Clinical trial NCT04465357
Conditions: Migraine
Sponsor: Merle Diamond
Start date: 2020-10-22; Completion date: 2022-06-03
Enrollment: 55 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the efficacy of erenumab on functional impact due to Migraine in adults.

Detailed description:
This is a single group, multicenter, open-label study with a study population of patients who meet International Classification of Headache Disorders 3rd edition (ICHD-III) criteria for migraine with or without aura and have 4 to 20 migraine days per month. This is a single-group supportive care study with one arm and no masking. A maximum of 54 participants will be enrolled to study intervention. All participants in this single-group study will complete a 4-week run-in period. After the run-in period, eligible participants will be enrolled to study intervention and enter a 12-week treatment period.

Arms: arm 1: Participants received 140 mg/mL administered subcutaneously once every 4 weeks in the abdomen, thigh, or upper arm for three months (12 weeks).
Interventions: intervention 1: Erenumab-Aooe 140 MG/ML [Aimovig]
Intervention descriptions: intervention 1: 140 mg/mL administered subcutaneously

Protocol documents:
Prot_000.pdf: 
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Title Page 
Protocol Title: A Multicenter, Open Label Study Assessing the Efficacy of erenumab on 
Functional Impact of Migraine  
Protocol Number: 19-001AM 
Amendment Number: NA 
Investigational Product: 140 mg erenumab-aooe 
Study Phase: Phase 4 
Sponsor Name: Merle L. Diamond, MD 
Legal Registered Address:  Diamond Headache Clinic 
1460 North Halsted St 
Suite 501 
Chicago, IL 60642 
Approval Date: 16-Sep-2020 
 
 


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Sponsor Signatory: 
 
 
 
 
 
Merle L. Diamond, MD  
President, Managing Director, Diamond Headache Clinic 
and Medical Monitor 
 
Date 
 
 
 
 
 
 
 
 
Principal Investigator Signatory: 
 
 
 
 
 
Investigative Site Principal Investigator  
 
 
Date 
 
 


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Table of Contents 
1. 
Protocol Summary ..........................................................................................................6 
1.1. 
Synopsis ............................................................................................................................6 
1.2. 
Schedule of Activities (SoA) ............................................................................................9 
2. 
Introduction ...................................................................................................................11 
2.1. 
Study Rationale ...............................................................................................................11 
2.2. 
Background .....................................................................................................................11 
2.3. 
Benefit/Risk Assessment ................................................................................................12 
3. 
Objectives and Endpoints ............................................................................................13 
4. 
Study Design ..................................................................................................................16 
4.1. 
Overall Design ................................................................................................................16 
4.2. 
End of Study Definition ..................................................................................................17 
5. 
Study Population ...........................................................................................................18 
5.1. 
Inclusion Criteria ............................................................................................................18 
5.2. 
Exclusion Criteria ...........................................................................................................19 
5.3. 
Screen Failures ................................................................................................................20 
6. 
Study Intervention ........................................................................................................21 
6.1. 
Study Intervention(s) Administered ................................................................................21 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................21 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................21 
6.4. 
Study Intervention Compliance ......................................................................................21 
6.5. 
Concomitant Therapy .....................................................................................................22 
6.5.1. 
Prohibited Medications ...................................................................................................22 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................23 
7.1. 
Discontinuation of Study Intervention ............................................................................23 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................23 
7.3. 
Lost to Follow up ............................................................................................................23 
8. 
Study Assessments and Procedures.............................................................................25 
8.1. 
Efficacy Assessments .....................................................................................................25 
8.1.1. 
Migraine Functional Impact Questionnaire (MFIQ) .......................................................25 
8.1.2. 
Migraine Interictal Burden Scale (MIBS-4) ...................................................................25 
8.1.3. 
Migraine Days via Daily Headache Diary (DHD) ..........................................................25 
8.1.4. 
Work Productivity and Activity Impairment- Migraine (WPAI-
M) ....................................................................................................................................26 
8.1.5. 
Neuro-QoL Sleep Disturbance Short Form (SDSF) .......................................................26 
8.1.6. 
General Self-Efficacy Short Form (GSE-SF) .................................................................26 


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8.1.7. 
Brief Measure of Worry Severity (BMWS) ....................................................................26 
8.1.8. 
Activity and Sleep via wearable device ..........................................................................26 
8.1.9. 
Functional Assessment of Migraine Scale (FAMS) .......................................................26 
8.2. 
Safety Assessments .........................................................................................................26 
8.2.1. 
Physical and Neurological Examinations .......................................................................26 
8.2.2. 
Vital Signs .......................................................................................................................27 
8.2.3. 
Electrocardiograms .........................................................................................................27 
8.2.4. 
Clinical Safety Laboratory Assessments ........................................................................27 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring ...........................................................28 
8.3. 
Adverse Events and Serious Adverse Events .................................................................28 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................28 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................29 
8.3.3. 
Follow-up of AEs and SAEs ...........................................................................................29 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................29 
8.3.5. 
Pregnancy ........................................................................................................................30 
8.4. 
Treatment of Overdose ...................................................................................................30 
8.5. 
Pharmacokinetics ............................................................................................................30 
8.6. 
Genetics ..........................................................................................................................30 
8.7. 
Biomarkers ......................................................................................................................30 
8.8. 
Immunogenicity Assessments.........................................................................................30 
8.9. 
Medical Resource Utilization and Health Economics ....................................................30 
9. 
Statistical Considerations .............................................................................................31 
9.1. 
Statistical Hypotheses .....................................................................................................31 
9.2. 
Sample Size Determination ............................................................................................31 
9.3. 
Populations for Analyses ................................................................................................31 
9.4. 
Statistical Analyses .........................................................................................................31 
9.4.1. 
General considerations ....................................................................................................32 
9.4.2. 
Primary endpoint .............................................................................................................32 
9.4.3. 
Secondary endpoint(s) ....................................................................................................32 
9.4.4. 
Tertiary/exploratory endpoint(s) .....................................................................................32 
9.4.5. 
Other safety Analyses .....................................................................................................32 
9.5. 
Interim Analyses .............................................................................................................32 
9.6. 
Data Monitoring Committee (DMC) ..............................................................................32 
10. 
Supporting Documentation and Operational Considerations ..................................33 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................33 
10.1.1. Regulatory and Ethical Considerations ...........................................................................33 
10.1.2. Financial Disclosure ........................................................................................................33 
10.1.3. Informed Consent Process ..............................................................................................34 
10.1.4. Data Protection................................................................................................................34 


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10.1.5. Clinical Monitoring .........................................................................................................34 
10.1.6. Data Quality Assurance ..................................................................................................35 
10.1.7. Source Documents ..........................................................................................................36 
10.1.8. Study and Site Start and Closure ....................................................................................37 
10.1.9. Publication Policy ...........................................................................................................37 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................38 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................39 
10.3.1. Definition of AE .............................................................................................................39 
10.3.2. Definition of SAE ...........................................................................................................40 
10.3.3. Recording and Follow-Up of AE and/or SAE ................................................................41 
10.3.4. Reporting of SAEs ..........................................................................................................43 
10.3.5. Reporting of Safety Data to the manufacturer (Amgen) .................................................45 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................48 
10.5. 
International Classification of Headache Disorders, 3rd edition: 
Migraine with and without aura ......................................................................................50 
10.6. 
Appendix 9: Abbreviations .............................................................................................52 
11. 
References ......................................................................................................................55 
 


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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: A Multicenter, Open Label Study Assessing the Efficacy of erenumab on 
Functional Impact due to Migraine 
 
Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary 
To evaluate the efficacy of erenumab-aooe on 
the overall functional impact of migraine. 
Change in Migraine Functional Impact 
Questionnaire (MFIQ) overall impact on 
usual activities item score from baseline to the 
final 4-week treatment period within subjects 
treated with erenumab-aooe. 
Secondary 
To evaluate the efficacy of erenumab-aooe on 
specific aspects of the functional impact of 
migraine 
Change in Migraine Functional Impact 
Questionnaire (MFIQ) domain scores from 
baseline to the final 4-week treatment period 
within subjects treated with erenumab-aooe: 
• Impact on physical functioning 
• Impact on usual activities 
• Impact on emotional functioning 
• Impact on social functioning 
To evaluate the efficacy of erenumab-aooe on 
the following parameters during each 4-week 
treatment period: 
Change from baseline to each 4-week 
treatment month within subjects treated with 
erenumab-aooe on the following: 
• Functional impact of migraine 
Global Migraine Functional Impact 
Questionnaire (MFIQ) scores: 
• Overall impact on usual activities 
• Impact on physical functioning 
• Impact on usual activities 
• Impact on emotional functioning 
• Impact on social functioning 


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Objectives 
Endpoints 
• Migraine interictal burden 
• Migraine interictal burden scale 
(MIBS-4) scores 
• Migraine days 
• Number of migraine days 
• Work Productivity and Activity 
Impairment 
• Work Productivity and Activity 
Impairment- Migraine (WPAI-M) 
scores 
• Sleep disturbance 
• Neuro-QoL Sleep Disturbance Short 
Form (SDSF) scores 
• Self-Efficacy 
• General Self-Efficacy Short Form 
(GSE-SF) scores 
• Severity of worry 
• Brief Measure of Worry Severity 
(BMWS) scores 
Exploratory 
To evaluate the efficacy of erenumab on 
activity and sleep. 
Change from baseline to each 4-week 
treatment month within subjects treated with 
erenumab-aooe on activity and sleep 
measured though a wearable device. 
To evaluate the efficacy of erenumab on 
functional impact of migraine. 
Change from baseline to each 4-week 
treatment month within subjects treated with 
erenumab-aooe on Functional Assessment of 
Migraine Scale (FAMS) scores. 
To evaluate the correlation between the 
Functional Assessment of Migraine Scale 
(FAMS) and other migraine related Patient 
Reported Outcome (PRO) measures. 
Correlation between Functional Assessment 
of Migraine Scale (FAMS) and the following 
migraine related Patient Reported Outcome 
(PRO) measures: 
• Global Migraine Functional Impact 
Questionnaire (MFIQ) 
• Migraine interictal burden scale 
(MIBS-4) 
• Work Productivity and Activity 
Impairment- Migraine (WPAI-M) 
• Neuro-QoL Sleep Disturbance Short 
Form (SDSF) 
• General Self-Efficacy Short Form 
(GSE-SF) 


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Objectives 
Endpoints 
• Brief Measure of Worry Severity 
(BMWS) 
Safety 
To evaluate the safety and tolerability of 
subjects treated with erenumab-aooe. 
Safety and tolerability of erenumab-aooe in 
study participants via collection of adverse 
events and safety evaluations. 
 
Overall Design: 
This is a single group, multicenter, open-label study with a study population of patients who 
meet International Classification of Headache Disorders 3rd edition (ICHD-III) criteria for 
migraine with or without aura and have 4 to 20 migraine days per month. 
Disclosure Statement: 
This is a single-group supportive care study with one arm and no masking. 
Number of Participants: 
A maximum of 54 participants will be enrolled to study intervention.  
Note: "Enrolled" means a participant's, or their legally acceptable representative’s, agreement to 
participate in the clinical study following completion of the informed consent process and the 4-
week run-in period. Potential participants who are screened for the purpose of determining 
eligibility for the study, but do not participate in the study via at least one administration of IP, 
are not considered enrolled. 
Intervention Groups and Duration:  
All participants in this single-group study will complete a 4-week run-in period. After the 
run-in period, eligible participants will be enrolled to study intervention and enter a 12-
week treatment period. 
Data Monitoring Committee: No 


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1.2. 
Schedule of Activities (SoA) 
 
Procedure 
Screening 
Treatment 
Early Discontinuation 
Visit 1  
 
Day -33 to Day -28 
Visit 2 
(Enrollment) 
Day 1 
Visit 3 
 
Day 29 
± 3 
Visit 4 
 
Day 57 
± 3 
Visit 5 
 
Day 85 
± 3 
 
Informed consent 
X 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
Demography 
X 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
Neurological examination 
X 
 
 
 
 
 
Medical history 
(includes migraine history and substance usage) 
X 
 
 
 
 
 
Prior and concomitant medications history 
X 
 
 
 
 
 
Urine pregnancy test 
(WOCBP only) 
X 
X 
X 
X 
X 
X 
Laboratory assessments 
(CMP)  
X 
 
 
 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
PHQ-9 
X 
X 
X 
X 
X 
X 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 


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Procedure 
Screening 
Treatment 
Early Discontinuation 
Visit 1  
 
Day -33 to Day -28 
Visit 2 
(Enrollment) 
Day 1 
Visit 3 
 
Day 29 
± 3 
Visit 4 
 
Day 57 
± 3 
Visit 5 
 
Day 85 
± 3 
 
Dispense activity tracker 
X 
 
 
 
 
 
Dispense diary URL and instructions 
X 
 
 
 
 
 
Migraine Functional Impact Questionnaire 
(MFIQ) 
X 
X 
X 
X 
X 
X 
MIBS-4 
 
X 
X 
X 
X 
X 
Work Productivity and Activity Impairment- 
Migraine (WPAI-M) 
 
X 
X 
X 
X 
X 
Neuro-QoL Sleep Disturbance Short Form 
(SDSF) 
 
X 
X 
X 
X 
X 
General Self-Efficacy Short Form (GSE-SF) 
 
X 
X 
X 
X 
X 
Brief Measure of Worry Severity (BMWS) 
 
X 
X 
X 
X 
X 
Functional Assessment of Migraine Scale 
(FAMS) 
 
X 
X 
X 
X 
X 
AE review 
 
X 
X 
X 
X 
X 
SAE review 
 
X 
X 
X 
X 
X 
Diary review 
 
X 
X 
X 
X 
X 
Concomitant medication review 
 
X 
X 
X 
X 
X 
IP injection 
 
X 
X 
X 
 
 


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2. 
Introduction 
2.1. 
Study Rationale 
This study is being conducted to evaluate the efficacy and safety of erenumab-aooe on the 
functional impact of migraine in adult participants age 18 to 65 years old, who meet International 
Classification of Headache Disorders 3rd edition (ICHD-III; Appendix 5) criteria for migraine 
with or without aura and have 4 to 20 migraine days per month.  
2.2. 
Background 
The burden of Migraine can extend well beyond the pain phase and affect more than just work 
and school attendance. Patients with frequent Episodic Migraine and Chronic Migraine are 
known to experience the impact of migraine even on days they do not have migraine pain or 
associated symptoms such as nausea, photophobia, or phonophobia. Most of the focus of 
migraine management is placed on migraine pain and associated symptom relief while the 
functional impact of migraine is often overlooked.  
 
