A Phase 4, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Galcanezumab Versus Rimegepant in Adult Participants With Episodic Migraine
Phase: PHASE4
Conditions: Migraine, Episodic Migraine
Sponsor: Eli Lilly and Company

 
 
 
 
Protocol: I5Q-MC-CGBD(d) 
 
 
A Phase 4, Randomized, Double-Blind, Placebo-Controlled Study Evaluating 
the Efficacy and Safety of Galcanezumab Versus Rimegepant in Adult 
Participants with Episodic Migraine 
 
 
NCT05127486 
 
 
Approval Date: 02-Nov-2022 

CONFIDENTIAL 
Protocol number I5Q-MC-CGBD(d) 
1 
Title Page 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of galcanezumab (LY2951742), unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.  
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: A Phase 4, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the 
Efficacy and Safety of Galcanezumab Versus Rimegepant in Adult Participants 
with Episodic Migraine
Protocol Number: I5Q-MC-CGBD 
Amendment Number: d 
Compound: Galcanezumab (LY2951742) 
Brief Title: A Study to Investigate the Efficacy and Safety of Galcanezumab Versus Rimegepant 
in Adult Participants with Episodic Migraine 
Study Phase: 4 
Acronym: CHALLENGE-MIG 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s) 
IND: 111295 
Approval Date: Protocol Amendment (d) Electronically Signed and Approved by Lilly on date 
provided below. 
Document ID: VV-CLIN-075435 
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Protocol number I5Q-MC-CGBD(d) 
 
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Medical Monitor Name and Contact Information will be provided separately. 
 
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Protocol number I5Q-MC-CGBD(d) 
 
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Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Amendment c 
22-Sep-2022 
Amendment b 
18-Feb-2022 
Amendment a 
06-Aug-2021 
Original Protocol 
09-Jun-2021 
Amendment d  
The amendment is considered to be substantial because it is likely to have a significant impact on 
the safety or the rights of study participants. 
Overall Rationale for the Amendment: 
The purpose of this amendment is to modify the contraceptive requirements for women of child 
bearing potential. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1. 
Inclusion Criteria: 
Criterion 7(b) 
Updated the contraception 
requirements from 2 effective forms 
to single form 
Modified to align with recent 
internal guidance 
 
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Protocol number I5Q-MC-CGBD(d) 
 
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Table of Contents 
1. 
Protocol Summary ..........................................................................................................7 
1.1. 
Synopsis ............................................................................................................................7 
1.2. 
Schema ............................................................................................................................10 
1.3. 
Schedule of Activities (SoA) ..........................................................................................11 
2. 
Introduction ...................................................................................................................16 
2.1. 
Study Rationale ...............................................................................................................16 
2.2. 
Background .....................................................................................................................16 
2.3. 
Benefit/Risk Assessment ................................................................................................17 
3. 
Objectives, Endpoints, and Estimands .......................................................................18 
4. 
Study Design ..................................................................................................................21 
4.1. 
Overall Design ................................................................................................................21 
4.1.1. 
Study Period I: Screening (Visit 1) .................................................................................21 
4.1.2. 
Study Period II: Prospective Baseline (Visit 2) ..............................................................21 
4.1.3. 
Study Period III: Double-Blind Treatment (Visits 3–6) .................................................22 
4.2. 
Scientific Rationale for Study Design ............................................................................23 
4.3. 
Justification for Dose ......................................................................................................23 
4.4. 
End of Study Definition ..................................................................................................23 
5. 
Study Population ...........................................................................................................24 
5.1. 
Inclusion Criteria ............................................................................................................24 
5.2. 
Exclusion Criteria ...........................................................................................................25 
5.3. 
Lifestyle Considerations .................................................................................................27 
5.4. 
Screen Failures ................................................................................................................27 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant .....................................28 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................29 
6.1. 
Study Intervention(s) Administered................................................................................29 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................30 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................30 
6.4. 
Study Intervention Compliance ......................................................................................31 
6.5. 
Dose Modification ..........................................................................................................32 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................32 
6.7. 
Treatment of Overdose ...................................................................................................32 
6.8. 
Concomitant Therapy .....................................................................................................32 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................34 
7.1. 
Discontinuation of Study Intervention ............................................................................34 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................34 
7.1.2. 
QTc Stopping Criteria .....................................................................................................35 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................35 
7.3. 
Lost to Follow up ............................................................................................................36 
8. 
Study Assessments and Procedures.............................................................................37 
8.1. 
Efficacy Assessments .....................................................................................................37 
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8.1.1. 
Primary Efficacy Assessment .........................................................................................37 
8.1.2. 
Secondary Efficacy Assessments ....................................................................................37 
8.1.3. 
Tertiary Efficacy Assessment .........................................................................................38 
8.2. 
Safety Assessments .........................................................................................................38 
8.2.1. 
Physical Examinations ....................................................................................................38 
8.2.2. 
Vital Signs .......................................................................................................................38 
8.2.3. 
Electrocardiograms .........................................................................................................39 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................39 
8.2.5. 
Pregnancy Testing ...........................................................................................................39 
8.2.6. 
Suicidal Ideation and Behavior Risk Monitoring ...........................................................39 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................40 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................41 
8.3.2. 
Pregnancy ........................................................................................................................42 
8.4. 
Pharmacokinetics ............................................................................................................44 
8.5. 
Pharmacodynamics .........................................................................................................44 
8.6. 
Genetics ..........................................................................................................................44 
8.7. 
Biomarkers ......................................................................................................................44 
8.8. 
Immunogenicity Assessments.........................................................................................44 
8.9. 
Health Economics ...........................................................................................................44 
9. 
Statistical Considerations .............................................................................................45 
9.1. 
Statistical Hypotheses .....................................................................................................45 
9.1.1. 
Multiplicity Adjustment ..................................................................................................45 
9.2. 
Analyses Sets ..................................................................................................................46 
9.3. 
Statistical Analyses .........................................................................................................46 
9.3.1. 
General Considerations ...................................................................................................46 
9.3.2. 
Primary Endpoint(s)/Estimand(s) Analysis ....................................................................47 
9.3.3. 
Secondary Endpoints/Estimands Analysis ......................................................................47 
9.3.4. 
Safety Analyses ...............................................................................................................48 
9.3.5. 
Other Analyses ................................................................................................................49 
9.4. 
Interim Analysis ..............................................................................................................49 
9.5. 
Sample Size Determination ............................................................................................49 
10. 
Supporting Documentation and Operational Considerations ..................................50 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................50 
10.1.1. Regulatory and Ethical Considerations ...........................................................................50 
10.1.2. Informed Consent Process ..............................................................................................50 
10.1.3. Data Protection................................................................................................................51 
10.1.4. Committees Structure......................................................................................................51 
10.1.5. Dissemination of Clinical Study Data.............................................................................52 
10.1.6. Data Quality Assurance ..................................................................................................52 
10.1.7. Source Documents ..........................................................................................................54 
10.1.8. Study and Site Start and Closure ....................................................................................54 
10.1.9. Publication Policy ...........................................................................................................55 
10.1.10. Investigator Information .................................................................................................55 
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10.2. 
Appendix 2: Treatments Allowed and Treatments not Allowed as 
Concomitant Therapy .....................................................................................................56 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................59 
10.3.1. Definition of AE .............................................................................................................59 
10.3.2. Definition of SAE ...........................................................................................................60 
10.3.3. Recording and Follow-Up of AE and/or SAE ................................................................61 
10.3.4. Reporting of SAEs ..........................................................................................................63 
10.3.5. Regulatory Reporting Requirements ...............................................................................63 
10.4. 
Appendix 4: Clinical Laboratory Tests ...........................................................................64 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................66 
10.5.1. Hepatic Evaluation Testing .............................................................................................66 
10.5.2. Close Hepatic Monitoring ...............................................................................................67 
10.5.3. Additional Hepatic Data Collection (Hepatic Safety CRF) in 
Study Participants Who Have Abnormal Liver Tests During the 
Study ...............................................................................................................................69 
10.6. 
Appendix 6: Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................70 
10.7. 
Appendix 7: Abbreviations and Definitions ...................................................................74 
10.8. 
Appendix 8: Protocol Amendment History ....................................................................78 
11. 
References ......................................................................................................................86 
 
