Erenumab as a Therapeutic Approach for the Management of Trigeminal Neuropathic Pain (TNP)
Phase: PHASE2
Conditions: Trigeminal Neuropathy
Sponsor: University of Maryland, Baltimore

Erenumab as a therapeutic approach for the management 
of Trigeminal Neuropathic Pain (TNP) 
Protocol Number: HP-00097072 (UMB) 
Grant Number: Amgen ISS 20207273 
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 TNP 
 
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Erenumab as a therapeutic approach for the 
management of Trigeminal Neuropathic Pain 
(TNP) 
Protocol Number: HP-00097072 (UMB) 
Grant Number: Amgen ISS 20207273 
Principal Investigator: Marcela Romero Reyes DDS, PhD 
IND/IDE Sponsor: IND EXEMPT 
Draft or Version Number:  <1.2> 
March, 30th, 2022  
 

 
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STATEMENT OF COMPLIANCE 
{Begin required text}   
The study will be conducted in accordance with the International Conference on 
Harmonization 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. 
{End required text} 

 
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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: 04/24/2022 
 
Name: Marcela Romero Reyes DDS,PhD 
 
Title: Clinical Associate Professor, Director, Brotman Facial Pain Clinic 
 

 
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TABLE OF CONTENTS 
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 ....... 15 
2.1 
Background Information ........................................................................................ 15 
2.2 
Rationale .............................................................................................................. 16 
2.3 
Potential Risks and Benefits ................................................................................. 17 
2.3.1 
Potential Risks .......................................................................................... 17 
2.3.2 
Potential Benefits ...................................................................................... 19 
3 
OBJECTIVES ................................................................................................................... 20 
3.1 
Study Objectives ................................................................................................... 20 
3.2 
Study Outcome Measures .................................................................................... 20 
3.2.1 
Primary ...................................................................................................... 20 
3.2.2 
Secondary ................................................................................................. 21 
4 
STUDY DESIGN .............................................................................................................. 23 
5 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................. 25 
5.1 
Subject Inclusion Criteria ...................................................................................... 25 
5.2 
Subject Exclusion Criteria ..................................................................................... 27 
5.3 
Strategies for Recruitment and Retention ............................................................. 28 
5.4 
Treatment Assignment Procedures ....................................................................... 29 
5.4.1 
Randomization Procedures (if applicable) ................................................. 29 
5.4.2 
Masking Procedures (if applicable) ............................................................ 30 
5.5 
Subject Withdrawal ............................................................................................... 30 
5.5.1 
Reasons for Withdrawal ............................................................................ 30 
5.5.2 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention ............................................................................................... 31 
5.6 
Premature Termination or Suspension of Study .................................................... 31 
6 
STUDY INTERVENTION .................................................................................................. 33 
6.1 
Study Product Description .................................................................................... 33 
6.1.1 
Acquisition ................................................................................................. 33 
6.1.2 
Formulation, Packaging, and Labeling....................................................... 33 
6.1.3 
Product Storage and Stability .................................................................... 34 
6.2 
Dosage, Preparation and Administration of Study Product .................................... 34 
6.3 
Modification of Study Product Administration for a Subject ................................... 35 
6.4 
Accountability Procedures for the Study Product .................................................. 36 
6.5 
Assessment of Subject Compliance with Study Product Administration ................ 36 

 
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6.6 
Concomitant Medications/Treatments ................................................................... 36 
7 
STUDY SCHEDULE ......................................................................................................... 39 
7.1 
Pre-Screening ....................................................................................................... 39 
7.2 
Screening and Baseline Visit (Visit 0, 4 weeks period) .......................................... 39 
7.3 
Treatment Visits .................................................................................................... 40 
7.4 
Follow up and final Study Visit, Visit 5 (Day 112, 4 weeks after Visit 4 ) ................ 43 
7.5 
Withdrawal Visit .................................................................................................... 44 
7.6 
Unscheduled Visit ................................................................................................. 44 
8 
STUDY PROCEDURES /EVALUATIONS ........................................................................ 45 
8.1 
Study Procedures/Evaluations .............................................................................. 45 
8.2 
Laboratory Procedures/Evaluations ...................................................................... 47 
8.2.1 
Clinical Laboratory Evaluations ................................................................. 47 
8.2.2 
Special Assays or Procedures ................................................................... 47 
8.2.3 
Specimen Preparation, Handling, and Storage .......................................... 48 
8.2.4 
Specimen Shipment .................................................................................. 48 
9 
ASSESSMENT OF SAFETY ............................................................................................ 49 
9.1 
Specification of Safety Parameters ....................................................................... 49 
9.1.1 
Unanticipated Problems ............................................................................ 49 
9.1.2 
Adverse Events ......................................................................................... 50 
9.1.3 
Serious Adverse Events ............................................................................ 50 
9.2 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 50 
9.3 
Characteristics of an Adverse Event ..................................................................... 51 
9.3.1 
Relationship to Study Intervention ............................................................. 51 
9.3.2 
Expectedness of SAEs .............................................................................. 51 
9.3.3 
Severity of Event ....................................................................................... 52 
9.4 
Reporting Procedures ........................................................................................... 53 
9.4.1 
Unanticipated Problem Reporting to IRB and AMGEN .............................. 53 
9.4.2 
Serious Adverse Event Reporting to AMGEN Safety and UMB IRB .......... 54 
9.4.3 
Reporting of SAEs and AEs to FDA .......................................................... 58 
9.4.4 
Events of Special Interest (if applicable) .................................................... 58 
9.4.5 
Reporting of Pregnancy ............................................................................. 58 
9.5 
Halting Rules ........................................................................................................ 58 
10 
STUDY OVERSIGHT ....................................................................................................... 59 
11 
CLINICAL SITE MONITORING ........................................................................................ 60 
12 
STATISTICAL CONSIDERATIONS .................................................................................. 61 
12.1 
Study Hypotheses ................................................................................................. 61 
12.2 
Sample Size Considerations ................................................................................. 61 
12.3 
Planned Interim Analyses (if applicable) .................. Error! Bookmark not defined. 
12.3.1 Safety Review .............................................. Error! Bookmark not defined. 
12.3.2 Efficacy Review ............................................ Error! Bookmark not defined. 
12.4 
Final Analysis Plan ............................................................................................... 62 
13 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .................. 64 