Individuals experiencing frequent migraine attacks regularly find themselves engaged in 
preparatory or compensatory behaviors, hoping to minimize lost productivity or compromised 
quality of life, even before attacks begin. These types of behaviors originate from the fear and 
dread of the inevitable migraine attacks to come and lead to a significant diminution of quality of 
life before the pain has even started1,2. Patients frequently cancel plans with family and friends or 
avoid making commitments in the first place based on their anticipation of a migraine episodes. 
Even worse, these fears and behavior changes also tend to exacerbate co-occurring conditions 
such as anxiety, depression, and sleep disorders, further contributing to poor quality of life. 
Unfortunately, migraine prevention trials have traditionally focused on reduction of migraine 
days as a primary endpoint and have largely ignored the significant health and lifestyle burdens 
also associated with migraine and associated symptoms.  
  
This study aims to capture changes in functional impact of migraine after participants begin 
treatment with erenumab-aooe. In addition to using a variety of scales to capture these changes 
we also plan to use activity trackers to allow detailed monitoring of daily activity and sleep 
patterns. This approach has been used in a variety of clinical trials over a wide range of disease 
states with success and we feel its addition will enrich the results obtained through 
administration of traditional questionnaires.  We hypothesize that participants treated with 
erenumab will demonstrate improvements in a variety of measures of daily activity. Results from 
this study will be a significant contribution to the medical literature and bring value to providers 


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Page 12 of 55 
 
as they manage expectations with patients regarding the functional impact erenumab-aooe on 
migraine prophylaxis efforts. 
2.3. 
Benefit/Risk Assessment 
Detailed information about the known and expected benefits and risks and reasonably expected 
adverse events of erenumab-aooe may be found in the Package Insert. 


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3. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the efficacy of erenumab-aooe on 
the overall functional impact of migraine. 
Change in Migraine Functional Impact 
Questionnaire (MFIQ) overall impact on 
usual activities item score from baseline to the 
final 4-week treatment period within subjects 
treated with erenumab-aooe. 
Secondary 
To evaluate the efficacy of erenumab-aooe on 
specific aspects of the functional impact of 
migraine 
Change in Migraine Functional Impact 
Questionnaire (MFIQ) domain scores from 
baseline to the final 4-week treatment period 
within subjects treated with erenumab-aooe: 
• Impact on physical functioning 
• Impact on usual activities 
• Impact on emotional functioning 
• Impact on social functioning 
To evaluate the efficacy of erenumab-aooe on 
the following parameters during each 4-week 
treatment period: 
Change from baseline to each 4-week 
treatment month within subjects treated with 
erenumab-aooe on the following: 
• Functional impact of migraine 
Global Migraine Functional Impact 
Questionnaire (MFIQ) scores: 
• Overall impact on usual activities 
• Impact on physical functioning 
• Impact on usual activities 
• Impact on emotional functioning 
• Impact on social functioning 
• Migraine interictal burden 
• Migraine interictal burden scale 
(MIBS-4) scores 
• Migraine days 
• Number of migraine days 
• Work Productivity and Activity 
Impairment 
• Work Productivity and Activity 
Impairment- Migraine (WPAI-M) 
scores 


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Objectives 
Endpoints 
• Sleep disturbance 
• Neuro-QoL Sleep Disturbance Short 
Form (SDSF) scores 
• Self-Efficacy 
• General Self-Efficacy Short Form 
(GSE-SF) scores 
• Severity of worry 
• Brief Measure of Worry Severity 
(BMWS) scores 
Exploratory 
To evaluate the efficacy of erenumab on 
activity and sleep. 
Change from baseline to each 4-week 
treatment month within subjects treated with 
erenumab-aooe on activity and sleep 
measured though a wearable device. 
To evaluate the efficacy of erenumab on 
functional impact of migraine. 
Change from baseline to each 4-week 
treatment month within subjects treated with 
erenumab-aooe on Functional Assessment of 
Migraine Scale (FAMS) scores. 
To evaluate the correlation between the 
Functional Assessment of Migraine Scale 
(FAMS) and other migraine related Patient 
Reported Outcome (PRO) measures. 
Correlation between Functional Assessment 
of Migraine Scale (FAMS) and the following 
migraine related Patient Reported Outcome 
(PRO) measures: 
• Global Migraine Functional Impact 
Questionnaire (MFIQ) 
• Migraine interictal burden scale 
(MIBS-4) 
• Work Productivity and Activity 
Impairment- Migraine (WPAI-M) 
• Neuro-QoL Sleep Disturbance Short 
Form (SDSF) 
• General Self-Efficacy Short Form 
(GSE-SF) 
• Brief Measure of Worry Severity 
(BMWS) 
 
 
 


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Objectives 
Endpoints 
Safety 
To evaluate the safety and tolerability of 
subjects treated with erenumab-aooe. 
Safety and tolerability of erenumab-aooe in 
study participants via collection of adverse 
events and safety evaluations. 
 


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4. 
Study Design 
 
4.1. 
Overall Design 
This is a multicenter, open label study assessing the interictal impact of erenumab-aooe in 
participants with migraine. The study population will consist of 54 participants 18 to 65 years 
old, with at least 4 and up to 20 migraine days per month (inclusive) following ICHD-III criteria 
for migraine with or without aura. 
 
At Visit 1, the participant will sign the informed consent indicating they are willing to participate 
in the study and will provide basic demographic information, have a comprehensive review of 
their medical history and prior and concomitant medications. A physical and neurological 
examination (including vital signs) will be performed as well as a 12-lead Electrocardiography 
(ECG), screening CMP labs, and the PHQ-9 will be completed. Women of childbearing potential 
(WOCB) will complete a urine pregnancy test. All participants will complete the MFIQ 
questionnaire. Inclusion and Exclusion criteria will also be reviewed. Participants who meet the 
study criteria will be dispensed the activity tracker and its associated phone application 
instructions, as well as their unique Daily Headache Diary (DHD) URL and its instructions. 
Participants will then enter into a 28-day run-in period.  During the 28-day run-in period, all 
participants will be monitored through the use of electronic Daily Headache Diary (DHD) to 
ensure they continue to meet all inclusion criteria, and none of the exclusion criteria.   During 
this run-in period, participants will continue treating their migraines and other defined conditions 
with their usual treatment providing it has been stable for a minimum of 3 months. Daily 
electronic diaries will be used to assess symptoms and treatment response throughout the run-in 
period. 
 
Visit 2 will take place 28 to 33 days following Visit 1. Those participants who (1) continue to 
meet eligibility criteria (2) experienced 4-20 migraine days that meet ICHD-III criteria for 
migraine and (3) have completed at least 23/28 diary days will be eligible to be enrolled into the 
study. At this visit a physical examination (including vital signs) will be performed, WOCB will 
complete a urine pregnancy test, and all participants will complete the PHQ-9. Medical history 
and/or adverse events and concomitant medications will be reviewed and updated as needed. 
Participant’s DHD will be reviewed for compliance, and participants will complete the following 
questionnaires: 
• MFIQ 
• MIBS-4 
• WPAI-M 


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Page 17 of 55 
 
• SDSF 
• GSE-SF 
• BMWS 
• FAMS 
Finally, all eligible participants will receive an injection of 140 mg erenumab-aooe. Participants 
will continue completing diary headache diaries for the remainder of the trial. 
 
Visits 3-5 will take place on days 29 (+/-3d), 57 (+/-3d), and 85 (+/-3d), following Visit 2.  At 
each visit: a physical examination (including vital signs) will be performed, WOCB will 
complete a urine pregnancy test, and all participants will complete the PHQ-9. Medical history 
and/or adverse events and concomitant medications will be reviewed and updated as needed. 
Participant’s DHD will be reviewed for compliance, and participants will complete the following 
questionnaires: 
• MFIQ 
• MIBS-4 
• WPAI-M 
• SDSF 
• GSE-SF 
• BMWS 
• FAMS 
Finally, all eligible participants will receive an injection of 140 mg erenumab-aooe. Visit 5 (End 
of Study) will not include injections but will include comprehensive metabolic panel (CMP) 
laboratory. 
4.2. 
End of Study Definition 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit (Visit 5) or the last scheduled procedure shown in the SoA. 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in 
the trial globally. 


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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. willing to participate and sign informed consent; 
2. ability to understand informed consent and study procedures, including able to use the 
electronic Daily Headache Diary; 
3. in good general health based on investigator’s judgment; 
4. must be between 18 to 65 years of age, inclusive, at time of Visit 2; 
5. have migraine with or without aura meeting the diagnostic criteria listed in the 
International Classification of Headache Disorders 3rd edition (ICHD-III; Appendix 5); 
6. verification of headache frequency through prospectively collected baseline information 
during the 28-day screening/baseline phase reporting 4-20 migraine days and no more 
than 20 total headache days; 
7. onset of migraine before age 50; 
8. able to differentiate migraine from other primary headache types allowed in the study 
(e.g., tension-type headache); 
9. stable history of migraine at least 3 months prior to screening with headache free periods; 
10. not currently taking a migraine preventive OR has been taking a stable dose of a 
preventive for at least 90 days prior to screening and agrees to not start, stop, or change 
medication and/or dosage during the study period; 
* * participants on migraine preventive should have stable headache pattern  
11. Must answer “Moderately”, “Very Much”, or “Extremely” to Item 16 (In the past 7 days, 
overall, how much did a migraine affect your usual activities?) on the Migraine 
Functional Impact Questionnaire (MFIQ) at screening; 
12. women may be included only if they have a negative pregnancy test at screening and 
baseline, are sterile, or postmenopausal. Women of childbearing potential (WOCBP) 
whose male partners are potentially fertile (i.e., no vasectomy) must use highly effective 
birth control methods for the duration of the study (i.e., starting at screening). Definitions 
of WOCBP, sterile and postmenopausal women, male contraception, and highly effective 


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and acceptable birth control methods are to be determined based on investigator’s 
judgment; 
13. demonstrated compliance with the electronic Daily Headache Diary during the 28-day 
screening/baseline phase as defined by entry of headache data on a minimum of 23 days; 
14. is willing to wear activity/sleep tracker throughout the duration of the trial; 
15. has a smartphone and willing to install activity tracker app on phone. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
1. unable to understand the study requirements, the informed consent, or complete headache 
records as required per protocol; 
2. pregnant, actively trying to become pregnant, or breast-feeding;  
3. history of substance abuse and/or dependence, in the opinion of the Investigator; 
4. history of impaired renal function that, in the investigator’s opinion, contraindicates 
participation in this study; 
5. suffers from a serious illness, or an unstable medical condition, one that could require 
hospitalization, or could increase the risk of adverse events; 
6. a psychiatric condition, in the opinion of the investigator, that may affect the 
interpretation of efficacy and safety data or contraindicates the participant’s participation 
in the study; 
7. received nerve blocks or trigger point injections in the previous 8 weeks or plans to 
receive them during the study; 
8. prior exposure in the last 6 months to biologics or drugs specifically targeting the 
calcitonin gene-related peptide (CGRP) pathway; 
9. has failed more than 3 classes of medications for the prevention of migraine, or >6 
migraine preventative medications of any type due to lack of efficacy; 
10. received any investigational agents within 30 days prior to Visit 1 (6 months for any 
investigational biological products unless previous study blind has been broken and 
subject was known to have received placebo); 
11. plans to participate in another clinical study at any time during this study; 
12. history of medication overuse of opioids or butalbital, as defined by opioid or butalbital 
use ≥10 days/month in previous 12 months or during run-in period; Medication Overuse 
Headache (MOH) with other medication types will be allowed but must be documented; 


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13. unstable medication use for migraine prevention (changes in the last 3 months);  
14. clinically relevant lab results at screening as determine by the investigator; 
15. clinically relevant or significant ECG abnormalities as determine by the investigator, 
including ECG with QT interval corrected for heart rate (QTc) using Fridericia's 
correction formula (QTcF) > 500 msec; 
16. history of any of the following cardiovascular conditions: 
a. Moderate to severe congestive heart failure (New York Heart Association class III 
or IV); 
b. Recent (within past 12 months) cerebrovascular accident, myocardial infarction, 
coronary stenting; 
c. Uncontrolled hypertension as defined by a confirmed systolic blood pressure > 
160 mmHg or diastolic blood pressure > 100 mmHg.  
17. active HIV or Hepatitis C infection; 
18. allergy to latex; 
19. score of > 0 on question 9 on Patient Health Questionnaire (PHQ-9) at any visit; 
20. have any other condition, that in the judgment of the investigator, would make the 
participant unsuitable for inclusion, or would interfere with the participant participating 
in or completing the study. 
5.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to study intervention at Visit 2. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
permitted in certain situations to rescreen, after discussion with the study medical monitor. 
However, participants that test positive, through urine testing, as pregnant, or are determined to 
be of significant suicide risk, are not allowed to be rescreened. 
Rescreened participants should be assigned a new participant number (i.e., different than the 
initial screening participant number). 


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6. 
Study Intervention 
6.1. 
Study Intervention(s) Administered 
Description: 
Erenumab-aooe is a calcitonin gene-related peptide (CGRP) receptor antagonist subcutaneous 
injection indicated for the preventive treatment of migraine in adults, see product insert for 
detailed information. 
Dosing and administration: 
140 mg/mL administered subcutaneously once monthly in the abdomen, thigh, or upper arm. 
 