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Protocol number I5Q-MC-CGBD(d) 
 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title:  
A Phase 4, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of Galcanezumab Versus Rimegepant in Adult Participants with Episodic Migraine 
Brief Title:  
A Study to Investigate the Efficacy and Safety of Galcanezumab Versus Rimegepant in Adult 
Participants with Episodic Migraine 
Rationale: 
Identification of CGRP signaling in the pathophysiology of migraine led to the development and 
approval of 4 novel migraine-specific preventive biologics. One of these, galcanezumab, is a 
humanized monoclonal antibody that selectively and potently binds to CGRP and prevents 
CGRP from binding to the receptor and has demonstrated efficacy in migraine prevention with a 
favorable safety profile (Emgality package insert, 2019). 
More recently, oral CGRP receptor antagonists, gepants, have been approved for the acute 
treatment of migraine. One of these, rimegepant, has recently been approved by the FDA for the 
preventive treatment of migraine (Nurtec ODT package insert, 2021).  
To date, there are no studies that have directly compared the efficacy and safety between CGRP 
antagonists in migraine prevention, creating a gap in the information needed by healthcare 
providers and their participants to make informed decisions regarding their treatment.  
This study will compare the efficacy and safety of galcanezumab to rimegepant in participants 
with episodic migraine.  
Objectives, Endpoints, and Estimands: 
Objectives 
Endpoints 
Primary 
 
To assess whether galcanezumab is superior 
to rimegepant in the prevention of migraine in 
participants with episodic migraine. 
The percentage of participants with ≥50% 
reduction from baseline in monthly migraine 
headache days across the 3-month double-
blind treatment period. 
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Protocol number I5Q-MC-CGBD(d) 
 
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Objectives 
Endpoints 
Key Secondary Objectives 
 
If galcanezumab is statistically superior to 
rimegepant on the primary objective, the 
following key secondary objectives will be 
tested with adjustment for multiplicity: 
 
 To compare galcanezumab with 
rimegepant with respect to monthly 
migraine headache days. 
 The overall mean change from baseline in 
the number of monthly migraine headache 
days across the 3-month double-blind 
treatment period. 
 To compare galcanezumab with 
rimegepant with respect to 75% response 
rate. 
 The percentage of participants with ≥75% 
reduction from baseline in monthly 
migraine headache days across the 3-
month double-blind treatment period. 
 To compare galcanezumab with 
rimegepant with respect to monthly 
migraine headache days at:  
o Month 3 
o Month 2 
o Month 1 
 The mean change from baseline in the 
number of monthly migraine headache 
days at:  
o Month 3 
o Month 2 
o Month 1 
 To compare galcanezumab with 
rimegepant with respect to migraine 
headache days with acute (abortive) 
migraine treatment. 
 The overall mean change from baseline in 
the number of monthly migraine headache 
days requiring medication for the acute 
treatment of migraine or headache across 
the 3-month double-blind treatment 
period. 
 To compare galcanezumab with 
rimegepant with respect to change in 
functioning. 
 The mean change from baseline in the 
Role Function-Restrictive (RF-R) domain 
score of the Migraine-Specific Quality of 
Life Questionnaire version 2.1 (MSQ 
v2.1) at Month 3. 
 To compare galcanezumab with 
rimegepant with respect to 100% response 
rate. 
 The percentage of participants with 100% 
reduction from baseline in monthly 
migraine headache days across the 3-
month double-blind treatment period. 
 
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Protocol number I5Q-MC-CGBD(d) 
 
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Overall Design 
Study CGBD is a multi-site, randomized, double-blind, double-dummy, parallel-group, Phase 4 
study with 3 study periods in participants who meet ICHD criteria for a diagnosis of migraine 
with or without aura with an episodic frequency of 4 to 14 migraine headache days per month.  
Brief Summary: 
The purpose of this study is to assess whether galcanezumab is superior to rimegepant in the 
prevention of migraine in participants with episodic migraine.  
The study duration will be approximately 5 months. 
The treatment duration will be approximately 3 months. 
The visit frequency will be approximately monthly.  
Number of Participants: 
Approximately 1150 participants will be screened to achieve a minimum of approximately 575 
randomized study participants.  
Intervention Groups and Duration: 
Interventions: 
 Galcanezumab 120 mg subcutaneous injection once monthly, with a 240 mg loading dose 
as the initial dose 
 Rimegepant 75 mg oral tablet every other day 
Participants will be given placebo in a double-dummy design. 
Data Monitoring Committee: No 
 
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Protocol number I5Q-MC-CGBD(d) 
 
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1.2. 
Schema 
 
Abbreviations: ODT = oral disintegrating tablet; QM = every month; QOD = every other day; SC = subcutaneous. 
a Screening Period is 3-30 days in length. 
b Eligibility is determined between a minimum of 30 days and a maximum of 40 days. Investigators have up to 5 additional days, if needed, to schedule 
participant’s Visit 3 appointment. 
c Randomization occurs at Visit 3. Participants randomized to galcanezumab will receive a loading dose of 240 mg at the first administration only. 
Note: Participants will be given placebo in a double-dummy design.  
 
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Protocol number I5Q-MC-CGBD(d) 
 
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1.3. 
Schedule of Activities (SoA) 
SP I – Screening 
Visit 1 procedures may be conducted over more than 1 day as long as all 
activities are completed within the allowable visit tolerance. 
SP II – 
Prospective 
Baseline 
SP III – Double-Blind 
Treatment 
ET 
Comments 
Visit Number 
1 
2 
3 
4a 
5a 
6 
 
 
Month relative to randomization (V3) 
* 
** 
 
1 
2 
3 
 
*Screening lasts from 3 to 30 days. 
** Eligibility is determined between a minimum of 30 days and 
a maximum of 40 days. Investigators have up to 5 additional 
days, if needed, to schedule participant’s Visit 3 
appointment. 
For scheduling purposes, a month is 30 days. 
Interval allowance (days) 
 
 
- 
±2 
±2 
±2 
 
 
Telephone Visit 
 
 
 
X 
X 
 
 
See footnote a. 
Informed consent 
X 
 
 
 
 
 
 
The ICF must be signed before any protocol-specific tests or 
procedures are performed. 
Inclusion and exclusion, review and confirm 
X 
X 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Substance use 
X 
 
 
 
 
 
 
Substances: alcohol, caffeine, nicotine, tobacco 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
AE 
X 
X 
X 
X 
X 
X 
X 
Any events that occur after signing the ICF are considered AEs 
as defined in Section 10.3. 
Physical Evaluation 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
12-lead ECG (local) 
X 
 
 
 
 
X 
X 
ECGs should be collected prior to blood draws. Participants 
should be supine for approximately 5 to 10 minutes before 
ECG collections and remain supine but awake during the ECG 
collection. 
See Section 8.2.3 for additional details. 
Vital signs 
X 
 
X 
 
 
X 
X 
Includes body temperature, sitting blood pressure, and pulse. 
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SP I – Screening 
Visit 1 procedures may be conducted over more than 1 day as long as all 
activities are completed within the allowable visit tolerance. 
SP II – 
Prospective 
Baseline 
SP III – Double-Blind 
Treatment 
ET 
Comments 
Visit Number 
1 
2 
3 
4a 
5a 
6 
 
 
Month relative to randomization (V3) 
* 
** 
 
1 
2 
3 
 
*Screening lasts from 3 to 30 days. 
** Eligibility is determined between a minimum of 30 days and 
a maximum of 40 days. Investigators have up to 5 additional 
days, if needed, to schedule participant’s Visit 3 
appointment. 
For scheduling purposes, a month is 30 days. 
Interval allowance (days) 
 
 
- 
±2 
±2 
±2 
 
 
Telephone Visit 
 
 
 
X 
X 
 
 
See footnote a. 
Blood pressure and pulse will be measured in triplicate after 
participant has been sitting for at least 5 minutes, and prior to 
blood draws. 
Physical examination 
X 
 
 
 
 
 
 
 
Neurological examination 
X 
 
 
 
 
 
 
 
Laboratory Tests and Sample Collections 
Hematology 
X 
 
 
 
 
X 
X 
 
Clinical chemistryb 
X 
 
 
 
 
X 
X 
 
Urinalysis 
X 
 
 
 
 
X 
X 
 
UDS 
X 
 
 
 
 
 
 
Participants may re-test, but must be negative at or prior to V2 
Serum pregnancy or FSH for female 
participantsc 
 
X 
 
 
 
X 
X 
Collect serum pregnancy for WOCBP only.  
Collect FSH at V2 to confirm post-menopausal status in 
women aged 40 to 55 (inclusive) as outlined in footnote c. 
Additional pregnancy tests (beyond those required per the 
SoA) should be performed at any time during the trial if a 
menstrual period is missed, there is clinical suspicion of 
pregnancy, or as required by local law or regulation. 
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SP I – Screening 
Visit 1 procedures may be conducted over more than 1 day as long as all 
activities are completed within the allowable visit tolerance. 
SP II – 
Prospective 
Baseline 
SP III – Double-Blind 
Treatment 
ET 
Comments 
Visit Number 
1 
2 
3 
4a 
5a 
6 
 
