsular diagnostic/therapeutic injections 
 Injections of anesthetic agents into the trigeminal nerve 
 Trigger point injections 
 Botulinum toxin (type A or Type B) injections 
 
Multiple types of surgical treatments 
 Alloplastic joint implants 
 Arthrocentesis 
 Arthroscopic surgery 
 Arthrotomy or arthroplasty 
 Condylectomy (partial or complete) 
 Disc repair procedures 
 Diskectomy without or with replacement 
 Eminectomy or eminoplasty (articular surface recontouring) 
 Mandibular condylotomy 
 Nerve obliteration 
 Orthognathic surgery – for correction of jaw deformities could also be done as an adjunct to 
   definitive joint treatment when related to deformities resulting in TMJ dysfunction. 
 Partial or total joint reconstruction 
 Removal of failed implants  
 
Multiple types of Behavior Modification 
 ABA 
 Cognitive behavior therapy 
 Educational behavior therapy 
 Positive Mental Attitude 
 
Other Miscellaneous Treatments 
 Acupuncture 

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Page 17 of 27 
 
 Acupressure 
 Allergy Treatments 
 Biofeedback 
 Chiropractic treatments  
 Continuous Passive Motion (CPM) therapy 
 Dry needling 
 Low level laser 
 Massage Therapies 
 Nutrition 
 Physical Therapy Treatments  
 Pulsed radiofrequency energy – Energex 
 Tru-Denta combination of therapies 
 Ultrasonic therapy with(out) medicines 
 
Alternative Therapies 
 Crystals 
 Magnets 
 Power bands 
 Pressure point bands 
 Tragus piercing 
 
(Multiple non-predictable treatments suggest no predictable treatment for TMD has been found.) 
 
 
 

Version Date: Amend 8- January 12, 2023 
 
Page 18 of 27 
 
Appendix C – Diagnostic Criteria for Temporomandibular Disorders Symptom 
Questionnaire 
 
 

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Page 19 of 27 
 
 
 

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Page 20 of 27 
 
Appendix D – Brief Pain Inventory (BPI) 
 
BRIEF PAIN INVENTORY (BPI) 
 
For the following questions, please answer for your facial, jaw or TMD pain:  
 
1. Please rate your pain by circling the one number that best describes your pain at its worst 
in the last week. 
  
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
No 
Pain as bad as  
 
Pain 
you can imagine 
 
 
2. Please rate your pain by circling the one number that best describes your pain at its least 
in the last week. 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
No 
Pain as bad as  
 
Pain 
you can imagine 
 
 
3. Please rate your pain by circling the one number that best describes your pain on the 
average. 
 
    
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
No 
Pain as bad as  
 
Pain 
you can imagine 
 
 
4. Please rate your pain by circling the one number that tells how much pain you have right 
now. 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
No 
Pain as bad as  
 
Pain 
you can imagine 
 
 
 
Circle the number that describes how, during the past week, pain has interfered with your: 
 
5. General Activity 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 Does Not 
Completely  
 Interfere 
Interferes 

Version Date: Amend 8- January 12, 2023 
 
Page 21 of 27 
 
6. Mood 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 Does Not 
Completely  
 Interfere 
Interferes 
 
 
7. Walking Ability 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 Does Not 
Completely  
 Interfere 
Interferes 
 
 
8. Normal Work (includes both work outside the and housework) 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 Does Not 
Completely  
 Interfere 
Interferes 
 
 
9. Relations with other People 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 Does Not 
Completely  
 Interfere 
Interferes 
 
 
10. Sleep 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 Does Not 
Completely  
 Interfere 
Interferes 
 
 
11. Enjoyment of Life 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 Does Not 
Completely  
 Interfere 
Interferes 
 
 
 

Version Date: Amend 8- January 12, 2023 
 
Page 22 of 27 
 
Appendix E – PEG (Pain, Enjoyment, General Activity) Scale and Pain Medication 
Assessment 
 
 
PEG Pain 
For the following questions, please answer for your facial, jaw or TMD pain: 
1. What number best describes your pain on the average in the last 24 hours?  
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
No 
Pain as bad as  
 
Pain 
you can imagine 
  
 
 
2. What number best describes how, in the last 24 hours, pain has interfered with your 
general activity 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
  
Does Not 
Completely  
 Interfere 
Interferes 
 
 
 
3. What number best describes how, in the last 24 hours, pain has interfered with your 
enjoyment of life 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
  
Does Not 
Completely  
 Interfere 
Interferes 
 
 
 
Pain Medication Assessment Questions 
 
A. 
 Did you take any medicines for pain today? 
• Yes 
• No 
 
B. 
If YES, were any of these medicines you took today for facial, jaw or TMD pain? 
• Yes 
• 
No  
 

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Page 23 of 27 
 
Appendix F – Patient Global Impression of Change (PGIC) 
 
 
Patient Global Impression of Change (PGIC)  
 
Since the start of the study (treatment), my overall facial, jaw or TMD pain is …. 
 