6.2. 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the storage and final disposition of unused study 
interventions are provided in the Package Insert. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study with one arm; potential randomization and/or blinding concerns are 
not applicable. 
 
6.4. 
Study Intervention Compliance 
All participants will be dosed at the site and will receive study intervention directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 


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administered in the clinic will be recorded in the source documents and recorded in the Case 
report form (CRF). 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Participants should not currently be taking a migraine preventive or have been taking a stable 
dose of a preventive for at least 90 days prior to screening and agrees to not start, stop, or change 
medication and/or dosage during the study period. 
6.5.1. 
Prohibited Medications 
Nerve blocks or trigger point injections in the previous 8 weeks prior to study or at any time 
during the study are prohibited. Prior exposure to biologics or drugs specifically targeting the 
CGRP pathway in the 6 months prior to or during the study are also prohibited. 
 


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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will not remain in the study. See the SoA for data to be collected at the time of 
discontinuation of study intervention and for any further evaluations that need to be completed. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• 
At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the time 
of study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
• 
The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• 
If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of consent. 
• 
If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records. 
7.3. 
Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study. 


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• 
Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 


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8. 
Study Assessments and Procedures 
• 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
8.1. 
Efficacy Assessments 
8.1.1. 
Migraine Functional Impact Questionnaire (MFIQ) 
Participants will complete an electronic version of the MFIQ within the clinic during visits 
outlined in the SoA. 
8.1.2. 
Migraine Interictal Burden Scale (MIBS-4) 
Participants will complete an electronic version of the MIBS-4 within the clinic during visits 
outlined in the SoA. 
8.1.3. 
Migraine Days via Daily Headache Diary (DHD) 
Headache and Migraine data will be recorded by the participants into an electronic daily 
headache diary (DHD) throughout the study. The DHDs are web-based and can be completed on 
any internet enabled device. Participants will be given their unique DHD URL at Visit 1. Site 
personnel will be responsible for instructing participants on the requirement for timely and daily 
completion of the DHD. Participants will be asked to record diary data each day for the previous 
day (24-hour period). If a participant does not experience a headache in the previous 24-hour 
period, the diary must still be completed as instructed. Participant’s diaries may vary day to day 
based on their responses. All participants should have at least 80% compliance with diary 
completion throughout the length of the study. Participants will record headache severity, 
symptoms, use of acute medications, as well as additional assessments as required. 


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8.1.4. 
Work Productivity and Activity Impairment- Migraine (WPAI-M) 
Participants will complete an electronic version of the WPAI-M within the clinic during visits 
outlined in the SoA. 
8.1.5. 
Neuro-QoL Sleep Disturbance Short Form (SDSF) 
Participants will complete an electronic version of the SDSF within the clinic during visits 
outlined in the SoA. 
8.1.6. 
General Self-Efficacy Short Form (GSE-SF) 
Participants will complete an electronic version of the GSE-SF within the clinic during visits 
outlined in the SoA. 
8.1.7. 
Brief Measure of Worry Severity (BMWS) 
Participants will complete an electronic version of the BMWS within the clinic during visits 
outlined in the SoA. 
8.1.8. 
Activity and Sleep via wearable device 
Participants’ activity and sleep data will be recorded via a sponsor-provided wearable device 
(e.g., Fitbit or similar). Participants may also be required to install the wearable device’s phone 
application on their personal phones in order for the data to be transferred to the sponsor. Site 
personnel will be responsible for instructing participants on the requirement(s) of the wearable 
device and its associated phone application if applicable. 
8.1.9. 
Functional Assessment of Migraine Scale (FAMS) 
Participants will complete an electronic version of the FAMS within the clinic during visits 
outlined in the SoA. 
 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical and Neurological Examinations 
• 
A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, and Gastrointestinal systems. Height and weight will also 
be measured and recorded. 
• 
A complete neurological examination will be performed. 


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• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2. 
Vital Signs 
• 
Oral temperature, pulse rate, respiratory rate, and blood pressure will be assessed. 
• 
Blood pressure and pulse measurements will be assessed. 
• 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (e.g., television, cell phones). 
• 
Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, and pulse. 
8.2.3. 
Electrocardiograms 
• 
Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3). The heart 
rate, PR, QRS, QT, and QTc intervals will be measured/calculated. Investigators will 
read final EKG’s and determine any abnormalities. The overall interpretation and 
determination of the clinical relevance of ECG findings will be the responsibility of the 
investigator  
8.2.4. 
Clinical Safety Laboratory Assessments 
• 
See Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA 
for the timing and frequency. 
• 
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the CRF. 
The laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant's condition. 
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or 
baseline or are no longer considered clinically significant by the investigator or medical 
monitor. 
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and Clinvest and the 
medical monitor notified. 
o All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SoA. 


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o If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded in the CRF. 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring 
Participants being treated with erenumab-aooe should be monitored appropriately and observed 
closely for suicidal ideation and behavior or any other unusual changes in behavior, especially at 
the beginning and end of the course of intervention, or at the time of dose changes, either 
increases or decreases. Consideration should be given to discontinuing the study medication in 
participants who experience signs of suicidal ideation or behavior, following a risk assessment.  
Baseline assessment of suicidal ideation and behavior/ intervention emergent suicidal ideation 
and behavior will be monitored during the study using PHQ-9.  
8.3. 
Adverse Events and Serious Adverse Events 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention or study (see Section 7). 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs will be collected from the signing of the informed consent form (ICF) until Visit 5 as 
specified in the SoA (Section 1.3). 
All AEs will be collected from the start of intervention until Visit 5 as specified in the SoA 
(Section 1.3). 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the CRF 
not the AE section. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 


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Page 29 of 55 
 
related to the study intervention or study participation, the investigator must promptly notify the 
sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and AEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the participant is lost to follow-up (as defined in Section 
7.3). Further information on follow-up procedures is provided in Appendix 10.3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study intervention under clinical investigation are met. 
• 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
• 
For all studies except those utilizing medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to 
local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. SUSARs will be reported to the manufacturer (Amgen) at the time of 
regulatory submission. 
• 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 


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8.3.5. 
Pregnancy 
• 
Details of all pregnancies in female participants and, female partners of male 
participants will be collected after the start of study intervention and until 5 terminal 
half-lives after the last dose. Pregnancies will be followed until delivery. 
• 
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 10.4. 
• 
Pregnancy/Lactation exposure and any associated reports/outcomes (i.e., unexpected 
pregnancy, pregnancy of partner, spontaneous abortion, congenital anomaly, etc.) will 
be reported to Amgen Safety within 1 business day of sponsor awareness, for reports 
meeting serious criteria. Non-serious reports will be reported to Amgen Safety within 
15 calendar days of sponsor awareness.   
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.4. 
Treatment of Overdose 
Not applicable, all treatments will be delivered in clinic by investigator or designee. 
8.5. 
Pharmacokinetics 
Not applicable, pharmacokinetic parameters are not evaluated in this study. 
8.6. 
Genetics 
Not applicable, genetics are not evaluated in this study. 
8.7. 
Biomarkers 
Not applicable, biomarkers are not evaluated in this study. 
8.8. 
Immunogenicity Assessments 
Not applicable, immunology assessments are not evaluated in this study. 
8.9. 
Medical Resource Utilization and Health Economics 
Not applicable, medical resource utilization and health economics are not evaluated in this study. 
 


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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
The null hypothesis of this study is that participants’ global Migraine Functional Impact 
Questionnaire (MFIQ) overall impact on usual activities item score will not be statistically 
different from baseline (Visit 2) to end of study (Visit 5) after 3 months dose of 140 mg 
erenumab-aooe. 
9.2. 
Sample Size Determination 
A meta-analysis of commonly used patient reported outcome (PRO) effect sizes was conducted 
to determine the expected effect size for the primary endpoint3. The meta-analysis revealed 
subjects on erenumab 140mg had an average change score on commonly used PROs with an 
effect size of d = 0.87. Additionally, prior research on the MFIQ showed an average correlation 
of r = 0.59 between the global MFIQ scores and these regularly utilized PROs4.  Due to the 
differences in study design between this study and prior studies, the novelty of the MFIQ and the 
uncertainty of its effect size, and to correct for potential replication errors5, we lowered the 
expected effect size to a more moderate effect size of d = 0.50.  
To determine the needed sample size for this study we utilized GPower Version 3.1.9.3 to 
conduct a power analysis for the primary endpoint analysis comparing baseline global MFIQ 
scores to the final 4-week treatment period’s global MFIQ scores utilizing a within group, 
repeated measures t-test. We utilized the conservative effect size of d = 0.50, alpha set at 0.05, 
and a power of .95. With these parameters the power analysis indicated a total of 54 subjects 
would need to be analyzed to detect this effect with .95 power. 
9.3. 
Populations for Analyses 
The following populations are defined: 
Population 
Description 
Full Analysis Population 
All participants enrolled and with at least one administration of 
IP, will be included in this study population. The Full Analysis 
Population will be used to analyze the primary efficacy and 
safety endpoints 
Note: Other populations may be defined in the SAP. 
9.4. 
Statistical Analyses 
The statistical analysis plan (SAP) will be finalized prior to database lock and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 


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section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. In case of a discrepancy, the SAP will supersede 
the protocol.  
9.4.1. General considerations 
A two-sided alpha of .05 will be used for statistical significance for all statistical tests. Given the 
small sample size and open-label nature of the study, no multiplicity adjustments will be made to 
control for family-wise type 1 error. A Last Observation Carried Forward (LOCF) method will 
be utilized to impute missing data where appropriate. 
9.4.2. 
Primary endpoint 
Data for the primary endpoint will be statistically analyzed via a within groups, repeated 
measures t-test, comparing change in subject’s global MFIQ scores from baseline to the final 4-
week treatment period (treatment month 3).   
9.4.3. 
 Secondary endpoint(s) 
Data for each of the secondary outcome measures will be statistically analyzed for within group 
changes via analysis of variance (ANOVA), dependent t-tests, or repeated measures chi-square 
(McNemar) tests as appropriate.   
9.4.4. 
Tertiary/exploratory endpoint(s) 
The Statistical Analysis Plan will describe any planned tertiary/exploratory analyses in greater 
detail. 
9.4.5. 
Other safety Analyses 
There will not be a formal statistical analysis for safety endpoints (adverse events, etc.); 
however, all adverse events will be summarized via tables and descriptive statistics as 
appropriate. 
9.5. 
Interim Analyses  
Not Applicable, i.e., there is not a planned interim analysis for this study. 
9.6. 
Data Monitoring Committee (DMC) 
Not Applicable, i.e., there is not a DMC for this study. 


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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable ICH Good Clinical Practice (GCP) Guidelines 
o Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
• 
Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
• 
The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study. 


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10.1.3. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. 
• 
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Health Insurance Portability and Accountability 
Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must also 
sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
• 
Participants who are rescreened are required to sign a new ICF. 
10.1.4. 
Data Protection 
• 
Participants will be assigned a unique identifier. Any participant records or datasets that 
are transferred outside of study site will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred. 
• 
The participant must be informed that his/her personal study-related data will be used 
by the study team in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for their 
data to be used as described in the informed consent  
• 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.5. 
Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, the reported trial data are accurate, complete, and verifiable, and the conduct of the 
trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonization cGCP), and with applicable regulatory requirement(s).  


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• Monitoring for this study will be performed by the Contract Research Organization 
(CRO).  
• Details of clinical site monitoring are documented in a Monitoring Plan (MP). The MP 
describes in detail who will conduct the monitoring, at what frequency monitoring will be 
done, at what level of detail monitoring will be performed, and the distribution of 
monitoring reports. 
10.1.6. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
• 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of participants are being protected; 
and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 2 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 


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records may be transferred to another location or party without written notification to 
the sponsor. 
10.1.7. 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• 
Data for this trial will be primarily collected in a web-based electronic data capture 
(EDC) REDCap platform.  The EDC access will be supplied by the sponsor with 
relevant training support to sites.  Sites will be responsible for training study subjects in 
the EDC system. All data specified should be captured by the site personnel or 
participants in the EDC system.  When possible, all eCRFs are to be completely filled 
out by personnel administering the study procedures in real-time at the time of the visit.  
All eCRFs that are completed in real-time at the time of the visit will be considered 
source documentation for this study. When allowed by the site’s IRB, any data entered 
on an eCRF which was not entered into REDCap in real-time at the time of the visit, or 
where such data originated from an external paper source document (e.g., signed 
Informed Consent Form (ICF) signature page, laboratory, procedure findings, etc.), will 
require paper source documents to be uploaded into the REDCap system to allow for 
source data verification monitoring.  When a site’s IRB does not allow for specific 
paper source documents to be uploaded into REDCap (e.g., the ICF signature pages, 
etc.), then those paper source documents will be reviewed during on-site monitor visits. 
• 
It is the investigator’s responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRF and confirmation the data is accurate, 
authentic, attributable, complete, and consistent.  The investigator or sub-investigator 
must sign the CRFs within the EDC system to attest the information contained with the 
CRF is true and causality of any safety information has been assessed.  All data must be 
reviewed and signed by the investigator or sub-investigator at the conclusion of the 
study for each subject.  The CRFs should not be made available in any form to third 
parties, without written permission from the sponsor. 


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10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. The first act of recruitment is the first site open and will be the study start date. 
 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up 
10.1.9. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 
• 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual site 
data. In this case, a coordinating investigator will be designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
 
• 
The tests detailed in Table 1 will be performed by the local laboratory. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
• 
Urine Pregnancy Testing  
Table 1: Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
White blood cell (WBC) 
count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cell (RBC) Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry1 
Blood urea nitrogen 
(BUN) 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
 
Glucose (nonfasting) 
Calcium 
Alkaline phosphatase 
 
Other Screening 
Tests 
 
The results of each test must be entered into the CRF. 
 
Investigators must document their review of each laboratory safety report. 
 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or 
SAE. 
 
 
 


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Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 


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A SAE is defined as any untoward medical occurrence that, at any dose: 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the investigator to send photocopies of the participant’s medical 
records in lieu of completion of the AE/SAE CRF page. 