 
Month relative to randomization (V3) 
* 
** 
 
1 
2 
3 
 
*Screening lasts from 3 to 30 days. 
** Eligibility is determined between a minimum of 30 days and 
a maximum of 40 days. Investigators have up to 5 additional 
days, if needed, to schedule participant’s Visit 3 
appointment. 
For scheduling purposes, a month is 30 days. 
Interval allowance (days) 
 
 
- 
±2 
±2 
±2 
 
 
Telephone Visit 
 
 
 
X 
X 
 
 
See footnote a. 
Urine pregnancy 
X 
 
X 
X 
X 
 
 
Collect for WOCBP only. 
Prior to dosing at V3, V4, and V5, a patient must test negative 
for pregnancy.  
Patients will self-administer urine pregnancy tests at home at 
V4 and V5. 
If the urine pregnancy test is positive, both SC and oral study 
interventions should be withheld and a serum pregnancy test 
conducted. 
Scales, Questionnaires, and Outcome Measures 
ePRO and headache medication log training 
 
X 
 
 
 
 
 
 
ePRO daily diary  
 
Participant completes daily 
 
Headache medication log (paper) 
 
The participant records the date, name, dose, and number of acute 
medications taken 
The headache medication log should be returned to site staff at 
the final office visit or ET visit. 
Collect ePRO diary and paper headache 
medication log 
 
 
 
 
 
X 
X 
 
Participant training video (participation in a 
clinical trial) 
 
X 
 
 
 
 
Videos may be viewed at either V2 or V3. 
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SP I – Screening 
Visit 1 procedures may be conducted over more than 1 day as long as all 
activities are completed within the allowable visit tolerance. 
SP II – 
Prospective 
Baseline 
SP III – Double-Blind 
Treatment 
ET 
Comments 
Visit Number 
1 
2 
3 
4a 
5a 
6 
 
 
Month relative to randomization (V3) 
* 
** 
 
1 
2 
3 
 
*Screening lasts from 3 to 30 days. 
** Eligibility is determined between a minimum of 30 days and 
a maximum of 40 days. Investigators have up to 5 additional 
days, if needed, to schedule participant’s Visit 3 
appointment. 
For scheduling purposes, a month is 30 days. 
Interval allowance (days) 
 
 
- 
±2 
±2 
±2 
 
 
Telephone Visit 
 
 
 
X 
X 
 
 
See footnote a. 
Participant training video (self-injection of 
study intervention) 
 
X 
 
 
 
 
MSQ v2.1 
 
 
X 
 
 
X 
X 
Participant-rated assessments completed onsite should be 
completed prior to administration of study intervention and 
clinical examination.  
MIDAS 
 
 
X 
 
 
X 
X 
PGI-S 
 
 
X 
 
 
X 
X 
Randomization and Dosing 
Randomization 
 
 
X 
 
 
 
 
 
Study intervention administration at site (SC 
and ODT) 
 
 
X 
 
 
 
 
Study intervention will be administered by unblinded study 
personnel onsite at V3 (both SC and ODT) after all other visit 
procedures are completed. 
Dispense study intervention and ancillary 
supplies 
 
 
X 
 
 
 
 
Study intervention is dispensed by unblinded study personnel 
in ancillary containers. 
Administration of ODT study intervention at 
home 
 
 
 
X 
 
Participants will self-administer their ODT every other day at 
home. 
Administration of SC study intervention at 
home 
 
 
 
X 
X 
 
 
Participants to self-administer the SC study intervention at 
home prior to the telephone visit with the study site. 
Return unused study intervention and ancillary 
supplies 
 
 
 
 
 
X 
X 
Return any unused study intervention in the ancillary 
containers to unblinded site personnel. 
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Abbreviations: AE = adverse event; ECG = electrocardiogram; ePRO = electronic patient-reported outcomes; ET = early termination; FSH = follicle stimulating 
hormone; ICF = informed consent form; MIDAS = Migraine Disability Assessment; MSQ v2.1 = Migraine-Specific Quality of Life Questionnaire version 
2.1; ODT = orally disintegrating tablet; PGI-S =Patient Global Impression of Severity; SC = subcutaneous; SP = study period; UDS = urine drug screen; V = 
visit; WOCBP = woman of childbearing potential. 
aVisits 4 and 5 are to confirm/assess the following: administration of study intervention prior to the telephone call; WOCBP completed a urine pregnancy test 
prior to administration of study intervention; and collection/review spontaneously reported AEs and concomitant medications. Participants to be reminded to 
complete the ePRO diary daily and record any acute migraine medication use into the headache medication log. 
bSelected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may be required in follow-up with participants in consultation with 
Lilly, or its designee. See Section 10.5 for more details regarding specific hepatic monitoring tests. If the participant has discontinued the trial and returns for 
hepatic follow-up, the site should use the 800 series as the visit designation. 
cFSH is collected to confirm post-menopausal status at V2 in women aged 40 to 55 (inclusive) with an intact uterus, not on hormone therapy, who has had 
cessation of menses for at least 12 consecutive months without an alternative medical cause, AND with an FSH >40 mIU/mL. 
 
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Protocol number I5Q-MC-CGBD(d) 
 
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2. 
Introduction 
2.1. 
Study Rationale 
Identification of CGRP signaling in the pathophysiology of migraine led to the development and 
approval of 4 novel migraine-specific preventive biologics. One of these, galcanezumab, is a 
humanized monoclonal antibody that selectively and potently binds to CGRP and prevents 
CGRP from binding to the receptor and has demonstrated efficacy in migraine prevention with a 
favorable safety profile (Emgality package insert, 2019). 
More recently, oral CGRP receptor antagonists, gepants, have been approved for the acute 
treatment of migraine. One of these, rimegepant, has recently been approved by the FDA for the 
preventive treatment of episodic migraine (Nurtec ODT package insert, 2021).  
To date, there are no studies that have directly compared the efficacy and safety between CGRP 
antagonists in migraine prevention, creating a gap in the information needed by healthcare 
providers and their participants to make informed decisions regarding their treatment.  
This study will compare the efficacy and safety of galcanezumab to rimegepant in participants 
with episodic migraine.  
2.2. 
Background 
Migraine is a chronic, debilitating condition that is the second highest cause of disability 
worldwide (Vos et al. 2017), and is associated with a substantial impact on the participant’s 
quality of life and ability to work (Leonardi and Raggi 2019). Guidelines recommend preventive 
treatment in participants with more than 3 days per month of headache-related disability (Lipton 
and Silberstein 2015). 
CGRP is a potent vasodilator (Brain et al. 1985) with well-established roles in neurogenic 
inflammation and nociception (Hirsch et al. 2013) and has been established as a valid therapeutic 
target in migraine (Chiang and Schwedt 2020). Early studies suggesting a role of CGRP in 
migraine showed increased plasma or serum levels of CGRP during migraine attacks (Goadsby 
et al. 1990; Goadsby and Edvinsson 1993; Juhasz et al. 2003; Juhasz et al. 2005). Additionally, 
CGRP infusion was shown to induce migraine attacks that were indistinguishable from a 
spontaneous attack in individuals with migraine (Lassen et al. 2002; Hansen et al. 2010). 
Subsequently, studies demonstrated that inhibition of CGRP signaling was efficacious in 
reducing the frequency of migraine (Charles and Pozo-Rosich 2019).  
The efficacy and safety of galcanezumab, a humanized monoclonal antibody that potently and 
selectively binds to CGRP to prevent CGRP-mediated biological effects, has been established in 
several clinical trials in episodic and chronic migraine, including 2 placebo-controlled, Phase 3 
clinical trials for preventive treatment in episodic migraine (Skljarevski et al. 2018; Stauffer 
et al. 2018).  
In addition, the efficacy and safety of rimegepant, a small molecule oral CGRP receptor 
antagonist, has been evaluated in a Phase 2/3 study for preventive treatment of migraine (Croop 
et al. 2021). 
No data are currently available that directly compare galcanezumab with an oral CGRP 
antagonist in a clinical study. This study will evaluate galcanezumab and rimegepant using the 
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same endpoints in the same clinical setting and will provide important information to clinicians 
when making treatment decisions for their participants. 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of galcanezumab may be found in the IB and USPI (Emgality package insert, 
2019). 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of rimegepant may be found in the Package Insert (Nurtec ODT package insert, 
2021).  
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3. 
Objectives, Endpoints, and Estimands 
Objectives 
Endpoints 
Primary 
 