 
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QUALITY CONTROL AND QUALITY ASSURANCE ........................................................ 65 
15 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................. 66 
15.1 
Ethical Standard ................................................................................................... 66 
15.2 
Institutional Review Board .................................................................................... 66 
15.3 
Informed Consent Process ................................................................................... 66 
15.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 67 
15.5 
Subject Confidentiality .......................................................................................... 67 
15.6 
Future Use of Stored Specimens and Other Identifiable Data ............................... 67 
16 
DATA HANDLING AND RECORD KEEPING ................................................................... 68 
16.1 
Data Management Responsibilities ....................................................................... 68 
16.2 
Data Capture Methods .......................................................................................... 68 
16.3 
Types of Data ....................................................................................................... 68 
16.4 
Schedule and Content of Reports ......................................................................... 69 
16.5 
Study Records Retention ...................................................................................... 69 
16.6 
Protocol Deviations ............................................................................................... 69 
17 
PUBLICATION/DATA SHARING POLICY ........................................................................ 70 
18 
LITERATURE REFERENCES .......................................................................................... 72 
SUPPLEMENTAL MATERIALS ................................................................................................ 76 
APPENDICES ........................................................................................................................... 77 
APPENDIX A: SCHEDULE OF EVENTS .................................................................................. 78 
 

 
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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) 
CBT 
Cognitive Behavioral Therapy 
CFR 
Code of Federal Regulations 
CGRP 
Calcitonin Gene Related Peptide 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSOC 
Clinical Study Oversight Committee 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DMFS 
Decayed, missing, and filled tooth surfaces 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EEG 
Electroencephalogram 
FDA 
Food and Drug Administration 
FFR 
Federal Financial Report 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
GCPS 
Graded Chronic Pain Scale 
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 
IDE 
Investigational Device Exemption 
IL-1β 
Interleukin 1 Beta 

 
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IL-4 
Interleukin 4 
IL-6 
Interleukin 6 
IL-10 
Interleukin 10 
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 
NIDCR 
National Institute of Dental and Craniofacial Research, NIH, DHHS 
NIH 
National Institutes of Health 
OCTOM 
Office of Clinical Trials Operations and Management, NIDCR, NIH 
OHRP 
Office for Human Research Protections 
PAF 
Peak Alpha Frequency 
PGIC 
Patient Global Impact of Change 
PHI 
Protected Health Information 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
QST 
Quantitative Sensory Testing 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
TNF-α 
Tumor Necrosis Factor alpha 
TNP 
Trigeminal Neuropathic Pain 
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 
Trigeminal Neuropathic Pain (TNP) 
Précis: 
A total of 40 patients (20 each arm) aged 18-65 years old of 
either sex, and any race or ethnicity, presenting trigeminal 
neuropathic pain 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, at the Oral and Maxillofacial Surgery Clinic  both at 
the University of Maryland, School of Dentistry, at the Pain 
Medicine Clinic at the University of Maryland, School of 
Medicine 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 compliance with 80 % completion of the 
DSD  and who meet the pain score (inclusion criteria) for 4 
weeks/28 days during the baseline period from Visit 0, 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 140 mg, 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 average monthly (28 days) pain score 
(>=30% reduction) from baseline to Visit 4 (the last monthly pain 
cycle), compared to placebo. Each monthly pain score 
represents the mean of daily pain intensity score values (0-10) 
derived from Daily Symptom Diaries within the month between 
visits. 
Secondary end points will be comparison with placebo of 
reduction of pain score from baseline to the end of 12 weeks, 
and between specific visits compared to the baseline, and 

 
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participant ratings of other pain related outcomes, impact of 
quality of life and emotional functioning. 
Exploratory end points are change of pro-inflammatory and 
anti-inflammatory cytokine profiles (Th1/Th2); change in 
nociceptive processing (thermal thresholds, pressure pain 
thresholds, allodynia), an EEG biomarker of pain sensitivity 
called peak alpha frequency (PAF). 
 
Objectives: 
 
Primary: To investigate the efficacy of Erenumab compared to 
placebo on the proportion of subjects who achieved at least 30% 
reduction in monthly average daily pain score from baseline to 
the end of treatment period. 
Secondary:  To investigate the efficacy of Erenumab compared 
to placebo on the reduction in monthly average daily pain score 
from baseline to the end of treatment period. 
To investigate the efficacy of Erenumab compared to placebo 
on the proportion of subjects who achieved a least 30% 
reduction in monthly average daily pain score from baseline to 
Visit 5 (follow-up/final visit).  
To determine the efficacy of Erenumab using functional 
measures related to TNP impact in daily activities, disability and 
emotional functioning measured by questionnaires (GCPAs, 
HADS, PGIC and PENN Facial Pain Scale).  
Exploratory: To explore changes in pro-inflammatory and anti-
inflammatory cytokines from plasma/serum induced by 
Erenumab. 
 
To determine the influence of Erenumab in nociceptive 
processing and sensitization using QST. 
To determine the influence of Erenumab in EEG-based peak 
alpha frequency. 
 
 
Population: 
40 adults of either sex and any ethnicity between the ages of 18 
and 65 years meeting the diagnostic criteria for Trigeminal 
neuropathic 
pain 
(idiopathic 
trigeminal 
neuralgia 
with 
concomitant continuous pain, painful post-traumatic trigeminal 
neuropathy or idiopathic painful trigeminal neuropathy), 
according to the diagnosis criteria based on the International 
classification of headache disorders ICHD-3 and International 

 
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classification 
of 
Orofacial 
Pains 
ICOP) 
and 
with 
no 
contraindications for the use of Erenumab, will be enrolled from 
the Brotman Facial Pain Clinic, the Oral and Maxillofacial 
Surgery clinic from the University of Maryland, School of 
Dentistry and the Pain Clinic at the Department of 
Anesthesiology, School of Medicine.  
Phase: 
II 
Number of Sites: 
University of Maryland, School of Dentistry  
Description of  
Intervention: 
Study drug is Erenumab 140 mg or an inert placebo will be 
administered by subcutaneous injection once a month (3 
cycles) over a 12-week period. 
Study Duration: 
30 months 
Subject 
Participation 
Duration: 
21 weeks 
Estimated Time to 
Complete 
Enrollment: 
Approximately 24 months. 

 
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Schematic of Study Design: 

 
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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: 410-706-0865 
Email: mromero@umaryland.edu 
  
Medical Monitor: 
DSMB  
 
 
Clinical Site 
Investigators: 
David A. Seminowicz, PhD 
Associate Professor  
Department of Neural and Pain Sciences 
University of Maryland, Baltimore 
School of Dentistry 
650 W. Baltimore St, Room 8263 
Baltimore, MD 21201 
Phone: 410-706-3476 
Email:  dseminowicz@umaryland.edu 
  
Institutions: 
University of Maryland, School of Dentistry  
 

 
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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 
Email: jlphillips@umaryland.edu  
 
Gary Warburton MD, DDS  
Associate Professor in Oral and Maxillofacial Surgery 
Department of Oral and Maxillofacial Surgery 
University of Maryland, Baltimore 
School of Dentistry  
650 W. Baltimore St, Room 1201 
Baltimore, MD 21201 
Phone: 410 706 7060 
Email: gwarburton@umaryland.edu  
 