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AE and SAE Recording 
• There may be instances when copies of medical records for certain cases are requested. 
In this case, all participant identifiers, with the exception of the participant number, 
will be redacted on the copies of the medical records before submission. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories:  
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 


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Assessment of Causality 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report. However, it is very important that 
the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested to elucidate 
the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• New or updated information will be recorded in the originally completed CRF. 
• The investigator will submit any updated SAE data within 24 hours of receipt of the 
information. 
10.3.4. 
Reporting of SAEs 
SAE Reporting to Sponsor and Medical Monitor via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to sponsor and medical monitor will be 
the electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the sponsor and medical monitor by telephone. 


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SAE Reporting to Sponsor and Medical Monitor via an Electronic Data Collection Tool 
• Contacts for SAE reporting can be found in the investigative site file. 
 
SAE Reporting to Sponsor and Medical Monitor via Paper CRF 
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the sponsor and medical monitor. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the investigative site file. 
 
 
 
 


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10.3.5. 
Reporting of Safety Data to the manufacturer (Amgen) 
The reporting of safety data to Amgen will comply with the ISS Safety Data Exchange 
Requirements and Research Agreement, to include the following: 
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 
 
 
 


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Device related adverse events: 
Safety Data 
Timeframe for submission to 
Amgen 
Send to 
Serious Adverse Device 
Effectc (SADE)  
Within 1 business day of Sponsor 
awareness  
Amgen Safety 
Adverse Device Effect 
(ADE)  
Not to exceed 15 calendar days of 
Sponsor awareness 
Amgen Safety 
Product Complaintd 
Immediately, not to exceed 1 
business day of Sponsor awareness 
Amgen Quality 
a Specific requirements are to be outlined in the Research Agreement. 
b Refer to local Safety representative (LSO) to clarify reporting requirements for the Amgen device per regulations in 
the country where the study is being conducted. 
c Adverse device effect is: any adverse event related to the use of a medical device. Adverse device effects include 
adverse events resulting from insufficient or inadequate instructions for use, adverse events resulting from any 
malfunction of the device, or adverse events resulting from use error or from intentional misuse of the device. 
d Product 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 
• 
User error (i.e, an act or omission of an act that results in a different combination product or medical device 
response than intended by the manufacturer or expected by the user, where the user attempted to use the 
combination product or medical device in good faith and experienced difficulty or deficiency administering 
the product). 
Reports of misuse of a combination product or medical device (i.e, the intentional and improper use of a combination 
product or medical device not in accordance with the authorized product information) are not considered Product 
Complaints. 
 
 


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Aggregate Safety Reports (as applicable): 
Safety Data 
Timeframe for submission to Amgen 
Send to 
Listing for Safety data 
reconciliationb 
Once per year and at the end of the study 
NASCR 
Manager 
Annual Safety Report 
(eg, EU Clinical Trial 
Directive DSUR and US IND 
Annual Report) 
 
Annually 
 
NASCR 
Manager 
Other aggregate analyses 
(any report containing Safety 
data generated during the 
course of the study) 
At the time of Sponsor submission to any 
body governing research conduct (eg. 
RA, IRB etc.) 
NASCR 
Manager 
Final (End of Study Report, 
including): 
• Unblinding data for blinded 
studies 
• Reports of unauthorized use 
of a marketed product 
 
At the time of Sponsor submission to any 
body governing research conduct (eg. 
RA, IRB etc.) but no later than 1 calendar 
year of study completion 
 
NASCR 
Manager 
a Specific requirements are to be outlined in the Research Agreement. 
b Listing for reconciliation should include all ICSRs submitted to Amgen Safety per contract (i.e. for studies in Table 1 
listing should include ADRs, SADRs, Other Safety Findings and serious and non-serious adverse device effects ; for 
studies in Table 2 listing should contain SUSARs, pregnancy and lactation exposure (and any associated 
reports/outcomes) and serious and non-serious adverse device effects; studies in table 3 do not require reconciliation). 
 
 


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Page 48 of 55 
 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
 
Definitions of Woman of Childbearing Potential (WOCBP), sterile and postmenopausal women, 
male contraception, and highly effective and acceptable birth control methods are to be 
determined based on investigator’s judgment; however, women in the following categories are 
not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should be 
considered. 
 
Contraception Guidance: 
Collection of Pregnancy Information 
Male participants with partners who become pregnant 


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• The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive Aimovog (erenumab-aooe). 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
Female Participants who become pregnant 
• 
The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant's pregnancy.  
• 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) 
or indication for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE.  
• 
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring 
at >22 weeks gestational age) is always considered to be an SAE and will be reported as 
such.  
• 
Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in Section 
8.3.4. While the investigator is not obligated to actively seek this information in former 
study participants, he or she may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention or be withdrawn from the study.  


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Page 50 of 55 
 
10.5. 
International Classification of Headache Disorders, 3rd edition: 
Migraine with and without aura 
 
1.1 Migraine without aura 
Description: Recurrent headache disorder manifesting in attacks lasting 4–72 hours Typical 
characteristics of the headache are unilateral location, pulsating quality, moderate or severe 
intensity, aggravation by routine physical activity and association with nausea and/or 
photophobia and phonophobia. 
 
Diagnostic criteria: 
A. At least five attacks fulfilling criteria B–D 
B. Headache attacks lasting 4–72 hours (when untreated or unsuccessfully treated) 
C. Headache has at least two of the following four characteristics: 
1. unilateral location 
2. pulsating quality 
3. moderate or severe pain intensity 
4. aggravation by or causing avoidance of routine physical activity (e.g. walking or 
climbing stairs) 
D. During headache at least one of the following: 
1. nausea and/or vomiting 
2. photophobia and phonophobia 
E. Not better accounted for by another ICHD-3 diagnosis. 
 
 


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1.2 Migraine with aura 
 
Description: Recurrent attacks, lasting minutes, of unilateral fully reversible visual, sensory or 
other central nervous system symptoms that usually develop gradually and are usually followed 
by headache and associated migraine symptoms. 
 
Diagnostic criteria: 
 
A. At least two attacks fulfilling criteria B and C 
B. One or more of the following fully reversible aura symptoms: 
1. visual 
2. sensory 
3. speech and/or language 
4. motor 
5. brainstem 
6. retinal 
C. At least three of the following six characteristics: 
1. at least one aura symptom spreads gradually over ≥5 minutes 
2. two or more aura symptoms occur in succession 
3. each individual aura symptom lasts 5–60 minutes 
4. at least one aura symptom is unilateral 
5. at least one aura symptom is positive 
6. the aura is accompanied, or followed within 60 minutes, by headache 
D. Not better accounted for by another ICHD-3 diagnosis. 
 


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Page 52 of 55 
 
10.6. 
Appendix 9: Abbreviations 
 
Abbreviation or Term 
Definition/Explanation 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ANOVA 
Analysis of variance 
BMWS 
Brief Measure of Worry Severity 
CFR 
Code of Federal Regulations 
CGRP 
Calcitonin gene-related peptide 
CIOMS 
Council for International Organizations of Medical Sciences 
CMP 
Comprehensive metabolic panel 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case report form 
CRO 
Contract Research Organization 
DHD 
Daily headache diary 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiography 
EDC 
Electronic Data Capture 
FAMS 
Functional Assessment of Migraine Scale 
FSH 
Follicle stimulation hormone 
GCP 
Good Clinical Practice 
GSE-SF 
General Self-Efficacy Short Form 
HIPAA 
Health Insurance Portability and Accountability Act 


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Page 53 of 55 
 
Abbreviation or Term 
Definition/Explanation 
HIT-6 
Headache Impact Test 
HRT 
Hormonal replacement therapy 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
ICHD-III 
International Classification of Headache Disorders 3rd edition 
IEC 
Independent Ethics Committee(s) 
IRB 
Institutional Review Board(s) 
LOCF 
Last observation carried forward 
MFIQ 
Migraine Functional Impact Questionnaire 
MIBS-4 
Migraine Interictal Burden Scale 
MOH 
Medication Overuse Headache 
MP 
Monitoring Plan 
MSQ 
Migraine-Specific Quality of Life Questionnaire 
PHQ-9 
9-Item Depression Patient Health Questionnaire 
PRO 
Patient reported outcome 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SDSF 
Neuro-QoL Sleep Disturbance Short Form 
SoA 
Schedule of Activities 
SUSAR 
Suspected unexpected serious adverse reactions 


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Page 54 of 55 
 
Abbreviation or Term 
Definition/Explanation 
WOCB 
Women of Childbearing Potential 
WPAI-M 
Work Productivity and Activity Impairment- Migraine 


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Page 55 of 55 
 
11. 
References 
 
1. Peres, M. F. P., Mercante, J. P. P., Guendler, V. Z., Corchs, F., Bernik, M. A., Zukerman, E., 
& Silberstein, S. D. (2007). Cephalalgiaphobia: a possible specific phobia of illness. The 
Journal of Headache and Pain, 8, 56-59. https://doi.org/10.1007/s10194-007-0361-3 
2. Mannix, S., Skalicky, A., Buse, D. C., Desai, P., Sapra, S. Ortmeier, B., . . . Hareendran, A. 
(2016). Measuring the impact of migraine for evaluating outcomes of preventive treatments 
for migraine headaches.  Health and Quality of Life Outcomes, 14(143). 
https://doi.org/10.1186/s12955-016-0542-3  
3. Lipton, R. B., Tepper, S. J., Reuter, U., Silberstein, S., Stewart, W. F., Nilsen, J., . . . Lenz, R. 
(2019). Erenumab in chronic migraine: patient-reported outcomes in a randomized double-
blind study. Neurology, 92(19), e2250-e2260. 
https://doi.org/10.1212/WNL.0000000000007452  
4. Kawata, A.K., Hareendran,A., Shaffer, S., Mannix, S., Thach, A., Desai, P., . . . Buse, D. C. 
(2019). Evaluating the psychometric properties of the Migraine Functional Impact 
Questionnaire (MFIQ). Headache, 59(8), 1253-1269. https://doi.org/10.1111/head.13569 
5. Open Science Collaboration. (2015). Estimating the reproducibility of psychological science. 
Science, 349(6241), aac4716. https://doi.org/10.1126/science.aac4716 
 
 
 
 
 

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Page 1 of 50 
Title Page 
Protocol Title: 
A Multicenter, Open Label Study Assessing the Efficacy of 
erenumab on Functional Impact of Migraine 
Protocol Number: 
 
19-001AM 
Amendment Number: 
N/A 
Investigational Product: 
140 mg erenumab-aooe 
Study Phase:  
 
Phase 4 
Sponsor Name: 
 
Merle L. Diamond, MD 
Legal Registered Address:  Diamond Headache Clinic 
1460 North Halsted St 
Suite 501 
Chicago, IL 60642 
Regulatory Agency Identifier Number(s): 
 
ClinicalTrials.gov ID: 
NCT04465357 
 
 
 
 
 


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Page 2 of 50 
Table of Contents 
Title Page ........................................................................................................................................1 
Table of Contents ...........................................................................................................................2 
Version History ..............................................................................................................................4 
1. 
Introduction .....................................................................................................................5 
1.1. 
Objectives and Endpoints .................................................................................................5 
1.2. 
Study Design .....................................................................................................................6 
1.2.1. 
Schedule of Activities (SoA) ............................................................................................9 
2. 
Statistical Hypotheses ...................................................................................................11 
2.1. 
Multiplicity Adjustment ..................................................................................................11 
3. 
Analysis Sets ..................................................................................................................12 
4. 
Statistical Analyses .......................................................................................................13 
4.1. 
General Considerations ...................................................................................................13 
4.1.1. 
Missing Data ...................................................................................................................13 
4.2. 
Primary Endpoint Analysis .............................................................................................13 
4.2.1. 
Definition of Endpoint ....................................................................................................14 
4.2.2. 
Main Analytical Approach ..............................................................................................14 
4.3. 
Secondary Endpoint Analysis .........................................................................................14 
4.3.1. 
Change in Migraine Functional Impact Questionnaire (MFIQ) 
Domain Scores from Baseline to the Final 4-Week Treatment 
Period ..............................................................................................................................14 
4.3.2. 
Change in Migraine Functional Impact Questionnaire (MFIQ) 
Global and Domain Scores from Baseline to Each 4-Week 
Treatment Period .............................................................................................................15 
4.3.3. 
Change in Migraine Interictal Burden Scale (MIBS-4) Scores 
from Baseline to Each 4-Week Treatment Period ..........................................................15 
4.3.4. 
Change in Migraine Days from Baseline to Each 4-Week 
Treatment Period .............................................................................................................16 
4.3.5. 
Change in Work Productivity and Activity Impairment – 
Migraine (WPAI-M) Scores from Baseline to Each 4-Week 
Treatment Period .............................................................................................................18 
4.3.6. 
Change in Neuro-QoL Sleep Disturbance Short Form (SDSF) 
Scores from Baseline to Each 4-Week Treatment Period ...............................................19 
4.3.7. 
Change in General Self-Efficacy Short Form 4a (GSE-SF) 
Scores from Baseline to Each 4-Week Treatment Period ...............................................19 
4.3.8. 
Change in Brief Measure of Worry Severity (BMWS) Scores 
from Baseline to Each 4-Week Treatment Period ..........................................................20 
4.4. 
Exploratory Endpoint Analysis .......................................................................................20 
4.4.1. 
Change in Activity and Sleep from Baseline to Each 4-Week 
Treatment Period .............................................................................................................20 


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4.4.2. 
Change in Functional Assessment of Migraine Scale (FAMS) 
Total Scores from Baseline to Each 4-Week Treatment Period .....................................21 
4.4.3. 
Correlation Between Functional Impact of Migraine Scale 
(FAMS) Total and Domain Subscale Scores and Other Migraine 
Related Patient Reported Outcome (PRO) Measures .....................................................22 
4.5. 
Safety Analyses...............................................................................................................22 
4.5.1. 
Adverse Events (AEs) .....................................................................................................22 
4.5.2. 
Additional Safety Assessments .......................................................................................23 
4.6. 
Other Analyses ................................................................................................................25 
4.7. 
Interim Analysis ..............................................................................................................25 
4.8. 
Changes to Protocol-planned Analyses ..........................................................................26 
5. 
Sample Size Determination ..........................................................................................27 
6. 
Supporting Documentation ..........................................................................................28 
6.1. 
Appendix 1: List of Abbreviations .................................................................................28 
6.2. 
Appendix 2: International Classification of Headache Disorders, 
3rd edition: Migraine with and without aura ...................................................................30 
6.2.1. 
Migraine without aura .....................................................................................................30 
6.2.2. 
Migraine with aura ..........................................................................................................31 
6.3. 
Appendix 3: Patient Reported Outcomes Scoring Manuals ...........................................32 
6.3.1. 
Migraine Functional Impact Questionnaire (MFIQ) .......................................................32 
6.3.2. 
Migraine Interictal Burden Scale (MIBS-4) ...................................................................34 
6.3.3. 
Work Productivity and Activity Impairment- Migraine (WPAI-
M) ....................................................................................................................................35 
6.3.4. 
Neuro-QoL Sleep Disturbance Short Form (SDSF) .......................................................37 
6.3.5. 
General Self-Efficacy Short Form (GSE-SF) .................................................................38 
6.3.6. 
Brief Measure of Worry Severity (BMWS) ....................................................................40 
6.3.7. 
Functional Assessment of Migraine Scale (FAMS) .......................................................41 
6.4. 
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................44 
6.4.1. 
Definition of AE .............................................................................................................44 
6.4.2. 
Definition of SAE ...........................................................................................................45 
6.4.3. 
Recording and Follow-Up of AE and/or SAE ................................................................46 
6.4.4. 
Reporting of SAEs ..........................................................................................................48 
7. 
References ......................................................................................................................50 
 
 


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Page 4 of 50 
Version History 
This statistical analysis plan (SAP) for Study 19-001AM is based on the protocol dated 16-Sep-
2020.  
 