To assess whether galcanezumab is superior 
to rimegepant in the prevention of migraine in 
participants with episodic migraine. 
The percentage of participants with ≥50% 
reduction from baseline in monthly migraine 
headache days across the 3-month double-
blind treatment period. 
Key Secondary Objectives 
 
If galcanezumab is statistically superior to 
rimegepant on the primary objective, the 
following key secondary objectives will be 
tested with adjustment for multiplicity: 
 
 To compare galcanezumab with 
rimegepant with respect to monthly 
migraine headache days. 
 The overall mean change from baseline in 
the number of monthly migraine headache 
days across the 3-month double-blind 
treatment period. 
 To compare galcanezumab with 
rimegepant with respect to 75% response 
rate. 
 The percentage of participants with ≥75% 
reduction from baseline in monthly 
migraine headache days across the 3-
month double-blind treatment period. 
 To compare galcanezumab with 
rimegepant with respect to monthly 
migraine headache days at:  
o Month 3 
o Month 2 
o Month 1 
 The mean change from baseline in the 
number of monthly migraine headache 
days at:  
o Month 3 
o Month 2 
o Month 1 
 To compare galcanezumab with 
rimegepant with respect to migraine 
headache days with acute (abortive) 
migraine treatment. 
 The overall mean change from baseline in 
the number of monthly migraine headache 
days requiring medication for the acute 
treatment of migraine or headache across 
the 3-month double-blind treatment 
period. 
 To compare galcanezumab with 
rimegepant with respect to change in 
functioning. 
 The mean change from baseline in the 
Role Function-Restrictive (RF-R) domain 
score of the Migraine-Specific Quality of 
Life Questionnaire version 2.1 (MSQ 
v2.1) at Month 3. 
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Objectives 
Endpoints 
 To compare galcanezumab with 
rimegepant with respect to 100% response 
rate. 
 The percentage of participants with 100% 
reduction from baseline in monthly 
migraine headache days across the 3-
month double-blind treatment period. 
Other Secondary Objectives 
 
To compare galcanezumab with rimegepant 
with respect to changes in disability and 
health-related quality of life. 
 
Changes from baseline to Month 3 on the 
following measures:  
 MSQ v2.1 total score, and Role 
Function-Preventive (RF-P) and 
Emotional Function (EF) domain 
scores 
 MIDAS (Migraine Disability 
Assessment) total score 
To describe the safety and tolerability of 
galcanezumab and rimegepant. 
 Analysis of: 
o treatment-emergent adverse events 
(TEAEs) 
o serious adverse events (SAEs) 
o discontinuation due to adverse events 
(AEs) 
o discontinuation rates 
o vital signs  
o laboratory measures 
Tertiary/Exploratory 
 
To compare galcanezumab with rimegepant 
with respect to change in participant global 
impression of the severity of migraine. 
Mean change from baseline in the Patient 
Global Impression of Severity (PGI-S) at 
Month 3. 
To compare galcanezumab with rimegepant 
with respect to change in moderate to severe 
headache days. 
The overall mean change from baseline in the 
number of monthly moderate to severe 
headache days across the 3-month double-
blind treatment period. 
To compare galcanezumab with rimegepant 
with respect to change in Total Pain Burden. 
Mean change from baseline in the Monthly 
Total Pain Burden across the 3-month double-
blind treatment period. 
 
 
 
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Migraine and Headache Endpoint Definitions: 
Diagnosis 
Definition/Criteria 
Migraine headache 
A headache, with or without aura, of ≥30 minutes duration, with both of the 
following required features (A and B): 
A. At least 2 of the following headache characteristics: 
 
Unilateral location 
 
Pulsating quality 
 
Moderate or severe pain intensity 
 
Aggravation by or causing avoidance of routine physical activity 
AND 
B. During headache at least 1 of the following: 
 
Nausea and/or vomiting 
 
Photophobia and phonophobia 
(Definition adapted from the standard IHS ICHD-3 definition) 
Probable migraine headache 
A headache of ≥30 minutes duration, with or without aura, but missing one of 
the migraine features in the IHS ICHD-3 definition. To be exact, it meets either 
at least 2 A criteria and 0 B criteria, or 1 A criteria and at least 1 B criteria. 
Migraine headache day 
(primary objective) 
A calendar day on which a migraine headache or probable migraine headache 
occurs. 
Migraine headache attack 
Beginning on any day a migraine headache or probable migraine headache is 
recorded and ends when a migraine-free day occurs. 
Non-migraine headache 
All headaches of ≥30 minutes duration not fulfilling the definition of migraine 
or probable migraine.  
Non-migraine headache day 
A calendar day on which a non-migraine headache occurs. 
Headache day 
A calendar day on which any type of headache occurs (including migraine, 
probable migraine, and non-migraine headache). 
Abbreviations: ICHD = International Classification of Headache Disorders; IHS = International Headache Society. 
 
Primary estimand/coprimary estimand 
See Sections 9.3.2 and 9.3.3 for estimands. 
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4. 
Study Design 
4.1. 
Overall Design 
Study CGBD is a multi-site, randomized, double-blind, double-dummy, parallel-group, Phase 4 
study with 3 study periods in participants who meet IHS-ICHD-3 (2018) criteria for a diagnosis 
of migraine with or without aura with an episodic frequency of 4 to 14 migraine headache days 
per month. 
Interventions: 
 Galcanezumab 120 mg SC once monthly, with a 240 mg loading dose as the initial dose 
 Rimegepant 75 mg ODT every other day 
Participants will be given placebo in a double-dummy design.  
Designated unblinded site personnel will be responsible for the receipt of study intervention 
shipments, handling, dispensing, and at V3, training administration of study interventions 
(galcanezumab, rimegepant, and respective placebo). The designated unblinded site personnel 
are also responsible for recording information in the Study Drug Administration Log and 
confirming treatment assignments.
Unblinded site personnel will not be involved in participant screening, enrollment, and 
assessment of efficacy or safety. It is critical that the blind is maintained throughout the study (3 
months). 
4.1.1. 
Study Period I: Screening (Visit 1) 
At Visit 1: 
 The study and potential risks will be explained to the participant.  
 The ICF must be signed before any study procedures are performed.  
 A full clinical assessment (including a comprehensive medical evaluation documenting 
medical history, and a physical and neurological examination [see SoA, Section 1.3]).  
Visit 1 may occur across more than 1 day and is complete when the last scheduled procedure of 
the screening assessment for the participant is completed. Participants are required to discontinue 
all excluded medications (see Sections 5, 6.8 and 10.2). 
Qualified participants will enter Study Period II (prospective baseline; Section 4.1.2) to 
determine their eligibility for the study (Inclusion Criteria #4 and #5) and to establish baseline 
data for comparison of endpoints during the treatment period. 
4.1.2. 
Study Period II: Prospective Baseline (Visit 2) 
At Visit 2: 
 Participants are to be set-up and trained on their ePRO diary and instructed to begin 
logging in daily (beginning the day of Visit 2) to the ePRO diary to answer questions 
about the occurrence of  
o headaches,  
o headache duration,  
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o headache features,  
o severity of headache, and  
o whether any acute headache medication was taken.  
 Participants will record the name, dose, and date of any acute headache medication on a 
separate paper headache medication log.  
NOTE: The headache medication log should be returned to site staff at the final office 
visit or early termination visit. 
Processing of Visit 2 in IWRS triggers the initial shipment of study intervention; therefore, 
ensure Visit 2 is completed in IWRS promptly. 
Sites will be notified via an eligibility report whether the participant met criteria and are eligible 
to be randomized at Visit 3 (See Section 4.1.3). Eligibility is assessed beginning on Day 30 
through Day 40, if needed, of the prospective baseline period. Investigators have up to 5 
additional days if needed to schedule participant’s Visit 3 appointment. 
To avoid biased reporting, participants must not be told the number of migraine headache 
days on which study qualification is based. 
At either Visit 2 or Visit 3: 
 If available and where local regulations and Ethical Review Boards allow, participants 
will also watch two training videos  
o Video 1: is designed to address participant expectation with regards to 
participation in trial which includes placebo and the difference between medical 
treatment and research 
o Video 2: self-injection of SC study intervention video 
NOTE: If the participant watched the video at Visit 2, they do not need to watch the 
video again at Visit 3. However, if the participant watched 1 video at Visit 2, the 
participant must watch the remaining video at Visit 3. 
4.1.3. 
Study Period III: Double-Blind Treatment (Visits 3–6) 
At Visit 3:  
 Participants meeting all eligibility requirements will be randomized in a 1:1 ratio to 
receive either galcanezumab subcutaneously or rimegepant ODT.  
o A participant will be considered enrolled in the study when randomization occurs. 
To preserve blinding throughout the study, each treatment group will receive both 
SC injection(s) monthly and an ODT every other day, as described in Section 6.1. 
 Participants receive first dose of study intervention as the last procedure of Visit 3.  
o The participant (or caregiver) will also be appropriately trained in how to 
administer SC injection and take the orally dissolving tablet. All participants will 
receive:  
▪ 2 SC injections of study intervention (2 galcanezumab injections of 
120 mg or 2 placebo injections), and  
▪ 1 ODT of study intervention (rimegepant 75 mg ODT or placebo ODT).  
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After Visit 3 
The monthly SC injections of study intervention will be administered by the participant or 
caregiver on the same day, but prior to, the scheduled telephone visits (Visits 4 and 5). Similarly, 
after Visit 3, participants will self-administer the ODT study intervention every other day.  
Visit 5 is the last dose of the injectable study intervention.  
The last dose of the ODT study intervention should be taken no later than the last scheduled 
office visit (Visit 6 [approximately 90 days after Visit 3]) or early termination.  
Participants will continue to log in and complete the ePRO diary each day.  
Participants may continue to take their allowed acute migraine headache medication (with some 
limitations; see Section 6.8 and 10.2) during the treatment period and will continue to record this 
use in the headache medication log. 
4.2. 
Scientific Rationale for Study Design 
This study will examine the effect of galcanezumab versus rimegepant in participants with 
episodic migraine.  
The length of the randomized, parallel, double-blind treatment period (3 months) is considered a 
sufficient duration to demonstrate the efficacy of a migraine preventive medication, given the 
validated mechanism in migraine prevention and observed onset of action for the CGRP 
antagonists, including galcanezumab and rimegepant (Dodick et al. 2014a, 2014b; Schwedt et al. 
2018; Croop et al. 2021; Kuruppu et al. 2021). 
The primary endpoint, 50% or greater reduction in monthly migraine headache days, was 
selected as it is a direct and clinically relevant measure, and it provides a reliable and valid 
measurement of the intended treatment effect (AHS 2019). 
4.3. 
Justification for Dose 
The galcanezumab dosing regimen used in this study is the approved dose for the treatment of 
migraine in adults (Emgality package insert, 2019).  
The rimegepant dosing regimen used in this study is the approved dose for the preventive 
treatment of episodic migraine in adults (Nurtec ODT package insert, 2021). 
4.4. 
End of Study Definition 
The end of the study is defined as the date of last scheduled procedure shown in the SoA for the 
last participant in the trial. 
A participant is considered to have completed the study if the participant has completed all 
periods of the study including the last scheduled procedure shown in the SoA. 
 