Thelma Wright MD, JD 
Assistant Professor, Director Pain Medicine Fellowship Program 
Department of Anesthesiology 
University of Maryland, Baltimore 
School of Medicine 
110 S Paca St #300 
Baltimore, MD 21201 
Phone: (410) 328-6720 
Email: twright@som.umaryland.edu 

 
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2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
2.1 
Background Information 
Pain is a major global health problem and it is unfortunate that the burden of chronic 
orofacial pain conditions still underestimated [1]. Some of the most prevalent and 
debilitating pain conditions arise from the structures innervated by the trigeminal system 
(head, face, intraoral structures, masticatory musculature, temporomandibular joint and 
associated structures).  
Chronic pain in the orofacial region can arise from different regions and etiologies. Pain 
attributed to a disorder of the trigeminal nerve such as trigeminal neuropathic pain 
conditions can cause severe psychosocial burden [2-4]. These conditions can arise 
idiopathically such as in some cases of trigeminal neuralgia but also from injury secondary 
to dental procedures, infection, neoplasia, disease or dysfunction of the peripheral and/or 
central nervous system [5-8]. For trigeminal neuropathic pain (TNP), pharmacological 
therapy is the first line of treatment with medication categories including anticonvulsants 
and antidepressants [9]. However, their effectiveness varies from patient to patient and 
undesired side effects can be present causing withdrawal from treatment or a decrease in 
dosage to an unsatisfactory level in many patients.  
Unfortunately, it is estimated that an effective drug for chronic pain is one that provides only 
partial relief for one out of five patients, while the remaining four patients experience no 
relief from pain [10, 11]. Data for TNP management is based on the evidence associated 
with neuropathic pain management in other parts of the body and of different etiologies [12, 
13] and currently we do not have any pharmacological approach exclusively for the 
management of trigeminal neuropathic pains based on evidence and approved by the FDA. 
Therefore, novel safer and targeted-directed therapies 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 [14]. Targeting the CGRP pathway has proven to be effective and safe 
for migraine therapeutics. Erenumab is the first antibody therapeutic targeting the CGRP 
receptor and is the first in its class to be FDA approved for the management of chronic 
migraine [15] and also approved for the prevention of episodic migraine, demonstrating its 
efficacy in randomized controlled clinical trials; in addition, to also show promising for the 
management post-traumatic headache attributed to brain injury [16, 17]. 

 
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Moreover, CGRP has been shown to have a significant role in other types of pains in the 
trigeminal system. We and others have shown that CGRP is also involved in other orofacial 
pains such as in temporomandibular disorders (TMD) [18] and we demonstrated that 
blocking CGRP with a CGRP receptor antagonist in a pre-clinical model of TMD, significantly 
decreased nociception [19] as well as we demonstrated its role in the comorbidity between 
migraine and TMD [20]. 
In regards orofacial pain of neuropathic origin, preclinical studies have shown that CGRP 
plays a role in trigeminal afferent sensitization [21] and blocking the CGRP receptor results 
in antinociceptive effects in models of trigeminal neuropathic pain [22]. In addition, there 
are reports indicating elevated CGRP levels in blood, cerebrospinal fluid, and plasma in 
trigeminal neuralgia patients [23-25]. 
The management of trigeminal neuropathic pains by inhibiting CGRP with an FDA approved 
medication that has been proved safe for another indication such as migraine which shares 
CGRP as a potential target, would be very promising. Therefore, the purpose of this study 
is to evaluate the efficacy of Erenumab for the management of trigeminal neuropathic pain. 
We have hypothesized that Erenumab - a monoclonal antibody that inhibits CGRP-receptor 
decreases pain symptomatology in patients suffering of trigeminal neuropathic pain.  
The study will be a randomized, double blind, placebo-controlled pilot trial comparing 
Erenumab vs Placebo. Participants will be evaluated for trigeminal neuropathic pain and 
have other related assessments. Blood samples will be collected, and participants will need 
to answer some questionnaires. We are going to assess changes in pain intensity and other 
pain outcomes related to trigeminal neuropathic pain. 
The ultimate goal of this pilot study is to provide the foundation for the treatment of 
trigeminal neuropathic pain based upon CGRP targeted approaches. 
2.2 
Rationale 
TNP are a considerable burden and affects significantly the quality of life of the sufferer 
[4]. There are medications for their management but while they may work for some 
patients, may not work for the others; in addition, side effects may be present for some 
patients with the need to decrease dosage to not optimal levels. Furthermore, the 
indications of these drugs are for other neuropathic pain disorders and currently there is 
no medication specifically indicated for the management of TNP based on its molecular 
pathophysiology.  
The calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in migraine 
pathophysiology [14].There is evidence showing that CGRP has a role in other disorders 
mediated by the trigeminal system in addition to migraine; CGRP has shown to have a 
role in orofacial pain such as in TMD [18-20] and in trigeminal neuropathic pain [21-25]. 

 
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Erenumab is the first antibody therapeutic targeting the CGRP receptor with FDA 
approval for migraine prevention [15] that is well tolerated and with a good safety profile 
[26-28]. Therefore, the scientific premise for this study is that inhibiting the CGRP pathway 
in trigeminal neuropathic pain will decrease pain and pain related outcomes in a safe and 
well tolerated manner for this patient population. 
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.  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). 
 High blood pressure: High blood pressure or worsening of high blood pressure. 
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 

 
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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). 
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. 
Quantitative Sensory Testing (QST): A QST examination will assess sensory impairment 
by applying different stimuli in different body parts,  and extraorally such as pressure or 
heat to the skin. 
Extraoral sensory testing: The quantitative sensory testing (QST) will include stroking 
and/or applying gentle pressure with a brush, in the face.  The examination will also 
include applying pressure with a probe on fingers, head and shoulders, and applying a 
heat sensor on the forearm. The test will be performed  extraorally  ipsilateral and 
contralateral to the area of pain. The potential, risks  is a slight risk of tissue trauma or 
burning but this is avoided because the procedure is under the control of the examiner 
and the subject can stop it at any time. Study personnel will be trained and calibrated to 
perform these procedures. 
General sensory testing:  
Thermal (heat) stimulation: The potential risk involves burning of the skin (ventral forearm) 
This will be avoided with the thermal probe temperature not exceeding 50 degrees 
Celsius. The research staff will take the following precautions against potential burn risk: 
1 1) provisions for immediate stimulus removal by the subject, and 2) provisions for skin 
temperature and duration of thermal stimulus by the researcher to include a built-in  
minimum and maximum temperature limitation system in the thermal stimulator. 
Discomfort of the subject will be minimized by delivering stimuli that are below the 
subject's self-reported thermal pain tolerance level.  
Mechanical cutaneous sensitivity: The potential risk involves transient discomfort. This is 
performed with weighted probes (2mm diameter; 8–512 mN forces) applied to the dorsum 
of digits 2, 3, and 4 of the left hand. Participants will be instructed to signal (verbally or by 
raising the right hand) when the sensation first becomes painful at which time the 
researcher  will remove the probe. Because the probe is completely under the control of 
the examiner, there is little opportunity for bruising from this procedure. 
These assessments will be performed on 2 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. 