SAP Version 
Date 
Change 
Rationale 
1 
13-Oct-2021 
Not applicable 
Original version 
2 
23-Mar-2022 
Revised Section 
4.1.1 Missing 
Data 
Clarification of how to handle missing data 


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1. 
Introduction 
1.1. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the efficacy of erenumab-aooe on the 
overall functional impact of migraine. 
Change in Migraine Functional Impact 
Questionnaire (MFIQ) overall impact on usual 
activities item score from baseline to the final 4-
week treatment period within subjects treated with 
erenumab-aooe. 
Secondary 
To evaluate the efficacy of erenumab-aooe on 
specific aspects of the functional impact of 
migraine 
Change in Migraine Functional Impact 
Questionnaire (MFIQ) domain scores from 
baseline to the final 4-week treatment period 
within subjects treated with erenumab-aooe: 
• 
Impact on physical functioning 
• 
Impact on usual activities 
• 
Impact on emotional functioning 
• 
Impact on social functioning 
To evaluate the efficacy of erenumab-aooe on the 
following parameters during each 4-week 
treatment period: 
Change from baseline to each 4-week treatment 
month within subjects treated with erenumab-aooe 
on the following: 
• 
Functional impact of migraine 
Global Migraine Functional Impact Questionnaire 
(MFIQ) scores: 
• 
Overall impact on usual activities 
• 
Impact on physical functioning 
• 
Impact on usual activities 
• 
Impact on emotional functioning 
• 
Impact on social functioning 
• 
Migraine interictal burden 
• 
Migraine interictal burden scale (MIBS-4) 
scores 
• 
Migraine days 
• 
Number of migraine days 
• 
Work Productivity and Activity 
Impairment 
• 
Work Productivity and Activity 
Impairment- Migraine (WPAI-M) scores 
• 
Sleep disturbance 
• 
Neuro-QoL Sleep Disturbance Short 
Form (SDSF) scores 
• 
Self-Efficacy 
• 
General Self-Efficacy Short Form (GSE-
SF) scores 


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Objectives 
Endpoints 
• 
Severity of worry 
• 
Brief Measure of Worry Severity 
(BMWS) scores 
Exploratory 
To evaluate the efficacy of erenumab on activity 
and sleep. 
Change from baseline to each 4-week treatment 
month within subjects treated with erenumab-aooe 
on activity and sleep measured though a wearable 
device. 
To evaluate the efficacy of erenumab on 
functional impact of migraine. 
Change from baseline to each 4-week treatment 
month within subjects treated with erenumab-aooe 
on Functional Assessment of Migraine Scale 
(FAMS) scores. 
To evaluate the correlation between the 
Functional Assessment of Migraine Scale 
(FAMS) and other migraine related Patient 
Reported Outcome (PRO) measures. 
Correlation between Functional Assessment of 
Migraine Scale (FAMS) and the following 
migraine related Patient Reported Outcome (PRO) 
measures: 
• 
Global Migraine Functional Impact 
Questionnaire (MFIQ) 
• 
Migraine interictal burden scale (MIBS-4) 
• 
Work Productivity and Activity 
Impairment- Migraine (WPAI-M) 
• 
Neuro-QoL Sleep Disturbance Short 
Form (SDSF) 
• 
General Self-Efficacy Short Form (GSE-
SF) 
• 
Brief Measure of Worry Severity 
(BMWS) 
 
 
Safety 
To evaluate the safety and tolerability of 
participants treated with erenumab-aooe. 
Safety and tolerability of erenumab-aooe in study 
participants via collection of adverse events and 
safety evaluations. 
 
1.2. 
Study Design 
This is a multicenter, open label study assessing the interictal impact of erenumab-aooe in 
participants with migraine. The study population will consist of 54 participants 18 to 65 years 
old, with at least 4 and up to 20 migraine days per month (inclusive) following ICHD-III criteria 
for migraine with or without aura. 


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At Visit 1, the participant will sign the informed consent indicating they are willing to participate 
in the study and will provide basic demographic information, have a comprehensive review of 
their medical history and prior and concomitant medications. A physical and neurological 
examination (including vital signs) will be performed as well as a 12-lead Electrocardiography 
(ECG), screening CMP labs, and the PHQ-9 will be completed. Women of childbearing potential 
(WOCB) will complete a urine pregnancy test. All participants will complete the MFIQ 
questionnaire. Inclusion and Exclusion criteria will also be reviewed. Participants who meet the 
study criteria will be dispensed the activity tracker and its associated phone application 
instructions, as well as their unique Daily Headache Diary (DHD) URL and its instructions. 
Participants will then enter into a 28-day run-in period.  During the 28-day run-in period, all 
participants will be monitored through the use of electronic Daily Headache Diary (DHD) to 
ensure they continue to meet all inclusion criteria, and none of the exclusion criteria.   During 
this run-in period, participants will continue treating their migraines and other defined conditions 
with their usual treatment providing it has been stable for a minimum of 3 months. Daily 
electronic diaries will be used to assess symptoms and treatment response throughout the run-in 
period. 
 
Visit 2 will take place 28 to 33 days following Visit 1. Those participants who (1) continue to 
meet eligibility criteria (2) experienced 4-20 migraine days that meet ICHD-III criteria for 
migraine and (3) have completed at least 23/28 diary days will be eligible to be enrolled into the 
study. At this visit a physical examination (including vital signs) will be performed, WOCB will 
complete a urine pregnancy test, and all participants will complete the PHQ-9. Medical history 
and/or adverse events and concomitant medications will be reviewed and updated as needed. 
Participant’s DHD will be reviewed for compliance, and participants will complete the following 
questionnaires: 
• MFIQ 
• MIBS-4 
• WPAI-M 
• SDSF 
• GSE-SF 
• BMWS 
• FAMS 
Finally, all eligible participants will receive an injection of 140 mg erenumab-aooe. Participants 
will continue completing diary headache diaries for the remainder of the trial. 
 
Visits 3-5 will take place on days 29 (+/-3d), 57 (+/-3d), and 85 (+/-3d), following Visit 2.  At 
each visit: a physical examination (including vital signs) will be performed, WOCB will 
complete a urine pregnancy test, and all participants will complete the PHQ-9. Medical history 


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Page 8 of 50 
and/or adverse events and concomitant medications will be reviewed and updated as needed. 
Participant’s DHD will be reviewed for compliance, and participants will complete the following 
questionnaires: 
• MFIQ 
• MIBS-4 
• WPAI-M 
• SDSF 
• GSE-SF 
• BMWS 
• FAMS 
Finally, all eligible participants will receive an injection of 140 mg erenumab-aooe. Visit 5 (End 
of Study) will not include injections but will include comprehensive metabolic panel (CMP) 
laboratory.


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1.2.1. 
Schedule of Activities (SoA) 
Procedure 
Screening 
Treatment 
Early 
Discontinuation 
Visit 1  
 
Day -33 to Day -28 
Visit 2 
(Enrollment) 
Day 1 
Visit 3 
 
Day 29 
± 3 
Visit 4 
 
Day 57 
± 3 
Visit 5 
 
Day 85 
± 3 
 
Informed consent 
X 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
Demography 
X 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
Neurological examination 
X 
 
 
 
 
 
Medical history 
(includes migraine history and substance usage) 
X 
 
 
 
 
 
Prior and concomitant medications history 
X 
 
 
 
 
 
Urine pregnancy test 
(WOCBP only) 
X 
X 
X 
X 
X 
X 
Laboratory assessments 
(CMP)  
X 
 
 
 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
PHQ-9 
X 
X 
X 
X 
X 
X 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
Dispense activity tracker 
X 
 
 
 
 
 
Dispense diary URL and instructions 
X 
 
 
 
 
 


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Page 10 of 50 
Procedure 
Screening 
Treatment 
Early 
Discontinuation 
Visit 1  
 
Day -33 to Day -28 
Visit 2 
(Enrollment) 
Day 1 
Visit 3 
 
Day 29 
± 3 
Visit 4 
 
Day 57 
± 3 
Visit 5 
 
Day 85 
± 3 
 
Migraine Functional Impact Questionnaire 
(MFIQ) 
X 
X 
X 
X 
X 
X 
MIBS-4 
 
X 
X 
X 
X 
X 
Work Productivity and Activity Impairment- 
Migraine (WPAI-M) 
 
X 
X 
X 
X 
X 
Neuro-QoL Sleep Disturbance Short Form 
(SDSF) 
 
X 
X 
X 
X 
X 
General Self-Efficacy Short Form (GSE-SF) 
 
X 
X 
X 
X 
X 
Brief Measure of Worry Severity (BMWS) 
 
X 
X 
X 
X 
X 
Functional Assessment of Migraine Scale 
(FAMS) 
 
X 
X 
X 
X 
X 
AE review 
 
X 
X 
X 
X 
X 
SAE review 
 
X 
X 
X 
X 
X 
Diary review 
 
X 
X 
X 
X 
X 
Concomitant medication review 
 
X 
X 
X 
X 
X 
IP injection 
 
X 
X 
X 
 
 


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2. 
Statistical Hypotheses 
The null hypothesis of this study is that participants’ global Migraine Functional Impact 
Questionnaire (MFIQ) overall impact on usual activities item score will not be statistically 
different from baseline (Visit 2) to end of study (Visit 5) after 3 months dose of 140 mg 
erenumab-aooe. 
2.1. 
Multiplicity Adjustment 
Given the small sample size and open-label nature of the study, no multiplicity adjustments will 
be made to control for family-wise type 1 error. 


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Page 12 of 50 
3. 
Analysis Sets 
Participant Analysis Set 
Description 
Full  
• 
All participants enrolled and with at least one administration of IP, 
will be included in this analysis set. The Full Analysis set will be 
used to analyze the efficacy and safety endpoints. 


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4. 
Statistical Analyses 
4.1. 
General Considerations 
• An alpha of .05 will be used for statistical significance for all statistical tests.  
• All statistically significant multivariate analyses will be followed by univariate post-hoc 
tests. 
• Univariate post-hoc tests will utilize appropriate multiple comparison adjustments 
(Bonferroni, Tukey, etc.) as needed.  
• If a variable name (e.g., from REDCap Cloud or Fitabase) is directly used in this 
document, it will appear in this format: [VARIABLE] 
• 95% Confidence Intervals will be used when necessary. 
4.1.1. 
Missing Data  
Missing data for full analysis population participants will be imputed as follows: 
• Missing values on questionnaire items will be handled according to the questionnaire’s 
scoring manual. When no guidance is specified in a questionnaire scoring manual, 
missing items will be left null and the score and/or sub-score will be imputed using a last 
observation carried forward (LOCF) method. This type of imputation replaces the 
missing value with the last observation value obtained for the participant. 
• Missing DHD entries (Monthly Migraine Days) will be imputed as follows: 
o < 14 DHDs completed: Participant’s average MMDs for that study period will be 
replaced with their last study period’s MMD using the LOCF method.  
o ≥ 14 DHDs completed: Participant’s average MMDs for that study period will be 
imputed based on the data available in that study period and prorated to 28 days. 
• Missing Garmin data (Steps and Sleep) will be imputed as follows: 
o < 14 days synced: Participant’s average steps and/or sleep for that study period 
will be replaced with their last study period’s steps and/or sleep using the LOCF 
method.  
o ≥ 14 days synced: Participant’s steps and/or sleep for the missing day will be 
imputed using the participant’s mean steps and/or sleep for the data available in 
that study period. 
 
4.2. 
Primary Endpoint Analysis 
Data for the primary endpoint will be statistically analyzed via a within groups, repeated 
measures t-test, comparing change in participant's MFIQ Global Item Overall Impact on Usual 
Activities (item # 16) scores from baseline (Visit 2) to the final 4-week treatment period (Visit 
5).   