1. Much better 
2. Moderately better 
3. A little better 
4. No change 
5. A little worse 
6. Moderately worse 
7. Much worse 
 
 

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Page 24 of 27 
 
Appendix G – Jaw Function Limitation Scale (JFLS-8) 
 
 
Jaw Functional Limitation Scale - 8 
 
For each of the items below, please indicate the level of limitation during the last month. If the 
activity has been completely avoided because it is too difficult, then circle '10'. If you avoid an 
activity for reasons other than pain or difficulty, leave the item blank. 
 
 
     No   
 
 
                              Severe 
     Limitation  
 
 
                  Limitation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright Ohrbach R. Available at http://www.rdc-tmdinternational.org 
Version 12May2013. No permission required to reproduce, translate, display, or distribute. 
1. Chew tough food 
0 
1 
2 
3 
4 
5   6 
7 
8 
9 
10 
2. Chew chicken (e.g., prepared in oven) 
0 
1 
2 
3 
4 
5  6 
7 
8 
9 
10 
3. Eat soft food requiring no chewing  
(e.g., mashed potatoes, apple sauce,  
pudding, pureed food) 
0 
1 
2 
3 
4 
5 
 6 
7 
8 
9 
10 
4. Open wide enough to drink from a cup 
0 
1 
2 
3 
4 
5  6 
7 
8 
9 
10 
5. Swallow 
0 
1 
2 
3 
4 
5  6 
7 
8 
9 
10 
6. Yawn 
0 
1 
2 
3 
4 
5  6 
7 
8 
9 
10 
7. Talk 
0 
1 
2 
3 
4 
5  6 
7 
8 
9 
10 
8. Smile 
0 
1 
2 
3 
4 
5  6 
7 
8 
9 
10 

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Page 25 of 27 
 
Appendix H – Depressive and anxiety symptoms (PHQ-4) 
 
 
 
PHQ-4: Depression (PHQ-2) and Anxiety (GAD-2) 
 
 
Over the last 2 weeks, how often have you been 
bothered by any of the following problems? 
Use a check () to indicate your answer for each item 
Not at 
all 
 
Several 
days 
 
More than 
half the 
days 
Nearly 
every 
 day 
(0) 
(1) 
(2) 
(3) 
1. 
Feeling nervous anxiety or on edge  
 
 
 
 
2. 
Not being able to stop or control worrying 
 
 
 
 
3.      Little interest or pleasure in doing things 
 
 
 
 
4.     Feeling down, depressed, or hopeless 
 
 
 
 
 
 
 
 
 

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Page 26 of 27 
 
Appendix I – Somatic symptom severity as measured by the SSS-8 
 
 
 
Somatic Symptom Scale (SSS-8) 
 
 
During the past 7 days, how much have you been bothered by any of the 
following problems? 
 
 
Not  
at all 
A little 
bit 
Some 
what 
Quite a 
bit 
Very 
much 
1. Stomach or bowel problems 
 0 
 1 
 2 
 3 
 4 
2. Back pain 
 0 
 1 
 2 
 3 
 4 
3. Pain in your arms, legs, or joints 
 0 
 1 
 2 
 3 
 4 
4. Headaches 
 0 
 1 
 2 
 3 
 4 
5. Chest pain or shortness of breath 
 0 
 1 
 2 
 3 
 4 
6. Dizziness 
 0 
 1 
 2 
 3 
 4 
7. Feeling tired or having low energy 
 0 
 1 
 2 
 3 
 4 
8. Trouble sleeping 
 0 
 1 
 2 
 3 
 4 
 
 
 
 

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Page 27 of 27 
 
11. 
Table 1 
 
ISS – Timeframes for Submission of Safety Data to Amgen 
 
For Interventional studies with Amgen IMPa: 
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 
a Specific requirements are to be outlined in the Research Agreement. 
 
For all study types – aggregate reportsa(as applicable): 
Safety Data 
Timeframe for submission to Amgen 
Send to 
Listing for Safety data 
reconciliationb 
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 
a Specific requirements are to be outlined in the Research Agreement. 
b Listing for reconciliation should include all ICSRs submitted to Amgen Safety per contract (i.e. 
for studies in Table 1 listing should include ADRs, SADRs, Other Safety Findings, USADEs, 
SADEs and non-serious ADEs ; for studies in Table 2 listing should contain SUSARs, 
pregnancy and lactation exposure (and any associated reports/outcomes), USADEs, SADEs 
and non-serious ADEs; studies in table 3 do not require reconciliation).