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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: 
Age 
1. Participant must be 18 to 75 years of age (inclusive) at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics 
2. Have a diagnosis of migraine as defined by IHS ICHD-3 guidelines (1.1 or 1.2) (ICHD-3 
2018), with a history of migraine headaches of at least 1 year prior to Visit 1, and migraine 
onset prior to age 50. 
3. Prior to Visit 1, have a history of 4 to 14 migraine headache days and at least 2 migraine 
attacks per month on average within the past 3 months. 
4. From Visit 2 to Visit 3 (prospective baseline period), have a frequency of 4 to 14 migraine 
headache days and at least 2 migraine attacks (Section 3, Migraine and Headache 
Endpoint Definitions table).  
To avoid biased reporting, participants must not be told the number of migraine 
headache days on which study qualification is based. 
5. From Visit 2 to Visit 3 (prospective baseline period), must achieve sufficient compliance 
with ePRO daily headache entries as demonstrated by completion of at least 80% of daily 
ePRO diary entries. 
Weight 
6. Body mass index (BMI) <40 kg/m2. 
Sex and Contraceptive/Barrier Requirements 
7. Males and females may participate in this trial. 
a. Males 
i. No male contraception is required except in compliance with specific local 
government study requirements. 
b. Females 
i. WOCBP must test negative for pregnancy at Visit 1. 
ii. WOCBP must agree to use 1 form of highly effective contraception during the 
study as well as for 5 months after the last dose of study intervention or remain 
completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship, as part of their preferred and usual lifestyle during the study and for 
5 months after the last dose of study intervention (refer to the Reference Manual 
for acceptable forms of contraception).  
Birth control is not required if the female is infertile due to surgical sterilization 
(examples of surgical sterilization include bilateral salpingo-oophorectomy, 
bilateral salpingectomy, bilateral oophorectomy, or total hysterectomy) or is post-
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menopausal. The post-menopausal state is defined as at least 6 weeks post-
surgical bilateral oophorectomy with or without hysterectomy at any age, 
confirmed by operative note; or a cessation of menses for at least 12 consecutive 
months not induced by a medical condition or hormone therapy, and a follicle-
stimulating hormone level >40 mIU/mL in women aged 40 to 55 years with an 
intact uterus; or at least 12 months of spontaneous amenorrhea in women aged 55 
years or older not on hormone therapy, or who have a diagnosis of menopause 
prior to starting hormone replacement therapy. 
Informed Consent 
8. Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
9. Agree not to post any personal medical data related to the study or information related to 
the study on any website or social media site (for example, Facebook, Twitter, LinkedIn, 
and Google+) until the entire trial has completed. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
10. Known hypersensitivity to rimegepant or galcanezumab, and their excipients, or to 
monoclonal antibodies or other therapeutic proteins. 
11. Have local reading of ECG at Visit 1 showing abnormalities compatible with acute 
cardiovascular events and/or serious cardiovascular risk, or have had myocardial 
infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass 
graft, or stroke within 6 months of screening, or have planned cardiovascular surgery or 
percutaneous coronary angioplasty. QTcF >450 msec for males or >470 msec for females 
based on the ECG at Visit 1 must be discussed and judged not clinically significant by the 
principal investigator and Lilly Medical informed prior to enrollment. 
12. Any liver tests outside the normal range at Visit 1 that are clinically significant. ALT >2x 
ULN, or TBL >1.5x ULN, or ALP >2x ULN must be judged not clinically significant by 
the principal investigator, and Lilly Medical informed prior to enrollment. 
13. Evidence of psychiatric disease by medical history, such as schizophrenia, personality 
disorders, or other serious mood or anxiety disorders.  
Note: Participants with major depressive disorder (MDD), an anxiety disorder, or bipolar 
disorder whose disease state is considered stable and expected to remain stable throughout 
the course of the study, in the opinion of the investigator, may be considered for inclusion 
if they are not on excluded medications. 
14. Participants who, in the clinician’s judgment, are actively suicidal and therefore deemed to 
be at significant risk for suicide, or have had clinically significant suicidal ideation within 
the past month (for example, includes some plan or intent to act), or have had any suicidal 
behavior within the past month. 
15. Women who are pregnant or nursing. 
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16. Have an acute, serious, or unstable medical condition that, in the judgment of the 
investigator, indicates a medical problem that would preclude study participation. 
Prior/Concomitant Therapy 
17. Current use or prior exposure to any CGRP antagonist (small molecule or antibody) for 
any indication, including those who have previously completed or withdrawn from this 
study or any other study investigating a CGRP antagonist (small molecule or antibody). 
18. Are currently receiving medication or other treatments for the prevention of migraine. 
Participants must have discontinued such treatment at least 5 days prior to Visit 2. 
Botulinum toxin A and B that has been administered in the head or neck area for 
therapeutic use must be discontinued at least 3 months prior to Visit 2. Nerve blocks or 
device use (such as transcranial magnetic stimulation) in the head or neck area or for 
migraine prevention must be discontinued at least 30 days prior to Visit 2. 
19. Exclusion Criterion [19] was removed. 
20. Concomitant use of inhibitors of P-gp and BCRP are prohibited, and use of moderate or 
strong CYP3A4 inhibitors and moderate or strong CYP3A inducers is prohibited. 
21. Participants who have used opioids or barbiturate containing analgesic >4 days per month 
for the treatment of pain in more than 2 of the past 3 months (opioid administration in an 
emergency setting may be an exception). 
22. History of drug or alcohol abuse/dependence within 1 year prior to Visit 1 (excessive or 
compulsive use as judged by the investigator), or currently using drugs of abuse (including 
opioids, barbiturates, and marijuana), or any prescribed or over-the-counter medication in 
a manner that the investigator considers indicative of abuse/dependence. 
23. Have a positive urine drug screen for any substances of abuse at Visit 1.  
Note: A retest is allowed if the urine drug screen is positive for any prescribed substance 
or if, in the judgment of the investigator, there is an acceptable medical explanation for the 
positive result. The results of the retest must be negative at or prior to Visit 2. 
i. 
Participants who have a positive urine drug screen for an amphetamine or 
benzodiazepine that are prescribed for an approved indication other than 
migraine or headache may be allowed in the study at the Investigator’s 
discretion providing the dose of the medication is stable for at least 2 months 
prior to Visit 2 and is expected to remain stable during Visit 2 through 6. The 
investigator must document their determination in the participant’s source 
medical records. 
ii. 
Participants who have a positive urine drug screen for cannabis or cannabinoids 
which is prescribed (not recreational) for a condition other than migraine or 
headache may be allowed in the study provided the use is not expected to affect 
the interpretation of study results or safety of the participant. The usage should 
remain consistent for the duration of the study. The investigator must document 
their determination in the participant’s source medical records. 
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Prior/Concurrent Clinical Study Experience 
24. Are currently enrolled in any other clinical trial involving a study intervention or any other 
type of medical research judged not to be scientifically or medically compatible with this 
study. 
25. Have participated within the last 30 days or within 5 half-lives (whichever is longer) in a 
clinical trial involving an investigational product. If the investigational product’s half-life 
is not known, 6 months should have passed prior to Visit 1. 
Diagnostic Assessments 
26. History of new daily persistent headache, cluster headache or migraine subtypes including 
hemiplegic (sporadic or familial) migraine, retinal migraine, and migraine with brainstem 
aura (basilar-type migraine) defined by IHS ICHD-3. 
27. In the 3 months prior to randomization, have other types of headache besides migraine or 
tension type headache as defined by IHS ICHD-3. In other words, participants can have 
migraine or tension-type headache, but they cannot have other types of headache in that 
time. For instance, medication overuse headache or cluster headache. 
33. Prior to Visit 1, a history of ≥15 headache days (migraine, probable migraine or any other 
headache) per month on average during the past 3 months or are suspected of suffering 
from chronic migraine as defined per IHS ICHD-3. 
28. History of head or neck injury within 6 months prior to Visit 1. 
29. History of traumatic head injury associated with significant change in the quality or 
frequency of their headaches. 
Other Exclusions 
30. Are investigator site personnel directly affiliated with this study and/or their immediate 
families. Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted. 
31. Are Lilly employees. 
32. In the opinion of the investigator have other issues which would interfere with compliance 
with the study requirements and completion of evaluations required for this study. 
5.3. 
Lifestyle Considerations 
Not applicable.  
5.4. 
Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently enrolled in the study. 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 SAE.  
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Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once with approval from Lilly Medical for only the criteria shown below. If 
rescreening is performed, the participant must sign a new ICF and will be assigned a new 
participant number.  
A participant may rescreen when sufficient time has passed for the participant to meet the 
duration requirement or condition of the following criteria during the study enrollment period:  
 Inclusion Criterion [1] (Age): if the participant is less than age 18 at the time of informed 
consent, they may be rescreened if they reach age 18 during the study enrollment period 
 Inclusion Criterion [7]: Negative pregnancy test 
 Exclusion Criterion [15]: Women who are pregnant or nursing 
 Exclusion Criterion [16]: Acute, serious, or unstable medical condition. Some patients 
may qualify for rescreen if the acute illness resolves or unstable condition is stabilized 
(e.g., uncontrolled or unstable hypertension or blood pressure) 
 Exclusion Criterion [18]: Washout of previous preventives for migraine headache  
 Exclusion Criterion [25]: Washout of previous investigational product 
 Participants who have become eligible to enroll in the study as a result of a protocol 
amendment 
Use of concomitant medication that requires a stable dose for a specific duration prior to Visit 2 
may be rescreened if additional time is needed to meet the duration requirement. 
In addition, after consultation with and approval by a Lilly Medical representative, a participant 
may be rescreened if there is an unexpected technical difficulty with the ePRO diary capture 
during the prospective baseline period. 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant 
Not applicable.  
 