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4.2.1. 
Definition of Endpoint 
The MFIQ is a 26-item self-report questionnaire. It is designed to measure the impact of 
migraine on physical, social, and emotional functioning over 4 domains: Physical Function (PF), 
Usual Activities (UA), Social Function (SF), and Emotional Function (EF). A single global 
item, Overall Impact on Usual Activities, assessing overall difficulty doing everyday 
activities is scored separately. Final transformed scores range from 0-100, with higher scores 
indicating more impact on the participant. For this endpoint we will be measuring changes in 
participant’s response on the single MFIQ Global Item Overall Impact on Usual Activities (item 
# 16). The item’s transformed score can range from 0-100, with higher scores indicating more 
impact on the participant. 
4.2.2. 
Main Analytical Approach 
The MFIQ Global Item Overall Impact on Usual Activities is defined as item #16 on the MFIQ. 
Only data from those participants who meet criteria for the Full Analysis set will be analyzed. 
Missing data will be imputed as outlined in the Migraine Functional Impact Questionnaire User 
Manual and Scoring Guide Version 1.0 (Appendix 6.3.1). The scores used to measure the 
primary endpoint will be taken using the participant’s self-reported data entered into the MFIQs 
administered at Visit 2 and Visit 5 (or Early Discontinuation). The null hypothesis of this study 
is that participants’ global MFIQ overall impact on usual activities item score will not be 
statistically different from baseline (Visit 2) to End of Study (Visit 5 or Early Discontinuation) 
after 3 months dose of 140 mg erenumab-aooe. 
4.3. 
Secondary Endpoint Analysis 
Data for each of the secondary outcome measures will be statistically analyzed for within group 
changes using repeated measures t-tests and/or repeated measures analysis of variance 
(ANOVA) with follow-up univariate tests as appropriate.   
4.3.1. 
Change in Migraine Functional Impact Questionnaire (MFIQ) Domain Scores 
from Baseline to the Final 4-Week Treatment Period 
4.3.1.1. 
Definition of Endpoint 
The MFIQ is a 26-item self-report questionnaire. It is designed to measure the impact of 
migraine on physical, social, and emotional functioning over 5 domains: Physical Function (PF), 
Usual Activities (UA), Overall impact on Usual Activities, Social Function (SF), and Emotional 
Function (EF). Final transformed scores range from 0-100, with higher scores indicating more 
impact on the participant. The specific domain scores to be analyzed for this endpoint include 
impact on Physical Functioning (PF), impact on Usual Activities (UA), impact on Emotional 
Functioning (EF), and impact on Social Functioning (SF). 


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4.3.1.2. 
Main Analytical Approach 
MFIQ domain scores will be derived as outlined in the Migraine Functional Impact 
Questionnaire User Manual and Scoring Guide Version 1.0 (Appendix 6.3.1). Only data from 
those participants who meet criteria for the Full Analysis set will be analyzed. Missing data will 
be imputed as outlined in the Migraine Functional Impact Questionnaire User Manual and 
Scoring Guide Version 1.0 (Appendix 6.3.1). Data will be statistically analyzed via within 
groups, repeated measures t-tests, comparing change in participant’s specific MFIQ domain 
scores from baseline (Visit 2) to End of Study (Visit 5 or Early Discontinuation).  
4.3.2. 
Change in Migraine Functional Impact Questionnaire (MFIQ) Global and 
Domain Scores from Baseline to Each 4-Week Treatment Period 
4.3.2.1. 
Definition of Endpoints 
The MFIQ is a 26-item self-report questionnaire. It is designed to measure the impact of 
migraine on physical, social, and emotional functioning over 5 domains: Physical Function (PF), 
Usual Activities (UA), Overall impact on Usual Activities, Social Function (SF), and Emotional 
Function (EF). Final transformed scores range from 0-100, with higher scores indicating more 
impact on the participant. For this endpoint we will be measuring participant’s response on the 
single MFIQ Global Item Overall Impact on Usual Activities (item # 16), as well as impact on 
the Physical Functioning (PF), Usual Activities (UA), Emotional Functioning (EF), and Social 
Functioning (SF) domains. 
4.3.2.2. 
Main Analytical Approach 
Global as well as the specific MFIQ domain scores will be derived as outlined in the Migraine 
Functional Impact Questionnaire User Manual and Scoring Guide Version 1.0 (Appendix 6.3.1).  
Only data from those participants who meet criteria for the Full Analysis set will be analyzed. 
Missing data will be imputed as outlined in the Migraine Functional Impact Questionnaire User 
Manual and Scoring Guide Version 1.0 (Appendix 6.3.1). Data will be analyzed via a repeated 
measures ANOVA comparing change in participant’s global and specific MFIQ domain scores 
from baseline (Visit 2) to each of the 4-week treatment periods (Visit 3, 4, and 5). Significant 
changes will be followed up using within groups, repeated measures t-tests as needed. 
4.3.3. 
Change in Migraine Interictal Burden Scale (MIBS-4) Scores from Baseline to 
Each 4-Week Treatment Period 
4.3.3.1. 
Definition of Endpoint 
The MIBS-4 is a 4-item, self-administered questionnaire which measures interictal migraine-
related burden in 4 domains: impairment in work or school, impairment in family and social life, 
difficulty making plans or commitments, and emotional/affective and cognitive distress. The 
MIBS-4 total score is derived from the summation of all four questions on each MIBS-4. Answer 
options for the MIBS-4 are coded as: 0 = Don’t know/NA, 0 = Never, 1 = Rarely, 2 = Some of the 
time, 3 = Much of the time, 4 = Most or all of the time. The range of total MIBS-4 score for each 


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Page 16 of 50 
time point is 0 to 12 (with higher scores indicating severe interictal burden of migraine on the 
participant’s daily activities).  
4.3.3.2. 
Main Analytical Approach 
See Appendix 6.3.2 for MIBS-4 scoring information. Only data from those participants who 
meet criteria for the Full Analysis set will be analyzed. Data for this secondary endpoint will be 
analyzed via a repeated measures ANOVA comparing changes in participant’s Migraine 
Interictal Burden Scale (MIBS-4) scores from baseline (Visit 2) to each of the 4-week treatment 
periods (Visit 3, 4, and 5). Significant changes will be followed up using within groups, repeated 
measures t-tests as needed.  
4.3.4. 
Change in Migraine Days from Baseline to Each 4-Week Treatment Period 
4.3.4.1. 
Definition of Endpoint 
Headache and Migraine data will be recorded by the participants into an electronic daily 
headache diary (DHD) throughout the study. The DHDs are web-based and can be completed on 
any internet enabled device using the participant’s unique log in credentials. Site personnel will 
be responsible for instructing participants on the requirement for timely and daily completion of 
the DHD.  
Clinic visits are to occur every 28 days throughout the study; however, in practice, there may or 
may not be an exact 28-day duration between two consecutive visits. As such, participants may 
have more or less than 28 diary entries between two consecutive visits. To account for this, the 
following will be utilized: 
• 
Baseline: eDiary information entered during the last 28 continuous days of the run-in 
period will serve as the “baseline” for calculating change from baseline. For example, if a 
participant’s run-in period is 31 days long, and the participant entered eDiary information 
for all 31 days, the last 28 days (leading up to first drug administration) will be used to 
calculate and derive endpoint variables, with the first three eDiary entries (days 1, 2, and 
3) being discarded from the analysis datasets.  
• 
Treatment Months: If a participant enters more than 28 days of eDiary information 
between clinic visits during the treatment phase of the study, the first 28 continuous day’s 
eDiary entries for each period/month will be used for analyses. For example, if a 
participant has a duration of 31 days between Visit 2 and Visit 3, and the participant 
entered eDiary information for all 31 days, the first 28 days (following Visit 2) of eDiary 
information will be used to calculate and derive endpoint variables, with the last three 
eDiary entries (days 29, 30, and 31) being discarded from the analysis datasets. 
Migraine headache days are defined in this study as an attack within a calendar day (00:00 to 
23:59) that meet at least one of the two following criteria: 
1. A headache attack that includes all of the following criteria: 


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A. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated) 
B. Headache has at least two of the following four characteristics: 
1. unilateral location 
2. pulsating quality 
3. moderate or severe pain intensity 
4. aggravation by or causing avoidance of routine physical activity (e.g., 
walking or climbing stairs) 
C. During headache at least one of the following: 
1. nausea and/or vomiting 
2. photophobia and phonophobia 
2. A headache attack of any duration with relief (defined as a “Yes” answer to the 
eDiary question “Did you get relief from taking the above medication(s) yesterday?” 
[HD_RLFYN]) from the following migraine-specific acute medication(s): 
• Advil (Ibuprofen) 
• Aleve (Naproxen) 
• Amerge (Naratriptan) 
• Axert (Almotriptan) 
• Butabitol 
• Cafergot (Ergotamine Tartrate/Caffeine) 
• Cambia (Diclofenac Potassium) 
• Cefaly 
• DHE 45 (Dihydroergotamine) 
• Ergomar (Ergotamine Tartrate Sublingual Tablets) 
• Excedrin Migraine 
• Fioricet 
• Fiorinal 
• Frova (Frovatriptan) 
• gammaCore Sapphire 
• Imitrex (Sumatriptan) 
• Indocin (Indomethacin) 
• Maxalt (Rizatriptan) 
• Midrin (Isometheptene Mucate, Dichloralphenazone and Acetaminophen) 
• Migerot (Ergotamine Tartrate/Caffeine Suppository) 
• Migranol 
• Migril (Ergotamine, Cylizine, and Caffeine) 
• Namenda (memantine) 
• Onzetra (Sumatriptan Nasal Powder) 
• Prednisone 


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Page 18 of 50 
• Relpax (Electriptan) 
• Reyvow (Lasmiditan) 
• Sumavel (Sumatriptan Needleless Injection) 
• Tivorbex (Indomethacin) 
• Treximet (Sumatriptan/Naproxen) 
• Tylenol (Acetaminophen) 
• Zembrace (Sumatriptan injection) 
• Zomig (Zolmitriptan) 
• Zorvolex (Diclofenac) 
4.3.4.2. 
Main Analytical Approach 
Only data from those participants who meet criteria for the Full Analysis set will be analyzed. 
Participants will be asked to record diary data each day for the previous day (24-hour period). If 
a participant does not experience a headache in the previous 24-hour period, the diary must still 
be completed as instructed. Participant’s diaries may vary day to day based on their responses. 
All participants should have at least 80% compliance with diary completion throughout the 
length of the study. Participants will record headache severity, symptoms, use of acute 
medications, as well as additional assessments as required. 
This frequency of migraine days will be derived from the participants’ eDiary entries. The 
eDiary entries are based on the count of days with migraine headaches for each 28-day time 
points (baseline, treatment month 1, treatment month 2, treatment month 3). Participants with 
less than 80% diary compliance for any study period (defined as <23 completed eDiaries during 
that study period/month) will be considered Missing Data for that entire study period/month. The 
number of migraine days for these study periods/months will be imputed using the LOCF 
method. Data for this secondary endpoint will be analyzed via a repeated measures ANOVA 
comparing participant’s mean change in the number of migraine days from baseline to each of 
the 4-week treatment periods. Significant changes will be followed up using within groups, 
repeated measures t-tests as needed. 
4.3.5. 
Change in Work Productivity and Activity Impairment – Migraine (WPAI-M) 
Scores from Baseline to Each 4-Week Treatment Period 
4.3.5.1. 
Definition of Endpoint  
The Work Productivity and Activity Impairment-Migraine (WPAI-M) is a 6-item self-
administered questionnaire that measures work productivity and the amount of time missed from 
work due to migraine. Scores are based on a percentage, so the range of scores is 0-100%, with 
higher scores indicating greater impairment and less productivity.  


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4.3.5.2. 
Main Analytical Approach 
See Appendix 6.3.3 for WPAI-M scoring information. Only data from those participants who 
meet criteria for the Full Analysis set will be analyzed. Data for this secondary endpoint will be 
analyzed via a repeated measures ANOVA comparing changes in participant’s total WPAI-M 
scores from baseline (Visit 2) to each of the 4-week treatment periods (Visit 3, 4, and 5). 
Significant changes will be followed up using within groups, repeated measures t-tests as 
needed. 
4.3.6. 
Change in Neuro-QoL Sleep Disturbance Short Form (SDSF) Scores from 
Baseline to Each 4-Week Treatment Period 
4.3.6.1. 
Definition of Endpoint  
The Neuro-QoL Sleep Disturbance Short Form (SDSF) is an 8-item, self-administered 
questionnaire which measures quality of sleep including difficulties and perception of sleep 
satisfaction. Possible scores range from 8 to 40, with higher scores indicating worse sleep habits. 
4.3.6.2. 
Main Analytical Approach 
See Appendix 6.3.4 for SDSF scoring information. The variable used to measure the secondary 
efficacy endpoint of change in Neuro-QoL Sleep Disturbance Short Form (SDSF) between 
treatment month scores will be calculated using the scales online scoring service 
(https://www.assessmentcenter.net). By using the online scoring service participants raw scores 
for this endpoint will be calculated into T-Scores which will allow for a standardized comparison 
between the treatment months. Only data from those participants who meet criteria for the Full 
Analysis set will be analyzed. Data for this secondary endpoint will be analyzed via a repeated 
measures ANOVA, comparing mean changes in participant’s total SDSF scores from baseline 
(Visit 2) to each of the 4-week treatment periods (Visit 3, 4, and 5). Significant changes will be 
followed up using within groups, repeated measures t-tests as needed. 
4.3.7. 
Change in General Self-Efficacy Short Form 4a (GSE-SF) Scores from Baseline to 
Each 4-Week Treatment Period 
4.3.7.1. 
Definition of Endpoint  
The General Self-Efficacy Short Form 4a (GSE-SF) is a 4-item, self-administered questionnaire 
where the participant is asked to rate their confidence in managing situations, problems, and 
events. Scores range from 4-20. Higher scores indicate the participant has more self-efficacy 
managing difficult situations.  