 
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EEG assessment. Peak alpha frequency (PAF): There is no potential risk or harm in the 
EEG assessment. PAF is based on a 5-minute, eyes-closed resting state EEG. The EEG 
device will be placed on the Scalp of the participants and EEG data will be collected using 
a CGX quick8r dry electrode system. Participants will be asked to make facial muscle 
contractions such as clenching their teeth, blinking, and saccades, while EEG is recorded. 
Participants may find uncomfortable the EEG device as well as the facial contractions, 
but these may only induce transitory discomfort. The facial contractions are necessary 
because will be used to aid in automated artefact removal. Participants will then be told 
to relax their muscles and resting state eyes closed EEG will be recorded for 5 minutes 
and used for PAF calculation.  
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. 
If Erenumab proves to be effective, this will be the first pharmacological approach 
specifically indicated for Trigeminal Neuropathic Pain (TNP) 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 TNP. 

 
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3 OBJECTIVES 
3.1 
Study Objectives 
Primary Objective 
To investigate the efficacy of Erenumab compared to placebo on the proportion of 
subjects who achieved at least 30% reduction in monthly average daily pain score from 
baseline to the end of treatment period. 
Secondary Objectives 
To investigate the efficacy of Erenumab compared to placebo on the reduction in monthly 
average daily pain score from baseline to the end of treatment period. 
To investigate the efficacy of Erenumab compared to placebo on the proportion of 
subjects who achieved a least 30% reduction in the monthly average daily pain score 
from baseline to Visit 5 (follow-up/final visit).  
To determine the efficacy of Erenumab using functional measures related to TNP impact 
in daily activities, disability and emotional functioning measured by questionnaires 
(GCPAs, HADS, PGIC and PENN Facial Pain Scale).  
 
Exploratory Objectives 
To explore changes in pro-inflammatory and anti-inflammatory cytokines from 
plasma/serum. 
To determine the influence of Erenumab in nociceptive processing and sensitization 
using QST. 
To determine the influence of Erenumab on PAF.  
 
3.2 
Study Outcome Measures 
3.2.1 
Primary 
The primary end point will be to achieve >=30% reduction (Yes/no) in monthly (28 days) 
average pain score from baseline to Visit 4 (the last monthly treatment cycle), compared 
to placebo. The daily pain intensity score will be measured on a 11-point (0-10) numeric 
rating scale (NPRS) and reported in the Daily Symptom Diary (DSD). The monthly mean 
pain intensity score will be determined from baseline (4 weeks/28 days), for each month 
during the 12 weeks of treatment. 

 
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The monthly mean pain intensity score will be calculated if a participant has at least 
80% compliance with the DSD. 
A relevant decrease in chronic pain showing a beneficial effect will be a reduction of 
>=30% from baseline in the average pain intensity score [29, 30]. 
3.2.2 
Secondary 
Efficacy will be investigated further using secondary outcomes: 
Secondary outcome measures will be a comparison with placebo of reduction of pain 
score from baseline continuously through to the end of 12 weeks (Visit 4).  
Assess the efficacy of Erenumab compared to placebo on the proportion of subjects 
who achieved a least 30% reduction in the monthly average daily pain score from 
baseline to Visit 5 (follow-up/final visit).  
A change in participant ratings compared to placebo from baseline of other pain related 
outcomes using functional measures related to TNP impact in daily activities, disability 
and emotional functioning measured by questionnaires (GCPAs, HADS, PGIC and 
PENN Facial Pain Scale), assessed over the length of the study.  
Functional measures related to TNP impact in daily activities, disability and emotional 
functioning:  
Penn Facial Pain Scale-Revised: Change/improvement in burden/disability of daily 
activities related to trigeminal neuropathic pain (e.g. chewing, eating, talking, touching) 
[31]. 
Graded Chronic Pain Scale (GCPS): Changes in pain intensity and pain related disability 
[32] 
Patient Global Impression of Change (PGIC): Assesses patient perspective of pain 
improvement [33]. 
Hospital Anxiety and Depression Scale: Change in  Anxiety and depression [34]. 
Exploratory Endpoint 
To investigate whether Erenumab decreases pro-inflammatory cytokine release and 
increase anti-inflammatory cytokine release (pro-inflammatory/anti-inflammatory panel 
profile: IL-6, TNF-α, IL1-β/IL-10, IL-4).  
To investigate whether eremumab induces changes in nociceptive processing and 
sensitization determined with QST measurements. In patients with persistent trigeminal 

 
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neuropathic pain altered pain modulation is present. We will investigate if erenumab 
influences sensitization [35-38].      
To investigate whether erenumab decreases pain sensitivity determined by PAF 
measurements during EEG assessment. In chronic pain patients, alpha rhythms are 
slower in frequency and elevated in power relative to matched, healthy controls [39, 40]. 
We have shown that PAF predicts future pain sensitivity in multiple experimental pain 
models [41-43]. We will examine whether erenumab can modulate PAF and therefore, 
influence pain sensitivity.  
 
 

 
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4 STUDY DESIGN 
This study is a single center, placebo-controlled, double blind, randomized, phase II pilot 
to evaluate the efficacy of Erenumab in the management of trigeminal neuropathic pain.  
40 patients (20 per each arm) aged 18-65 years old of either sex, and any race or ethnicity 
presenting trigeminal neuropathic pain (subjects with diagnosis based on the International 
classification of headache disorders ICHD-3 [44] and International classification of 
Orofacial Pains ICOP [8] of idiopathic trigeminal neuralgia with concomitant continuous 
pain, painful posttraumatic trigeminal neuropathy or idiopathic painful trigeminal 
neuropathy) 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 2.5 years, with an estimated duration of recruitment of 2 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, Pain 
Medicine Clinic at the University of Maryland, School of Medicine 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, disability, 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 end point will be a change in average monthly (28 days) pain score (>=30% 
reduction) from baseline to Visit 4 (the last monthly treatment cycle), compared to 
placebo. The daily pain intensity score will be measured on a 11-point (0-10) numeric 
rating scale (NPRS) and reported in the Daily Symptom Diary (DSD). The monthly mean 
pain intensity score will be determined from baseline (4 weeks/28 days), for each month 
during the 12 weeks of treatment. 

 
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5 STUDY ENROLLMENT AND WITHDRAWAL 
The study is planning to enroll a total of 40 subjects that will be randomly assigned to one 
of the two study groups. It is anticipated that a total of 200 subjects will be screened in 
order to meet recruitment goals. 
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, Pain 
Medicine Clinic at the University of Maryland, School of Medicine or by telephone. 
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. Trigeminal neuropathic pain symptoms for a minimum of 3 months prior to 
randomization visit, localized in any trigeminal distribution (intraoral or extraoral). 
4. Meets diagnostic criteria for Trigeminal neuropathic pain with diagnosis based on 
the International classification of headache disorders ICHD-3 [44] and International 
classification of Orofacial Pains ICOP [8].  
• Diagnosed with idiopathic trigeminal neuralgia with concomitant continuous pain 
per ICDH-3. 
 