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6. 
Study Intervention(s) and Concomitant Therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol. It is a pharmaceutical form of an active ingredient or placebo being 
tested or used as a reference in a clinical trial, including a product with a marketing authorization 
when used or assembled (formulated or packaged) in a way different from the approved form, or 
when used for an unapproved indication, or when used to gain further information about an approved 
use (FDA 2018). 
6.1. 
Study Intervention(s) Administered 
Group Name 
Galcanezumab 
Rimegepant 
Intervention 
Name 
Galcanezumab 
Rimegepant 
placebo 
Rimegepant 
Galcanezumab 
placebo 
Type  
Biologic 
Placebo 
Drug 
Placebo 
Dose 
Formulation 
Solution 
Placebo ODT 
ODT 
Placebo Solution 
Unit Dose 
Strength(s) 
120 mg 
N/A 
75 mg 
N/A 
Dosage 
Level(s) 
240 mg (2 
injections) 
loading dose, 
then 120 mg 
monthly 
1 tablet every 
other day 
75 mg every 
other day 
2 SC injections 
loading dose, then 
1 SC injection 
monthly 
Route of 
Administration 
SC 
Oral 
Oral 
SC 
Use 
Experimental 
IMP and 
NIMP 
IMP 
Sourcing 
Provided centrally by the sponsor 
Packaging and 
Labeling 
Study interventions will be provided in containers. Each container will be 
labeled as required per country requirement. 
Abbreviations: IMP = investigational medicinal product; N/A = not applicable; NIMP = non-investigational 
medicinal product; ODT = orally disintegrating tablet; SC = subcutaneous. 
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6.2. 
Preparation, Handling, Storage, and Accountability 
 The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
 Only participants enrolled in the study may receive study intervention. Only authorized 
study personnel may supply, prepare, 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 study personnel. 
 The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and 
final disposition records). 
 The designated unblinded site personnel will handle all study intervention preparation, 
handling and accountability 
 
 
 Further guidance and information for the final disposition of unused study interventions 
are provided 
.  
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is a randomized, double-blind, double-dummy study.  
Participants will be randomly assigned in a 1:1 ratio to receive study intervention. All 
participants will be centrally assigned to randomized study intervention using an IWRS. Before 
the study is initiated, the log in information and directions for the IWRS will be provided to each 
site. Participants will be stratified by baseline migraine frequency (<8 migraine headache days 
versus ≥8 migraine headache days). Randomization into 1 stratum may be discontinued at the 
discretion of the sponsor. 
Study intervention will be dispensed to the participant by the designated unblinded site personnel 
at Visit 3 as summarized in SoA. The participants will receive enough tablets and syringes for 
the double-blind treatment period with the longest possible visit interval between visits.  
Returned study intervention should not be re-dispensed to the participants.  
Treatment assignments will remain blinded to investigators, study site personnel directly 
involved in participant assessments, and participants. To preserve the blinding of the study, a 
minimum number of Lilly personnel will see the randomization table and treatment assignments 
before the study is completed. Designated unblinded site personnel are responsible for receipt of 
study intervention shipments, dispensing study intervention, confirming treatment assignments, 
and receipt of any unused study intervention by the participant. Designated unblinded site 
personnel will not be involved in any clinical aspects of the study, including clinical evaluations 
and AE assessments. It is critical that the blind is maintained throughout the study (3 months). 
 