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4.3.7.2. 
Main Analytical Approach 
See Appendix 6.3.5 for GSE-SF scoring information. The variable used to measure GSE-SF 
between treatment month scores will be calculated using the scales online scoring service 
(https://www.assessmentcenter.net). By using the online scoring service participants raw scores 
for this endpoint will be calculated into T-Scores which will allow for a standardized comparison 
between the treatment months).  Only data from those participants who meet criteria for the Full 
Analysis set will be analyzed. Data for this secondary endpoint will be analyzed via a repeated 
measures ANOVA comparing mean changes in participant’s total GSE-SF scores from baseline 
(Visit 2) to each of the 4-week treatment periods (Visit 3, 4, and 5). Significant changes will be 
followed up using within groups, repeated measures t-tests as needed. 
4.3.8. 
Change in Brief Measure of Worry Severity (BMWS) Scores from Baseline to 
Each 4-Week Treatment Period 
4.3.8.1. 
Definition of Endpoint  
The Brief Measure of Worry Severity (BMWS) is an 8-item, self-administered questionnaire that 
measures various components of dysfunctional worry. The BMWS total score is derived from the 
summation of all eight questions. Answer options for the BMWS are coded as: 0 = Not true at 
all, 1 = Somewhat true, 2 = Moderately true, 3 = Definitely true. The range of total BMWS score 
is 0 to 24 (with higher scores indicating more worry within the participant). 
4.3.8.2. 
Main Analytical Approach 
See Appendix 6.3.6 for BMWS scoring information. Only data from those participants who meet 
criteria for the Full Analysis set will be analyzed. Data for this secondary endpoint will be 
analyzed via a repeated measures ANOVA, comparing mean changes in participant’s total 
BMWS scores from baseline (Visit 2) to each of the 4-week treatment periods (Visit 3, 4, and 5). 
Significant changes will be followed up using within groups, repeated measures t-tests as 
needed. 
4.4. 
Exploratory Endpoint Analysis 
Data for each of the exploratory outcome measures will be statistically analyzed for within group 
changes comparing baseline (Visit 2) to each of the 4-week treatment periods (Visit 3, 4, and 5). 
via a repeated measures analysis of variance (ANOVA) and/or dependent t-tests tests as 
appropriate, as well as bivariate correlations. 
4.4.1. 
Change in Activity and Sleep from Baseline to Each 4-Week Treatment Period 
4.4.1.1. 
Definition of Endpoint 
The variables used to measure change in activity and sleep will be derived from participant’s 
activity tracker they are to wear and sync daily. The participants’ data are collected throughout 


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Page 21 of 50 
the course of the study. The data are synced on their app from the activity tracker and all 
information is then sent to Fitabase (https://www.fitabase.com). 
• Activity will be defined by totaling the participants steps [Steps] from each day per 
treatment period. 
• Sleep will be defined by totaling the participant’s seconds of sleep 
[DeepSleepDurationInSeconds] + [LightSleepDurationInSeconds] from each day per 
treatment period. Sleep seconds will be converted to minutes for reporting purposes. 
4.4.1.2. 
Main Analytical Approach 
All participant files from Fitabase will be downloaded and coded according to the current version 
of the Fitabase Garmin Data Dictionary (Last updated version 6/4/2020 as of time of writing). 
Only data from those participants who meet criteria for the Full Analysis set will be analyzed. 
Data for this exploratory endpoint will be statistically analyzed via a repeated measures 
ANOVA, comparing baseline changes in activity and sleep to each of the treatment month(s) 
activity and sleep. Significant changes will be followed up using within groups, repeated 
measures t-tests as needed. 
4.4.2. 
Change in Functional Assessment of Migraine Scale (FAMS) Total Scores from 
Baseline to Each 4-Week Treatment Period 
4.4.2.1. 
Definition of Endpoint 
Two versions of the Functional Assessment of Migraine Scale (FAMS) were administered to 
participants, including Research (FAMS-R) and Research Supplement (FAMS-RS). FAMS total 
score consists of all 27-items from both FAMS-R and FAMS-RS, self-administered in the form 
of a questionnaire, which evaluates the complete patient with migraine and their response to 
treatment. The FAMS total score is derived from the summation of all 27 questions. The range of 
total FAMS score is 27 to 135 (with lower scores indicating greater daily life burdens due to 
migraine). 
4.4.2.2. 
Main Analytical Approach 
See Appendix 6.3.7 for FAMS scoring information. Only data from those participants who meet 
criteria for the Full Analysis set will be analyzed. Data for this exploratory endpoint will be 
analyzed via a repeated measures ANOVA, comparing mean changes in participant’s Functional 
Assessment of Migraine Scale (FAMS) total scores from baseline (Visit 2) to each of the 4-week 
treatment periods (Visit 3, 4, and 5). Significant changes will be followed up using within 
groups, repeated measures t-tests as needed. 


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4.4.3. 
Correlation Between Functional Impact of Migraine Scale (FAMS) Total and 
Domain Subscale Scores and Other Migraine Related Patient Reported Outcome 
(PRO) Measures 
4.4.3.1. 
Definition of Endpoint 
See section 4.4.2.1 for full definition of FAMS total score. The FAMS-R consists of 18 items. 
Scores can be derived as the Total Score from the summation of all 18 items (range 18-90) or as 
the Functioning Subscale Score from the summation of all items except 10 and 17 (range 16-80). 
Both the Total and Functioning Subscale Scores interpret lower scores as an indication of greater 
daily life burdens due to migraine. Additionally, the FAMS-R includes a Medicine Subscale 
Score from the summation of only items 10 and 17 (range 2-10), which interprets lower scores as 
an indication of lower confidence in the efficacy of migraine medication. 
 
The FAMS-RS consists of 9 items. Scoring is divided across three subscales: Finance/Insurance 
Score (summation of items 1-3), Doctor/Provider Score (summation of items 4-6), and Education 
Score (summation of items 7-9), all of which range from 3-15. All subscales interpret lower 
scores as a greater day-to-day burden across the related subscale items. The PRO measures 
include Global MFIQ (see section 4.2.1), MIBS-4 (see section 4.3.3.1), WPAI-M (see section 
4.3.5.1), SDSF (see section 4.3.6.1), GSE-SF (see section 4.3.7.1), and BMWS (see section 
4.3.8.1) scores. 
4.4.3.2. 
Main Analytical Approach 
Only data from those participants who meet criteria for the Full Analysis set will be analyzed. 
Data for this exploratory endpoint will be analyzed via bivariate correlations between FAMS 
(total and subscales) and each of the above listed PRO measures. See Appendix 6.3 for scoring 
information on each of the measures. 
4.5. 
Safety Analyses 
The protocol states safety analyses would evaluate the safety and tolerability of participants 
treated with erenumab-aooe via collection of adverse events and safety evaluations. However, 
there will not be a formal statistical analysis for safety endpoints; rather, all safety endpoints will 
be summarized via tables and descriptive statistics as appropriate. Planned time points for all 
safety assessments are provided in the SoA. 
4.5.1. 
Adverse Events (AEs) 
Medical Dictionary for Regulatory Activities (MedDRA) Version 24.1 will be used to code all 
adverse events. AEs will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative), or identified by research staff 
during study safety assessment procedures. These AE descriptions will be updated in the final 
report via mapping to the MedDRA Naming Hierarchy, using verbatim terms (e.g., feeling 


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Page 23 of 50 
queasy) mapped to MedDRA Preferred Terms (PT) (e.g., Nausea), Highest Level Term (HLT), 
Highest Level Group Term (HLGT) and System Organ Class (SOC). Final AE tables will be 
created using the most appropriate MedDRA hierarchy for each AE class. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or serious adverse event (SAE) and remain 
responsible for following up AEs that are serious, considered related to the study intervention or 
study procedures, or that caused the participant to discontinue the study intervention or study. 
See Appendix 4 for Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting AEs. 
4.5.1.1. 
Adverse Events of Special Interest 
Based on the known warnings and precautions identified in AIMOVIG (erenumab) prescribing 
information, summary tables will be created for the below adverse events of special interest 
reported by all participants regardless of frequency. 
 
4.5.1.1.1. Injection Site Reactions 
This will include the subset of adverse events with a MedDRA coded HLT of Injection Site 
Reaction. 
4.5.1.1.2. Constipation 
This will include the subset of adverse events with a MedDRA coded PT of Constipation. 
4.5.1.1.3. Hypertension 
This will include the subset of adverse events with a MedDRA coded PT of Hypertension. 
 
4.5.2. 
Additional Safety Assessments 
Additional adverse events grouped by MedDRA coded SOC (unless further specificity is listed 
below or required) with ≥5% occurrence in participants treated with erenumab-aooe will be 
supplemented with tables of the below evaluations. 
4.5.2.1. 
Clinical Laboratory Evaluation 
• The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant's condition. 


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• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline 
or are no longer considered clinically significant by the investigator or medical monitor. 
• If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the etiology should be identified and Clinvest and the medical 
monitor notified. 
• If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded in the CRF. 
 
4.5.2.2. 
Electrocardiograms (ECG) 
• Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.2.1). The heart 
rate, PR, QRS, QT, and QTc intervals will be measured/calculated. Investigators will 
read final ECG’s and determine any abnormalities. The overall interpretation and 
determination of the clinical relevance of ECG findings will be the responsibility of the 
investigator. 
• AE table will be supplemented if ≥5% of participants treated with erenumab-aooe have 
AEs reported due to an abnormal ECG finding that have a MedDRA coded SOC of 
Cardiac disorders or ECG investigations. 
 
4.5.2.3. 
Physical and Neurological Examination Findings 
• A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, and Gastrointestinal systems. 
• Height and weight will also be measured and recorded. 
• A complete neurological examination will be performed. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• AE table will be supplemented if ≥5% of participants treated with erenumab-aooe have 
AEs reported that have a MedDRA coded PT of Weight increased or Weight decreased. 
• AE tables will be supplemented if ≥5% of participants treated with erenumab-aooe have 
reported AEs MedDRA coded as: 
o HLGT = Neurological disorders not elsewhere classified (NEC) 
o SOC = Cardiac disorders 
o SOC = Respiratory, thoracic and mediastinal disorders 
o SOC = Gastrointestinal disorders  
 


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4.5.2.4. 
Suicidal Ideation 
Participants being treated with erenumab-aooe should be monitored appropriately and observed 
closely for suicidal ideation and behavior or any other unusual changes in behavior, especially at 
the beginning and end of the course of intervention, or at the time of dose changes, either 
increases or decreases. Consideration should be given to discontinuing the study medication in 
participants who experience signs of suicidal ideation or behavior, following a risk assessment. 
Baseline assessment of suicidal ideation and behavior/ intervention emergent suicidal ideation 
and behavior will be monitored during the study using PHQ-9. 
AE table will be supplemented if ≥5% of participants treated with erenumab-aooe have AEs 
reported that have a MedDRA coded HLGT of Suicidal and self-injurious behaviours NEC. 
 
4.5.2.5. 
Vital Signs 
The following vital signs will be collected during the study: 
• Blood pressure and pulse measurements. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (e.g., television, cell phones). 
• Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, and pulse. 
• AE tables will be supplemented if ≥5% of participants treated with erenumab-aooe 
experience potentially significant vital sign change AEs including those outlined below: 
o AEs that have a MedDRA coded PT of: 
 Blood pressure systolic decreased 
 Blood pressure systolic increased 
 Blood pressure diastolic decreased 
 Blood pressure diastolic increased 
o AEs that have a MedDRA coded PT of Heart rate decreased or Heart rate 
increased. 
o AEs that have a MedDRA coded PT of Body temperature decreased or Body 
temperature increased 
 
4.6. 
Other Analyses 
Not Applicable, i.e., there are no other planned analysis for this study. 
4.7. 
Interim Analysis  
Not Applicable, i.e., there is not a planned interim analysis for this study. 


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Page 26 of 50 
4.8. 
Changes to Protocol-planned Analyses 
Not Applicable, i.e., there are no changes to the protocol-planned analysis for this study. 


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Page 27 of 50 
5. 
Sample Size Determination 
A meta-analysis of commonly used patient reported outcome (PRO) effect sizes was conducted 
to determine the expected effect size for the primary endpoint3. The meta-analysis revealed 
participants on erenumab 140mg had an average change score on commonly used PROs with an 
effect size of d = 0.87. Additionally, prior research on the MFIQ showed an average correlation 
of r = 0.59 between the global MFIQ scores and these regularly utilized PROs4.  Due to the 
differences in study design between this study and prior studies, the novelty of the MFIQ and the 
uncertainty of its effect size, and to correct for potential replication errors5, we lowered the 
expected effect size to a more moderate effect size of d = 0.50.  
To determine the needed sample size for this study we utilized G*Power Version 3.1.9.3 to 
conduct a power analysis for the primary endpoint analysis comparing baseline global MFIQ 
scores to the final 4-week treatment period’s global MFIQ scores utilizing a within group, 
repeated measures t-test. We utilized the conservative effect size of d = 0.50, alpha set at 0.05, 
and a power of .95. With these parameters the power analysis indicated a total of 54 participants 
would need to be analyzed to detect this effect with .95 power. 