• Diagnosed with Painful posttraumatic trigeminal neuropathy or idiopathic painful 
trigeminal neuropathy per ICOP. May include: 
o Subjects with a history of persistent pain of idiopathic origin or after dental 
extractions, mandibular fracture, surgical procedure, implant procedure and 
root canal therapy. 
5. Participants must have a minimum mean of average daily pain intensity score of 
4/10 in where 0= no pain and 10= maximum pain imaginable on a numerical rating 
scale (0-10), during the 4 weeks/28 days baseline period prior randomization. 

 
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6. 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.  
7. If taking prescription medication, opioid medication or OTC medications as needed 
or episodically for the management of pain agrees to discontinue its use prior to 
the Screening and Baseline Visit.  
8. 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. 
9. If subjects diagnosed with migraine, are allowed only if episodic.  
10. Agrees to not start any new prescription medication for the management of 
trigeminal neuropathic pain or other type of pain throughout the study. 
11. Agrees to not modify their prescription regimen for current trigeminal neuropathic 
pain or other types of pain throughout the study 
12. Agrees not to receive any injection therapy for the management of neuropathic 
pain or migraine (e.g. nerve blocks, SPG blocks, steroid injections, Botox) during 
the course of the study 
13. Agrees not to use any neuromodulatory device for the management of neuropathic 
pain or migraine during the course of the study 
14. Agrees not to undergo any surgical procedure for the management of 
neuropathic pain during the course of the study 
15. Agrees to not use CBT, biofeedback or acupuncture for the management of pain 
during the course of the study. 
16. 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)  
17. Willing and able to understand and comply with all study procedures and be 
available for the duration of the study. 

 
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5.2 
Subject Exclusion Criteria 
1. Participants with a history of congestive heart failure 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, uncontrolled high blood pressure, malignant 
disease, chronic constipation, any malabsorption disorders such as IBSc or any other 
severe acute or chronic medical or psychiatric condition (major depression, 
schizophrenia, dementia) or laboratory finding that may increase the risk associated with 
trial participation with Erenumab, that in the judgement of the investigators would interfere 
with study assessments and/or would make the participant inappropriate for entry into this 
trial. 
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. Participants with evidence or a history of drug or alcohol abuse within the past 12 
months or has been diagnosed with a substance abuse disorder. 
6. Participants with dental pain (determined pain of odontogenic/periodontal origin). 
7. Participants with significant neurological disorders. 
8. 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   
9. 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.  
10. Patients with hypersensitivity to Erenumab 
11. Participants with trigeminal neuropathic pain taken medications for the management 
of trigeminal neuropathic pain in where daily dosage has been modified within three 
weeks before baseline.  

 
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12. Neuroimaging showing the presence of neurovascular compression or AV 
malformation.13. Neuroimaging showing the presence of intracranial pathology (i.e. 
multiple sclerosis, tumor). 
14. Presence of extracranial pathology in the area of pain (tumor, lesion). 
15. Has been treated with another investigational drug or treatment within 30 days prior 
to the Screening and Baseline Visit  
16. Has commenced a new daily prescription medication for the management of pain 
within 30 days prior to the Screening and Baseline Visit 
17. Currently taking opioid medication whether episodically or daily, within 30 days prior 
to the Screening and Baseline Visit.  
18. Patients sensitive to Latex 
19. If planning to become pregnant, pregnant or breastfeeding. 
20. 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, the Clinic of Oral and Maxillofacial Surgery at the University of Maryland, 
School of Dentistry and from the Pain Clinic at the University of Maryland, School of 
Medicine, Department of Anesthesiology.  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 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). 

 
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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 study 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 CGRP pathway, which 
is FDA-approved for the prevention of migraine. 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 Baseline Phase period has finished (4 
weeks/28 days), 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= 20 participants 
2) Placebo: N=20 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.  
 
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.  

 
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5.4.2 
Masking 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 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.  
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, the Oral and Maxillofacial Surgery Clinic or the Pain Clinic at 
the medical school. 
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 

 
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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 orofacial pain 
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 
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 sponsor the PI, medical monitor, DSMB, or IRB. Written 

 
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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 of migraine. 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. 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 140 mg/mL. Each 1 mL 140 mg 
single-dose prefilled glass syringe contains 140 mg erenumab-aooe, acetate (2.0 mg), 
polysorbate 80 (0.10 mg), and sucrose (65 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 140 mg/mL 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, at pH 5.2. Storage requirements 
for the placebo are the same as for the active drug.   
6.1.2 
Formulation, Packaging, and Labeling 
Erenumab 140 mg, in 1 mL prefilled glass syringe will be used. The syringe is a prefilled 
glass syringe with a stainless-steel needle and delivers 1 mL of 140 mg/mL. Each 1 mL 
140 mg single-dose prefilled glass syringe contains 140 mg erenumab-aooe, acetate (2.0 
mg), polysorbate 80 (0.10 mg), and sucrose (65 mg) at pH 5.2. 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: 
• Name and address of the dispensing pharmacy 

 
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• Protocol number 
• Name of the drug labeled as “Erenumab or placebo” to protect the blinding 
• Strength of the drug or placebo (140 mg/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 stored in an allocated refrigerator specifically for 
its storage at the Brotman Facial Pain Clinic. 
6.2 
Dosage, Preparation and Administration of Study Product 
Erenumab 140 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 to sit at room temperature 
for at least 30 minutes protected from direct sunlight. 

 
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• Do not warm by using a heat source such as hot water or a microwave. 
• Do not shake the product. 
• 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.  After administration, the patient will wait 20 minutes in our 
clinic to make sure there is not any reaction. After the 20 minutes, study personnel 
will assess, schedule next visit and the patient will be free to leave. 
• 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 

 
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ulceration, oral mucosal blistering), alopecia and rash (eg, rash papular, exfoliative rash, 
rash erythematous, urticaria, blister) have been observed in post-marketing surveillance. 
Adverse reactions with the use of Erenumab have been hypersensitivity reactions, 
constipation with serious complications and hypertension. 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 if the participant decides against using Erenumab, he/she will be 
discontinued from the study (See 2.3.1 and 5.5.2).  
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 (nerve blocks, botox), will also be collected for all participants for the 30 days 
prior to the Screening and Baseline Visit. The concomitant medication/therapy information 
will also be updated at subsequent study visits (Visits 1-5). 
6.6.1 Allowable Pain Medication 
6.6.1.1 Prescription medications 
Participants who enter the study already on a daily regimen of a prescription medication 
for the management for trigeminal neuropathic pain or for other type of pain in other region 
of the body will be encouraged to continue that regimen throughout the study and it should 
not be modified. The usage of all prescription medications for pain during the study will 
be recorded and quantified at each visit. 