As the last procedure of Visit 3, the unblinded site personnel will train the participant/caregiver 
on SC administration, which may include injecting the contents of the first syringe and 
supervising the participant/caregiver in the administration of the second injection. The unblinded 
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site personnel should also train the participant how to take the ODT and supervise the participant 
opening the blister pack and taking the first dose of ODT. 
At the telephone visits at which an injection is to occur, self-injections are to occur on the same 
day as the scheduled telephone visit, prior to the start of visit procedures. 
In the event of a quality assurance audit, the auditor(s) will be allowed access to unblinded study 
intervention records at the site(s) to verify that randomization/dispensing has been done 
accurately. 
Emergency Unblinding 
This is a double-blind study in which participants, caregivers, and study site personnel who are 
performing clinical assessments are blinded to study intervention. The IWRS will be 
programmed with blind-breaking instructions. In case of an emergency, the investigator has the 
sole responsibility for determining if unblinding of a participants’ intervention assignment is 
warranted.  
Participant safety must always be the first consideration in making such a determination. If the 
investigator decides that unblinding is warranted, the investigator should make every effort to 
contact the sponsor prior to unblinding a participant’s intervention assignment unless this could 
delay emergency treatment for the participant. If a participant’s intervention assignment is 
unblinded, the sponsor must be notified immediately after breaking the blind. The date and 
reason that the blind was broken must be recorded. 
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be discontinued from the study. In cases where there are ethical reasons to have 
the participant remain in the study, the investigator must obtain specific approval from a sponsor 
medical monitor for the participant to continue in the study. 
6.4. 
Study Intervention Compliance 
At Visit 3, the dose of study intervention and study participant identification will be confirmed 
by unblinded site personnel prior to the time of dosing. The date and time of each dose 
administered will be recorded.  
Compliance will be assessed by the unblinded site personnel at the study site by counting 
returned unused ODT/syringes at Visit 6, and documented.  
 Participants should be instructed to return the unused ODT and syringes at Visit 6 in the 
ancillary containers provided at Visit 3. Other closed containers are acceptable as long as 
study intervention is not visible. 
A record of the number of syringes and ODT dispensed to and taken by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start and 
stop dates, including dates for intervention delays and/or dose reductions will also be recorded. 
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6.5. 
Dose Modification 
No dose modification will be allowed during the study. 
6.6. 
Continued Access to Study Intervention after the End of the Study 
Study intervention will not be made available to participants after conclusion of the study.  
6.7. 
Treatment of Overdose 
In the event of an overdose, it is recommended that the participant be monitored for any signs or 
symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately. 
The treating physician should: 
● Contact the medical monitor immediately. 
● Evaluate the participant to determine, in consultation with the medical monitor, whether 
study intervention should be interrupted. 
Refer to Nurtec ODT® USPI (2021) for details related to overdose of rimegepant ODT. 
6.8. 
Concomitant Therapy 
See Section 10.2 for a list of medications that are, and are not, allowed in this study.  
Any changes in the list of allowed/not allowed medications will be communicated to 
investigators and will not constitute a protocol amendment. The concomitant use of acute 
medications to treat migraine is allowed, with some limitations. Treatments used for the 
prevention of migraine, including nutraceuticals, pharmacological and nonpharmacological 
interventions, are not allowed at any time during Study Period II or III. Participants should have 
washed out all migraine preventive treatments at least 5 days prior to Visit 2. 
Botulinum toxin A or B in the head or neck area for therapeutic use is not allowed within 3 
months prior to Visit 2. Nerve blocks or use of therapeutic devices (such as transcranial magnetic 
stimulation) in the head or neck area or for migraine prevention are not allowed within 30 days 
before Visit 2. 
Participants will capture whether they took any acute headache medication as part of their daily 
ePRO diary entry during Study Periods II and III. Acute headache medication name, dose, and 
date will be recorded by participants during Study Periods II and III on a headache medication 
log, which will be returned to site staff at Visit 6 (the final study visit) or early discontinuation 
visit.  
For acetaminophen (or paracetamol), the maximal allowed dose will be 3 g/day from all 
acetaminophen-containing medicinal products. 
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 
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● Dosage information including dose and frequency for concomitant therapy of 
special interest 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Treatments used for the prevention of migraine, including nutraceuticals, pharmacological and 
nonpharmacological interventions, are not allowed at any time during Study Periods II and III. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.8. 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant should remain in 
the study to be evaluated for safety and efficacy assessments, unless criteria in Section 7.2 apply.  
A participant should be permanently discontinued from study intervention if:  
 the participant becomes pregnant during the study (see Section 8.3.2) 
 the participant requests to discontinue study intervention 
 clinical judgment of the investigator 
7.1.1. 
Liver Chemistry Stopping Criteria 
Interrupting study drug based on liver test elevations in participants with normal or near-
normal baseline liver tests 
In study participants with normal or near normal baseline liver tests (ALT, AST, ALP <1.5x 
ULN), the study drug should be interrupted and close hepatic monitoring initiate (see Section 
10.5.2) if one or more of these conditions occur: 
Elevation 
Exception 
ALT or AST >8x ULN 
 
ALT or AST >5x ULN for more than 2 weeks 
 
ALT or AST >3x ULN and either TBL >2x ULN or INR >1.5  
For participants with Gilbert’s syndrome: If 
baseline direct bilirubin is >0.5 mg/dL, then 
the doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN. 
ALT or AST >3x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >3x ULN when the source of increased ALP is the liver 
 
ALP >2.5x ULN and TBL >2x ULN  
For participants with Gilbert’s syndrome: If 
baseline direct bilirubin is >0.5 mg/dL, then 
the doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN. 
ALP >2.5x ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%) 
 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 and 
other consensus guidelines, with minor modifications. 
 
 
 
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Interrupting study drug based on elevated liver tests in participants with abnormal 
baseline liver tests 
In study participants with abnormal baseline liver tests (ALT, AST, ALP ≥1.5x ULN), the study 
drug should be interrupted if one or more of these conditions occur: 
Elevation 
Exception 
ALT or AST >4x baseline 
 
ALT or AST >3x baseline for more than 2 weeks 
 
ALT or AST >2x baseline and either TBL >2x ULN or INR >1.5  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then the doubling of direct bilirubin should 
be used for drug interruption decisions 
rather than TBL >2x ULN. 
ALT or AST >2x baseline with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >2.5x baseline when the source of increased ALP is the liver 
 