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Page 28 of 50 
6. 
Supporting Documentation 
6.1. 
Appendix 1: List of Abbreviations 
 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse Event 
ANOVA 
Analysis of variance 
BMWS 
Brief Measure of Worry Severity 
CMP 
Comprehensive metabolic panel 
CRF 
Case report form 
DHD 
Daily headache diary 
ECG 
Electrocardiography 
EF 
Emotional Function 
FAMS 
Functional Assessment of Migraine Scale 
FAMS-R 
Functional Assessment of Migraine Scale- Research 
FAMS-RS 
Functional Assessment of Migraine Scale- Research Supplement 
GSE-SF 
General Self-Efficacy Short Form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
ICHD-III 
International Classification of Headache Disorders 3rd edition 
IEC 
Independent Ethics Committee(s) 
IP 
Investigational Product 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFIQ 
Migraine Functional Impact Questionnaire 


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Page 29 of 50 
Abbreviation or Term 
Definition/Explanation 
MIBS-4 
Migraine Interictal Burden Scale 
PF 
Physical Function 
PHQ-9 
9-Item Depression Patient Health Questionnaire 
PRO 
Patient reported outcome 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SDSF 
Neuro-QoL Sleep Disturbance Short Form 
SF 
Social Function 
SoA 
Schedule of Activities 
UA 
Usual Activities 
WOCB 
Women of Childbearing Potential 
WPAI-M 
Work Productivity and Activity Impairment- Migraine 
 
 
 


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6.2. 
Appendix 2: International Classification of Headache Disorders, 3rd 
edition: Migraine with and without aura 
6.2.1. 
Migraine without aura 
Description: Recurrent headache disorder manifesting in attacks lasting 4–72 hours Typical 
characteristics of the headache are unilateral location, pulsating quality, moderate or severe 
intensity, aggravation by routine physical activity and association with nausea and/or 
photophobia and phonophobia. 
Diagnostic criteria: 
A. At least five attacks fulfilling criteria B–D 
B. Headache attacks lasting 4–72 hours (when untreated or unsuccessfully treated) 
C. Headache has at least two of the following four characteristics: 
1. unilateral location 
2. pulsating quality 
3. moderate or severe pain intensity 
4. aggravation by or causing avoidance of routine physical activity (e.g. walking or 
climbing stairs) 
D. During headache at least one of the following: 
1. nausea and/or vomiting 
2. photophobia and phonophobia 
E. Not better accounted for by another ICHD-3 diagnosis. 
 
 
 


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6.2.2. 
Migraine with aura 
 
Description: Recurrent attacks, lasting minutes, of unilateral fully reversible visual, sensory or 
other central nervous system symptoms that usually develop gradually and are usually followed 
by headache and associated migraine symptoms. 
 
Diagnostic criteria: 
 
A. At least two attacks fulfilling criteria B and C 
B. One or more of the following fully reversible aura symptoms: 
1. visual 
2. sensory 
3. speech and/or language 
4. motor 
5. brainstem 
6. retinal 
C. At least three of the following six characteristics: 
1. at least one aura symptom spreads gradually over ≥5 minutes 
2. two or more aura symptoms occur in succession 
3. each individual aura symptom lasts 5–60 minutes 
4. at least one aura symptom is unilateral 
5. at least one aura symptom is positive 
6. the aura is accompanied, or followed within 60 minutes, by headache 
D. Not better accounted for by another ICHD-3 diagnosis. 
 


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6.3. 
Appendix 3: Patient Reported Outcomes Scoring Manuals 
6.3.1. 
Migraine Functional Impact Questionnaire (MFIQ)  
 
Figure 1. MFIQ Conceptual Framework 
6.3.1.1. 
Scoring 
MFIQ items are scored on a 5-point response scale. Items ask about “level of difficulty” 
with activities, “frequency of impact,” or “level of impact.” Five items also include a “does 
not apply” response option.  
Item responses are summed to generate four domain scores: impact on Physical Function 
(PF; 5 items), Usual Activities (UA; 10 items), Social Function (SF; 5 items), and Emotional 
Function (EF; 5 items). A single global item assessing overall difficulty doing everyday 
activities is scored separately. A four-factor model showed the best fit to the data in an 
exploratory factor analysis. Five items were dropped from the draft version based on 
results from item-level analyses and qualitative interview results, resulting in the final 26-


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Page 33 of 50 
item instrument (version 2.0). Item response theory and a unidimensional CFA confirmed 
the four-factor structure and unidimensionality of the domains.  
Domain sum (raw) scores range from 5-25 for the PF domain, 10-50 for the UA domain, 1-5 
for the global item, 5-25 for the SF domain, and 5-25 for the EF domain (Table 1). Scores 
are transformed to a 0–100 scale, where higher score values indicate greater impact of 
migraine. No total score is currently created for the MFIQ.  
The formula below is used to transform raw domain score values into a 0–100 scale.  
            (Raw score – lowest possible raw score)  
Transformed score = ------------------------------------------------------------------------------- * 100  
                 (Highest possible raw score – lowest possible raw score) 
 
 
Table 1. MFIQ Domains and Scoring 
6.3.1.2. 
Missing Data Imputation Guidelines 
6.3.1.2.1. Item-Level Missing Data 
For each MFIQ domain, if <50% of the items within a domain are missing, the mean of the 
item scores that are present for that day is used to impute a score for the missing item(s). If 
≥50% of the items that make up a domain are missing, no domain score is calculated; the 
domain score is considered missing.  
For the purposes of domain scoring, “does not apply” (DNA response) are not considered 
missing and will be imputed with the mean of other non-missing items in the domain. 
 


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6.3.2. 
Migraine Interictal Burden Scale (MIBS-4)  
 
Figure 2. MIBS-4 with scoring key: This shows how each item should be calculated into the 
total with the level of interictal burden. Below is an example of how each item will be calculated 
(Buse et al., 2009). 
  
Example: 
Item 1: Some of the time (x2) 
Item 2: Never (x0) 
Item 3: Much of the time (x3) 
Item 4: Rarely (x1) 
Total MIBS-4 score: 1x2 + 1x0 + 1x3 + 1x4 = 2 + 0 + 3 + 4 = 9. This would be Severe interictal 
burden 
  
REDCap Cloud Variables used for this analysis: [MIBS-1], [MIBS-2], [MIBS-3], [MIBS-4] 
  


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REDCap Cloud values for each response are recorded as the participants answer, e.g., ‘Rarely’ 
instead of with the PRO’s assigned value. In the figure above the red box indicates the value for 
each response. In R the biostatistician will programmatically recode the responses into the 
following values to match the PRO’s: 
•      Don’t Know/NA = 0 
•      Never = 0 
•      Rarely = 1 
•      Some of the time = 2 
•      Much of the time = 3 
•      Most or all of the time = 3 
 
6.3.3. 
Work Productivity and Activity Impairment- Migraine (WPAI-M)  
The WPAI-M outcomes are calculated into percentages, higher numbers indicate greater 
impairment and less work productivity. 
Questions: 
1 = currently employed 
  
2 = hours missed due to specified problem 
  
3 = hours missed other reasons 
  
4 = hours actually worked 
  
5 = degree problem affected productivity 
while working 
  
6 = degree problem affected regular activities 
  
Scores:  
Multiply scores by 100 to express in 
percentages. 
  
  
Percent work time missed due to problem: 
Question 2/(Question 2 + Question 4) 
  
  
Percent impairment while working due to 
problem: 
Question 5 / 10 
  
  
Percent overall work impairment due to 
problem: 


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Question 2/(Question 2 + Question 4)+[(1-
(Question 2/(Question 2 + Question 
4)))x(Question 5/10)] 
  
  
Percent activity impairment due to problem: 
Question 6 / 10 
  
Figure 3. WPAI-M questions and scoring key: This shows each question and how each outcome 
is assessed. 
  
Example: 
Question 1 = Yes (1) No (0) 
Question 2 = 5 hours missed due to Migraine 
Question 3 = 0 hours missed for other reasons 
Question 4 = 35 hours worked 
Question 5 = 6 
Question 6 = 3 
  
Percent work time missed due to migraine: Q2/(Q2+Q4) = 5/(5+35) = 5/40 = 0.125 x 100 = 
12.5% 
  
Percent impairment while working due to migraine: Q5/10 = 6/10 = 0.6 = 60% 
  
Percent overall work impairment due to migraine: Q2/(Q2+Q4)+[(1-( Q2/(Q2+Q4)))x(Q5/10)] = 
5/(5+35) + [(1-(5/(5+35)))x(6/10)] = 
5/40+[(1-(5/(40)))x(0.6)] = 
0.125+[(1-0.125)x(0.6)] = 
0.125+[(0.875)x(0.6)] = 
0.125+0.525= 
0.525 x 100 = 52.5% 
  


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Percent activity impairment due to migraine: Q6/10 = 3/10 = .3 = 30% 
  
Results from example: This participant missed 12.5% of work due to migraine and while 
working their impairment was 60%. Their overall work impairment due to migraine was 52.5%. 
They also experienced 30% migraine impairment for other activities. 
  
REDCap Cloud Variables used for this analysis: [WPAIM_1], [WPAIM_2], [WPAIM_3], 
[WPAIM_4], [WPAIM_5], [WPAIM_6] 
 
6.3.4. 
Neuro-QoL Sleep Disturbance Short Form (SDSF)  
 
 
Figure 4. SDSF scoring table: This shows the values of the total raw score converted into the T-
Scores, outlined in the red boxes (NeuroQoL Quality of Life in Neurological Disorders Scoring 
Manual, 2015). These figures also allow data management to provide an accuracy check on the 
Health Measure output. 
  
In order to use the HealthMeasures online scoring assessment the biostatistician will need to 
follow the Assessment Center Scoring Service User Manual attached in Appendix 4. 
  
Answer options for the SDSF are coded as: 


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•      1 = Never 
•      2 = Rarely 
•      3 = Sometimes 
•      4 = Often 
•      5 = Always. 
The range of total SDSF score for each time point is 8 to 40 (with higher scores indicating more 
sleep disturbance). 
REDCap Cloud Variables used for this analysis: [SDSF-1], [SDSF-2], [SDSF-3], [SDSF-4], 
[SDSF-5], [SDSF-6], [SDSF-7] 
 
6.3.5. 
General Self-Efficacy Short Form (GSE-SF)  
 
Figure 5. GSE-SF scoring key: This shows the values of the total raw score converted into the T-


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Scores, outlined in the red boxes (General Self-Efficacy and Self-Efficacy for Managing Chronic 
Conditions Scoring Manual, 2017). These figures also allow data management to provide an 
accuracy check on the Health Measure output. 
  
In order to use the HealthMeasures online scoring assessment the biostatistician will need to 
follow the Assessment Center Scoring Service User Manual attached in Appendix 4. 
  
Answer options for the GSE-SF are coded as: 
•      1 = I am not at all confident 
•      2 = I am a little confident 
•      3 = I am somewhat confident 
•      4 = I am quite confident 
•      5 = I am very confident 
The range of total GSE-SF score for each time point is 4 to 20 (with higher scores indicate more 
self-efficacy managing difficult situations). 
REDCap Cloud Variables used for this analysis: [GSE14_C], [GSE19_C], [GSE11_C], 
[GSE20-C] 


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6.3.6. 
 Brief Measure of Worry Severity (BMWS)  
 
Figure 6. BMWS Questionnaire 
6.3.6.1. 
Scoring 
The BMWS total score is derived from the summation of all eight questions. Answer options for 
the BMWS are coded as: 0 = Not true at all, 1 = Somewhat true, 2 = Moderately true, 3 = 
Definitely true. The range of total BMWS score is 0 to 24 (with higher scores indicating more 
worry within the participant). 
 


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6.3.7. 
Functional Assessment of Migraine Scale (FAMS)  
 


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Figure 7. FAMS-R with scoring key: This shows how each item should be calculated for totals 
as well as subscales. 
 


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Figure 8. FAMS-RS with scoring key: This shows how each item should be calculated for the 
subscales. 
 
 


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6.4. 
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
6.4.1. 
Definition of AE 
AE Definition 
•      An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
•      NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
  
Events Meeting the AE Definition 
•      Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including 
those that worsen from baseline, considered clinically significant in the medical and 
scientific judgment of the investigator (i.e., not related to progression of underlying 
disease). 
•      Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
•      New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
•      Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
•      Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
•      The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or SAE. 
  
  
  


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Events NOT Meeting the AE Definition 
•      Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
•      The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
•      Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
•      Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
•      Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
6.4.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a.       Results in death 
b.      Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c.       Requires inpatient hospitalization or prolongation of existing hospitalization 
•      In general, hospitalization signifies that the participant has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in 
doubt as to whether “hospitalization” occurred or was necessary, the AE should be 
considered serious. 


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•      Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d.      Results in persistent disability/incapacity 
•      The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
•      This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e.       Is a congenital anomaly/birth defect 
f.        Other situations: 
•      Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious. 
•       Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
6.4.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
•      When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
•      The investigator will then record all relevant AE/SAE information in the CRF. 
•      It is not acceptable for the investigator to send photocopies of the participant’s medical 
records in lieu of completion of the AE/SAE CRF page. 
•      There may be instances when copies of medical records for certain cases are requested. In 
this case, all participant identifiers, with the exception of the participant number, will be 
redacted on the copies of the medical records before submission. 
•      The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 


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Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories: 
•      Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
•      Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
•      Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
  
Assessment of Causality 
•      The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. 
•      A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
•      The investigator will use clinical judgment to determine the relationship. 
•      Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
•      The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
•      For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
•      There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data. 
•      The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 


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•      The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
  
Follow-up of AEs and SAEs 
•      The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested to elucidate the 
nature and/or causality of the AE or SAE as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals. 
•      New or updated information will be recorded in the originally completed CRF. 
•      The investigator will submit any updated SAE data within 24 hours of receipt of the 
information. 
6.4.4. 
Reporting of SAEs 
SAE Reporting to Sponsor and Medical Monitor via an Electronic Data Collection Tool 
•      The primary mechanism for reporting an SAE to sponsor and medical monitor will be the 
electronic data collection tool. 
•      If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
•      The site will enter the SAE data into the electronic system as soon as it becomes available. 
•      After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
•      If a site receives a report of a new SAE from a study participant or receives updated data on 
a previously reported SAE after the electronic data collection tool has been taken off-line, 
then the site can report this information on a paper SAE form (see next section) or to the 
sponsor and medical monitor by telephone. 
•      Contacts for SAE reporting can be found in the investigative site file. 
  
SAE Reporting to Sponsor and Medical Monitor via Paper CRF 
•      Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the sponsor and medical monitor. 


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•      In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
•      Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
•      Contacts for SAE reporting can be found in the investigative site file. 
 
 
 


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Page 50 of 50 
7. 
References 
 
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2. Mannix, S., Skalicky, A., Buse, D. C., Desai, P., Sapra, S. Ortmeier, B., . . . Hareendran, A. 
(2016). Measuring the impact of migraine for evaluating outcomes of preventive treatments 
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(2019). Evaluating the psychometric properties of the Migraine Functional Impact 
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Science, 349(6241), aac4716. https://doi.org/10.1126/science.aac4716