 
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Rescue medications will be defined as over-the-counter topical anesthetics and over-
the-counter analgesics and anti-inflammatories. In case a patient presents pain, the 
medications described below may be used. 
6.6.1.2 Over-the-counter medications 
Topical anesthetics can be used as a rescue strategy for pain exacerbations. Benzocaine 
20% to use intraorally (orabase) or lidocaine 4% (aspercreme with lidocaine) to use 
extraorally could be used.  Participants using these topical non-prescription anesthetics 
during the study, will be recorded and their use will be quantified at each visit; the usage 
will be classified as either episodic or daily. 
Episodic use of non-prescription analgesics and anti-inflammatories (acetaminophen, 
NSAIDs) 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 Not allowed medications 
Participants cannot take as rescue medication or start therapy with any oral anti-
epileptics, SSRIs, SSNRIs, MAOIs, tricyclics antidepressants, tizanidine, baclofen, 
prednisone during the study (Please see Appendix B). In addition, they cannot receive 
any nerve blocks, onabotulinum toxin A injections, or use prescription compound topicals 
(except the ones that can be used as rescue mentioned above) or drug infusions for the 
management of TNP.  
Participants who are currently taking pain medication for TNP and the rescue medication 
was not helpful and are in need of other strategy due to TNP, they will need to be 
withdrawn from the study to follow up with TNP management (this being dosage 
adjustment of the medication they are currently taking for the management of TNP or 
other). 
Participants who are not currently taking pain medication for TNP, and the rescue 
medication was not helpful and are in need of other strategy. They will need to be 
withdrawn from the study to follow up with TNP management. 
 
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During the course of the study, participants will not be restricted in the use of non-
pharmacological therapies, excluding Cognitive Behavioral Therapy (CBT) and 
acupuncture. If a participant starts these for the complementary 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.  
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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, Oral Surgery 
Clinic or Pain Medicine Clinic (School of Medicine). 
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 within 2 weeks from the date of the pre-screening 
interview. 
7.2 
Screening and Baseline Visit (Visit 0, 4 weeks period) 
This visit will happen with 2 weeks after pre-screening. Participants will start the baseline 
period that will consist of 4 weeks. 
• 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 
• Perform QST examination 
• Perform EEG 
• Collect blood for Cytokine release assay 

 
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• Perform urine pregnancy test (in women with childbearing potential) 
• Provide instruction to complete 4 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  
The participant to be eligible requires to present symptoms of trigeminal neuropathic pain 
for a minimum of 3 months (12 weeks). In addition, 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 intensity score of 4/10 in where 0= no pain and 10= 
maximum pain imaginable on a numerical rating scale (0-10), during the 4 weeks/28 days 
baseline period prior randomization as specified in the inclusion criteria.  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/dental history to determine eligibility based on inclusion/exclusion 
criteria. 
• Record concomitant medications and therapies 
• Take blood pressure and collect weight 
• Assess and record adverse events (AEs) 
• Perform urine pregnancy test (in women of childbearing potential) 
• Review 4 questionnaires from Visit 0 in eCRF or collect and review the paper forms 

 
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• Provide instruction to complete 4 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+/-3 days/ 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 
• Assess and record adverse events (AEs) 
• Perform urine pregnancy test (in women of childbearing potential) 
• Review 4 questionnaires from Visit 1 in eCRF or collect and review the paper forms 
• Provide instruction to complete 4 new outcome measure questionnaires in paper 
or electronically for review at Visit 3. 
• 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+/- 3 days after 4 weeks from Visit 2) 
• Review Daily Symptom Diaries in eCRF or collect and review it in paper forms 

 
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• Assess compliance with Daily Symptom Diaries 
• Review medical history  
• Record concomitant medications and therapies 
• Take blood pressure and collect weight 
• Assess and record adverse events (AEs) 
• Perform urine pregnancy test (in women of childbearing potential) 
• Review 4 questionnaires from Visit 2 in eCRF or collect and review the paper forms 
• Provide instruction to complete 4 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+/- 3 days,4 weeks after Visit 3 
) 
• 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 
• Assess and record adverse events (AEs) 
• Perform QST 

 
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• Perform EEG 
• Collect blood for Cytokine release assay 
• Perform urine pregnancy test (in women of childbearing potential) 
• Review 4 questionnaires from Visit 3 in eCRF or collect and review the paper forms 
• Provide instruction to complete 4 new outcome measure questionnaires in paper 
or electronically for review at Visit 5. 
• Provide instruction to complete Daily Symptom Diaries electronically or provide 
them in paper forms 
• Schedule next visit 
 
7.4 
Follow up and final Study Visit, Visit 5 (Day 112 +/- 3 days, 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 4 questionnaires from Visit 4 in eCRF or collect and review the paper forms 
• Review medical history  
• Record concomitant medications and therapies 
• Take blood pressure and collect weight 
• Assess and record adverse events (AEs) 
• Perform urine pregnancy test (in women of childbearing potential) 
• Provide final instructions to subject (in case of AE showing later)  
• Complete a disposition form 
 

 
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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 administered 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 and during the course of 
the study 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, IL-6) 
and anti-inflammatory (IL10, IL4) cytokines by Luminex assay.  
• Sensory Testing/QST 
QST is a psychophysical procedure in which a test stimuli is applied at a defined intensity 
to a participant. The participant will report his/her perceptions of the intensity and the 
quality of the stimulus. We will be performing an extraoral QST [35-38].   
General sensory testing: 

 
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Mechanical cutaneous pain sensitivity: Will be performed with weighted probes (2mm 
diameter; 8–512 mN forces) applied to the dorsum of digits 2, 3, and 4 of the left hand.  
Thermal (heat) stimulation: Contact heat stimuli will be applied to the ventral forearm 
using a thermal probe temperature not exceeding 50 degrees Celsius. 
Extraoral chair side QST: The cotton swab test will test sensitivity to non-painful 
mechanical stimulation (low-sensitivity). With the use of a cotton swab, the skin will be 
gently stroked 3-4 times with strokes of 1-2 cm in length in the area of V1, V2 and V3 and 
we will compare responses between the non-painful side to the painful side to detect 
normosensitivity, hyposensitivity, hypersensitivity and allodynia.  
The spatula test will test temperature sensitivity following the same procedure as in the 
other 2 tests and temperature will be applied for 2-3 seconds. It is performed with a 
spatula that will be cold not exceeding 5 degrees Celsius or heated in a water bath until 
is 40 degrees Celsius.  
• EEG Assessment  
EEG assessment will be performed in all participants. In chronic pain patients, alpha 
rhythms are slower in frequency and elevated in power relative to matched, healthy 
controls[39, 40]. Within the alpha band, the frequency at which maximum power is 
displayed, known as peak alpha frequency (PAF), varies considerably amongst 
individuals [45]. We have shown that PAF predicts future pain sensitivity in multiple 
experimental pain models [41-43]. We will examine whether erenumab can modulate PAF 
and therefore mediate clinical effects. PAF is based on a 5-minute, eyes-closed resting 
state EEG.  
• Daily Symptom Diary 
Participants will be asked to complete the Daily Symptom Diary at the end of each day 
starting at the baseline phase and through the entire study (visits 1-5). Participants should 
have at least 80% compliance with the DSD the entire month, the equivalent of 23 
completed days. 
 
The diary collects the participant’s pain intensity (reported on a 0-10 numeric rating scale) 
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.  

 
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• Penn Facial Pain Scale-Revised: Brief 12 item questionnaire ( the higher the score 
the more pain and disability) to assess burden and restrictions of daily activities in 
patients with trigeminal neuralgia (e.g. chewing, eating, talking, touching) and 
assess and monitor the impact of treatment interventions [31]. 
• Graded Chronic Pain Scale (GCPS). The GCPS includes 7 items and assesses 2 
dimensions of pain: pain intensity and pain-related disability [32]. 
 
• 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 [33, 46]. 
 
• Hospital Anxiety and Depression Scale. Evaluates anxiety and depression with a 
14-item instrument [34]. 
 
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 1 and 4 by staff trained in phlebotomy. 
Blood samples will be evaluated then for the presence of pro-inflammatory (TNFα, IL1β, 
IL-6) 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. 

 
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8.2.3 
Specimen Preparation, Handling, and Storage 
Collection of blood will be performed by trained staff in phlebotomy at the School of 
Dentistry and serum/plasma isolation and storage will be held at the same school. 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, proinflammatory (TNFα, IL1β, IL-6 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 Center for Innovative 
Biomedical Resources (CIBR core). 

 
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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 antagonist FDA approved for the management of chronic migraine.  
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 and AMGEN. 
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.  
 
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; 

 
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• 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. 
• 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.  

 
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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. 
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 

 
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• 
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.  
Amgen Global Safety 

 
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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. 
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 

 
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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 

 
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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. 
• 
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. 
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 

 
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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. 
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.  

 
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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 Trigeminal 
Neuropathic Pain (TNP) 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 
 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 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 orofacial pain 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 primary efficacy hypothesis is a higher proportion of participants in Erenumab group 
will achieve at least 30% reduction in monthly average pain score from baseline (monthly 
data prior to Visit 1) to end of treatment (monthly data prior to Visit 4) than those in placebo 
group.   
The secondary efficacy hypothesis: 
To investigate the efficacy of Erenumab compared to placebo on the reduction in monthly 
average daily pain score from baseline to the end of 12-week treatment period.  
To investigate the efficacy of Erenumab compared to placebo on the proportion of 
subjects who achieved a least 30% reduction in the monthly average daily pain score 
from baseline to Visit 5 (follow-up/final visit).   
To determine the efficacy of Erenumab using functional measures related to TNP impact 
in daily activities, disability and emotional functioning measured by questionnaires 
(GCPAs, HADS, PGIC and PENN Facial Pain Scale).  
The exploratory hypothesis: 
Erenumab decreases the presence of pro-inflammatory cytokines (TNF-α, IL-6 and IL-
1β) and increases anti-inflammatory cytokines (IL-10 and IL-4) in blood/serum samples. 
Erenumab influences nociceptive modulation decreasing sensitization measured by QST.  
Erenumab modulates pain sensitivity measured by EEG/PAF. 
12.2 
Sample Size Considerations 
The sample size was calculated based on the primary objective to compare the 
percentage of participants who had at least 30% reduction in pain from baseline to end 
of the treatment between experimental groups. Gomez-Arguelles et al. reported a 
reduction in pain frequency in days from 12.26(SD, 3.86) at baseline to 5.16(SD, 2.16) 
after 12 weeks anticonvulsants therapy for a group of trigeminal neuropathic pain patients 
[47] The changes was estimated as a very large effect size Cohen’s d=2.1. The effect 
size in the animal studies has also been shown to be extremely large, approximately of 7 
SD [48]. We assume the proposed trial will have a large effect size with Cohen’s d=.8 or 
OR=4.2. Based on this assumption and two-sided type I error of =.05, a sample of n=36 
will provide sufficient power (Power >80%) to detect a large effect size between two 
groups [49]. This effect size could be interpreted as that about 58% of the participants in 
intervention group will reach at least 30% reduction in pain scores at the end of treatment 

 
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while 25% occur in the placebo group. Considering a 15% overall dropout rate, we will 
recruit N=40 participants (20 in each experimental group).       
12.3 
Final Analysis  
Descriptive statistics including measures of central tendency, dispersion and appropriate 
visualization approaches (e.g., box plots and spaghetti plots) will be performed on each 
outcome variable (pain scores, and outcomes in secondary and exploratory objectives) 
by time points and groups.  This will be done to ascertain distributional characteristics 
and ensure that the assumptions (e.g., normality) associated with the planned statistical 
procedures are met. When necessary, transformations will be performed. All analyses will 
be done in SAS and will follow an intent-to-treat philosophy.   
The main goal of the statistical analyses is to compare the changes in study primary and 
secondary endpoints between groups to evaluate efficacy of Erenumab. For the primary 
objective, the generalized Linear Mixed Models (GLMM) with binomial distribution will be 
used to assess the efficacy of Erenumab on the primary endpoint (i.e., at least 30% 
reduction in pain score; yes/no). The fixed effects included in the models will be treatment 
group (intervention versus placebo), time (dummy coded from baseline to visits 2-4), and 
the interaction terms of group by time. The random effects include the participants to 
account for correlations between repeated measures. The primary hypothesis will be 
tested by evaluating the interaction term of group and time from baseline to visit 4.  In the 
meantime, the Erenumab efficacy from baseline to visits 2 and 3 will be evaluated through 
the interaction terms at the corresponding time points. The secondary objective of the 
difference in change (>30% reduction) from baseline to visit 5 will also be evaluated using 
the similar GLMM model with the corresponding time (baseline, V2-V5), group and 
interaction terms between time and group.  The interaction of time (baseline to V5) and 
group will be evaluated to test the hypothesis. The difference from V4 to V5 will also be 
evaluated by contrast estimation from the model. We will use a significance level of two-
sided α < 0.05 as primary hypothesis test.   
Separate linear mixed models will be applied to test other secondary objectives (e.g., 
monthly mean pain scores, measures of daily activities and functions, etc.) and 
exploratory objectives (e.g., QST measures) where the outcome variables are 
continuous. The model and testing will be the same as described in the above primary 
objective. The use of mixed models will provide flexibility with regard to assumptions 
related to the covariance structure of the residuals and the presence of missing data for 
the repeated measures.  
Descriptive statistics for safety measures will also be calculated. 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). 
Missing Data 

 
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Participants may miss specific data points for a variety of reasons such as a missed visit, 
early withdrawal from the study, or inability to evaluate an endpoint at a time point. If 
participants miss entering data in the DSD, the missing data will be imputed by the mean 
of observed daily data if the missing days are less than 80% within a month. If the missing 
days are more than 80%, the monthly measurement from the previous month will be 
carried forward to replace the missing value for continuous endpoints.   
If there is significant dropout, we will identify baseline characteristics that differ between 
those dropped out and retained. Maximum likelihood methods will be used for primary 
analyses, which address non-informative dropout [missing at random (MAR)]. If 
"informative" dropout is present, we will consider sensitivity analyses that add these 
relevant baseline covariates to make the MAR assumption more plausible [50]  

 
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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 AMGEN and 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, Oral Surgery 
Clinic or Pain Medicine 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 questionnaires 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. 

 
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The consent process will be documented in the clinical or research record.   
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. 
Children will not be included in the study since Erenumab has not been validated in 
children and because TNP 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. 
The urinary sample taken for the pregnancy test will discarded after the test is 
performed. 

 
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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 

 
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pain threshold testing information, laboratory test results and serum/plasma cytokines will 
be collected in the study. 
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.  No records will be destroyed without the written consent of the sponsor if 
applicable.  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 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 Drugs and Biologics: Controlled, clinical investigations, other than Phase I 
investigations, of a product subject to FDA regulation;  

 
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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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Lars, E., The CGRP Pathway in Migraine as a Viable Target for Therapies. 
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Michot, B., et al., CGRP receptor blockade by MK-8825 alleviates allodynia in 
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28. 
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Farrar, J.T., et al., Clinical importance of changes in chronic pain intensity 
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31. 
Symonds, T., et al., Measuring the impact of trigeminal neuralgia pain: the Penn 
Facial Pain Scale-Revised. J Pain Res, 2018. 11: p. 1067-1073. 
32. 
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133-49. 
33. 
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management of peripheral neuropathic pain: Clinical relevance and correlations 
in daily practice. Eur J Pain, 2019. 23(6): p. 1117-1128. 
34. 
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Psychiatr Scand, 1983. 67(6): p. 361-70. 
35. 
Svensson, P., et al., Neurosensory testing of orofacial pain in the dental clinic. J 
Am Dent Assoc, 2012. 143(8): p. e37-9. 
36. 
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associated factors - Cardiovascular responsiveness and psychological status. 
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37. 
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on Neuropathic Pain (DFNS): Standardized protocol and reference values. PAIN, 
2006. 123(3): p. 231-243. 
38. 
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39. 
Sarnthein, J., et al., Increased EEG power and slowed dominant frequency in 
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40. 
de Vries, M., et al., Altered resting state EEG in chronic pancreatitis patients: 
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41. 
Seminowicz, D.A., et al., A novel cortical biomarker signature for predicting pain 
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42. 
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linked to high pain susceptibility in transition to sustained pain. bioRxiv, 2018: p. 
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in a human model of sustained, musculoskeletal pain. J Neurophysiol, 2019. 
122(4): p. 1784-1793. 
44. 
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45. 
Bazanova, O.M. and D. Vernon, Interpreting EEG alpha activity. Neurosci 
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46. 
Hurst, H. and J. Bolton, Assessing the clinical significance of change scores 
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48. 
Doyle, T., et al., Targeting the Overproduction of Peroxynitrite for the Prevention 
and Reversal of Paclitaxel-Induced Neuropathic Pain. The Journal of 
Neuroscience, 2012. 32(18): p. 6149-6160. 
49. 
Faul, F., et al., G*Power 3: a flexible statistical power analysis program for the 
social, behavioral, and biomedical sciences. Behav Res Methods, 2007. 39(2): p. 
175-91. 
50. 
Son, H., E. Friedmann, and S.A. Thomas, Application of pattern mixture models 
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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 
• Behavioral Intervention Manual (if applicable) 
• Calibration protocol (if applicable) 
• Repository Instructions (if applicable) 
• Biosafety Precautions (if applicable) 
• Ionizing Radiation safety (if applicable) 
• 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 
 
• Appendix A: Schedule of Events 
• Appendix B: List of medications used for the management of neuropathic pain 
• 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 
RandomizationB and Treatment 
(12 weeks of treatment/3 cycles 
of Erenumab) 
Follow 
Up 
Early 
termination 
Clinic Visit 
 
V0 
V1C 
V2 
V3 
V4 
V5 
ET 
Study Day/ 
0-2 weeks 
prior to V0 
4 weeks 
prior V1 
Day 0 
Day 
28 
Day 
56 
Day 
84 
Day 
112 
 
Procedures 
 
 
 
 
 
 
 
 
Contact 
Information 
X 
 
 
 
 
 
 
 
Pre-screening 
interview Script 
X 
 
 
 
 
 
 
 
Informed 
consentD 
 
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 E 
 
X 
X 
X 
X 
X 
 
 
Collect Daily 
Symptom 
Diaries E 
 
X 
X 
X 
X 
X 
X 
 
Assess 
compliance 
with Daily 
Symptom 
Diaries  
 
X 
X 
X 
X 
X 
 
 
Provide study 
drug injectionF 
 
 
X 
X 
X 
 
 
 
 
 

 
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Study Phase 
Pre-
screeningA 
Screening 
and 
Baseline 
RandomizationB and 
Treatment 
(12 weeks of treatment/3 
cycles of Erenumab) 
Follow 
Up 
Early 
termination 
Clinic Visit 
 
V0 
V1c 
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 
QST 
 
X 
 
 
 
X 
 
 
EEG 
 
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 ScaleG 
 
X 
X 
X 
X 
X 
X 
X 
Penn Facial 
Pain Scale-
Revised G 
 
X 
X 
X 
X 
X 
X 
X 
 Patient Global 
Impression of 
ChangeG 
 
X 
X 
X 
X 
X 
X 
X 
Hospital Anxiety 
and Depression 
IndexG 
 
X 
X 
X 
X 
X 
X 
X 
 
APPENDIX B: List of medications used for the management of neuropathic pain 
• Anticonvulsants and channel blockers: Including but not limited to: 

 
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o Carbamazepine, gabapentin, pregabalin, oxcarbazepine, 
verapamil, divalproex sodium, topiramate 
• Tricyclics Antidepressants: Including but not limited to: 
o Amitriptyline, nortriptyline, imipramine, desipramine, doxepin 
• Serotonin and Norepinephrine Reuptake Inhibitors: Including but not limited to: 
o Duloxetine (Hcl), venlafaxine 
• Muscle relaxants: Including but not limited to 
o  Baclofen 
o Tizanadine