ALP >2x baseline and TBL >2x ULN  
For participants with Gilbert’s syndrome: 
If baseline direct bilirubin is >0.5 mg/dL, 
then the doubling of direct bilirubin should 
be used for drug interruption decisions 
rather than TBL >2x ULN. 
ALP >2x baseline with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 and 
other consensus guidelines, with minor modifications. 
Resuming study drug after elevated liver tests 
Resumption of the study drug can be considered only in consultation with the Lilly-designated 
medical monitor, if the liver test results return to baseline, and if a self-limited non-drug etiology 
is identified. Otherwise, the study drug should be discontinued. 
For suggested actions and follow-up hepatic assessments, see Section 10.5. 
7.1.2. 
QTc Stopping Criteria 
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QT interval corrected using Fridericia’s formula [QTcF]) after enrollment, the 
investigator or qualified designee will determine if the participant can continue in the study and 
if any change in participant management is needed. This review of the ECG printed at the time of 
collection must be documented. Any new clinically relevant finding should be reported as an AE.  
7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study:  
● at any time at his/her own request  
● at the request of his/her designee (for example, parents or legal guardian) 
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● at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons 
● if enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study 
● if the participant, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent. 
Discontinuation 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 from both the study intervention and 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. Site personnel or designee are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site.  
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8. 
Study Assessments and Procedures 
 Study procedures and their timing are summarized in the SoA.  
 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. 
Primary Efficacy Assessment 
8.1.1.1. 
ePRO Diary 
Starting at Visit 2, participants will be asked to use an ePRO device to record headache 
information, including reporting headaches, intensity of headache, headache features, and 
whether any acute headache medication was taken. The system also will be used to collect 
information about migraine-associated symptoms (for example, photophobia, phonophobia, 
nausea, and/or vomiting). 
8.1.2. 
Secondary Efficacy Assessments 
8.1.2.1. 
Migraine-Specific Quality of Life Questionnaire Version 2.1 
The Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) is a self-
administered health status instrument that was developed to address the physical and emotional 
impact on functioning that is of specific concern to individuals suffering from migraine 
headaches.  
The instrument consists of 14 items that address 3 domains: (1) Role Function-Restrictive; (2) 
Role Function-Preventive; and (3) Emotional Function (Jhingran et al. 1998b). The restrictive 
domain specifically measures disability as related to the impact on performance of normal 
activities, with the preventive domain addressing complete functional impairment and the 
emotional domain assessing the feelings related to disabling monthly migraine headache days. 
Responses are given using a 6-point Likert-type scale, ranging from “none of the time” to “all of 
the time.” Raw scores for each domain are computed as a sum of item responses, with the 
collective sum providing a total raw score that is then converted to a 0 to 100 scale, with higher 
scores indicating a better health status, and a positive change in scores reflecting functional 
improvement (Jhingran et al. 1998a; Martin et al. 2000). The instrument was designed with a 
4-week recall period and is considered reliable, valid, and sensitive to change in functional 
impairment due to migraine (Jhingran et al. 1998b; Bagley et al. 2012). 
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8.1.2.2. 
Migraine Disability Assessment 
The Migraine Disability Assessment (MIDAS) is a patient-rated scale which was designed to 
quantify headache-related disability over a 3-month period. This instrument consists of 5 items 
that reflect the number of days reported as missed, or with reduced productivity at work or home 
and social events. Each question is answered as the number of days during the past 3 months of 
assessment, ranging from 0 to 90, with the total score being the summation of the 5 numeric 
responses. A higher value is indicative of more disability (Stewart et al. 1999a, 1999b, 2001).  
This instrument is considered highly reliable and valid, and is correlated with clinical judgment 
regarding the need for medical care (Stewart et al. 1999a, 1999b, 2001). For clinical 
interpretability, 4 categorical grades were developed based on the total score: Grade I (0 to 5) is 
for little or no disability, Grade II (6 to 10) is for mild disability, Grade III (11 to 20) is for 
moderate disability, and Grade IV (21+) is for severe disability. The severe disability category 
has subsequently been subdivided into Grade IV-A (severe [21 to 40]) and Grade IV-B (very 
severe [41 to 270]) because a high proportion of patients with chronic migraine are in Grade IV 
(Blumenfeld et al. 2011). 
8.1.3. 
Tertiary Efficacy Assessment 
8.1.3.1. 
The Patient Global Impression of Severity 
The Patient Global Impression of Severity (PGI-S) scale (Guy 1976) is a patient-rated instrument 
that measures illness severity. For this study, the participant will be instructed as follows: 
“Considering migraine as a chronic condition, how would you rate your level of illness?” The 
PGI-S includes a range of possible responses, from 1 (“normal, not at all ill”) to 7 (“extremely 
ill”). 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
 A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight 
will also be measured and recorded. 
 Neurological examinations will be conducted to assess for any signs of preexisting or 
treatment-emergent neurological abnormalities.  
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.2. 
Vital Signs 
Vital signs will include body temperature, blood pressure, and pulse. Blood pressure and pulse 
will be measured in triplicate in the sitting position after the participant has rested for at least 5 
minutes, and before collection of blood samples and dosing (if dosing is on the same day), 
according to the SoA (Section 1.3), and following the study-specific recommendations included 
in the Reference Manual for the study. 
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8.2.3. 
Electrocardiograms 
Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) and Reference 
Manual using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTcF intervals. In the event the ECG machine does not automatically calculate 
the QTcF interval, the QTcF interval may be manually calculated. ECGs should be collected 
prior to blood draws and dosing. Participants must be supine for approximately 5 to 10 minutes 
before ECG collection and remain supine but awake during ECG collection. 
Refer to Section 5.2 for exclusion criteria related to ECG findings. 
8.2.4. 
Clinical Safety Laboratory Tests 
See Appendix 2 for the list of clinical laboratory tests to be performed and the SoA for the timing 
and frequency. 
The investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE. The laboratory results must be 
retained with source documents unless a Source Document Agreement or comparable document 
cites an electronic location that accommodates the expected retention duration. 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 the double-
blind treatment period 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 the sponsor notified. 
 All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SoA, standard collection requirements, and laboratory 
manual. 
If laboratory values from non-protocol specified laboratory assessments performed at an 
investigator-designated local laboratory require a change in participant management or are 
considered clinically significant by the investigator (for example, SAE or AE or dose 
modification), then report the information as an AE.  
8.2.5. 
Pregnancy Testing  
WOCBP must undergo pregnancy testing according to the SoA. 
8.2.6. 
Suicidal Ideation and Behavior Risk Monitoring 
Participants with migraine may occasionally develop SIB. 
Participants who experience signs of SIB should undergo a risk assessment. All factors 
contributing to SIB should be evaluated and consideration should be given to discontinuation of 
the study intervention.  
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When informed consent or assent has been given, participants/caregivers should be alerted about 
the emergence of unusual changes in behavior, as well as the emergence of SIB and to report 
such symptoms immediately to the study investigator. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints 
The definitions of the following events can be found in Appendix 3: 
 AEs 
 SAEs 
These events will be reported by the participant (or, if necessary, 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 these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study intervention or the study (see Section 7). 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs 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).  
For PCs, the unblinded site personnel are responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality.  
A PC is any written, electronic, or oral communication that alleges deficiencies related to the 
identity, quality, durability, reliability, safety, effectiveness, or performance of a trial 
intervention. When the ability to use the study intervention safely is impacted, the following are 
also PCs: 
 Deficiencies in labeling information, and 
 Use errors for device or drug-device combination products due to ergonomic design 
elements of the product. 
Sponsor collects PCs on study interventions and drug delivery systems used in clinical studies in 
order to ensure the safety of study participants, monitor quality, and to facilitate process and 
product improvements. 
Participants will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the study interventions so that the situation can be assessed. Note: 
The designated unblinded site personnel are responsible for handling all aspects of PCs. 
Note: AEs/SAEs that are associated with a PC will also follow the processes outlined in 
Section 8.3.1 of the protocol. 
For the time periods for detecting and reporting PCs, see Section 8.3.1. 
 Follow-up applies to all participants, including those who discontinue study intervention. 
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 The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the PC. 
 New or updated information will be recorded on the originally completed PC form with 
all changes signed and dated by the investigator and submitted to the sponsor. 
Note: An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a PC and as an AE/SAE. 
8.3.1. 
Timing and Mechanism for Collecting Events 
This table describes the timing, deadlines, and mechanism for collecting events. 
Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
Adverse Event 
AE 
Signing of 
the ICF 
Participation 
in study has 
ended 
As soon as possible 
upon site awareness 
AE CRF 
N/A 
Serious Adverse Event 
SAE and SAE 
updates – prior 
to start of study 
intervention and 
deemed 
reasonably 
possibly related 
with study 
procedures 
Signing of 
the ICF 
Start of 
intervention 
Within 24 hours of 
awareness 
SAE paper form 
SAE paper 
form 
SAE and SAE 
updates – after 
start of study 
intervention 
Start of 
intervention 
Participation 
in study has 
ended 
Within 24 hours of 
awareness 
SAE paper form 
SAE paper 
form 
SAEa – after 
participant’s 
study 
participation has 
ended and the 
investigator 
becomes aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
Pregnancy 
Pregnancy in 
WOCBP and 
female partners 
of male 
participants 
After the 
start of study 
intervention 
At least 5 
months after 
the last 
subcutaneous 
injection of 
study 
intervention 
Within 24 hours (see 
Section 8.3.2) 
Pregnancy paper 
form 
N/A 
Product Complaints 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 24 hours of 
awareness 
PC form 
N/A 
PC not 
associated with 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
PC form 
N/A 
Updated PC 
information 
— 
— 
As soon as possible 
upon site awareness 
Originally 
completed PC form 
with all changes 
signed and dated by 
the investigator 
N/A 
PC (if 
investigator 
becomes aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
PC form 
 
Abbreviations: AE = adverse event; CRF = case report form; ICF = informed consent form; N/A = not applicable; 
PC = product complaint; SAE = severe adverse event; WOCBP = woman of childbearing potential. 
a SAEs after study participation should not be reported unless the investigator deems them to be possibly related to 
study treatment or study participation. 
8.3.2. 
Pregnancy 
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 study 
intervention. 
● 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 gestational age, 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 gestational age, 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 <20 weeks gestational age) or still birth 
(occurring at ≥20 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 
protocol Section 8.3.1. 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. If the participant is discontinued from the 
study, follow the standard discontinuation process. The follow up on the 
pregnancy outcome should continue independent of intervention or study 
discontinuation.  
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8.4. 
Pharmacokinetics 
PK parameters are not evaluated in this study. 
8.5. 
Pharmacodynamics 
PD parameters are not evaluated in this study. 
8.6. 
Genetics 
Genetics is not evaluated in this study. 
8.7. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.8. 
Immunogenicity Assessments 
Immunogenicity assessments are not evaluated in this study. 
8.9. 
Health Economics 
Medical resource utilization and health economics parameters are not evaluated in this study. 
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9. 
Statistical Considerations 
The SAP will be finalized prior to unblinding, and it will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of the most important endpoints, including primary and key 
secondary endpoints. 
9.1. 
Statistical Hypotheses 
The primary objective is to demonstrate that galcanezumab is superior to rimegepant in reducing 
migraine headaches as measured by average monthly response rate across a 3-month period (in 
this case, the 3-month double-blind period). If one lets πG and πR = the true 3-month average 
monthly 50% response rates for galcanezumab and rimegepant respectively, the null and 
alternative hypotheses are as follows: 
H0: 𝜋𝐺 ≤ 𝜋𝑅 against Ha: 𝜋𝐺 > 𝜋𝑅 
The corresponding hypotheses for secondary objectives with response rate based estimands (for 
example, average monthly 75% response rate) are identical as those for the primary (with 
corresponding changes to the true response rate of interest).  
For secondary objectives that are to demonstrate the superiority of galcanezumab over 
rimegepant as measured by continuous measures (for example, reduction from baseline in 
monthly migraine headache days), the null and alternative hypotheses would be of the form: 
H0: 𝜇𝐺 ≤ 𝜇𝑅 against Ha: 𝜇𝐺 > 𝜇𝑅 
Where μG and μR are the true mean reductions for galcanezumab and rimegepant, respectively. 
While all hypotheses given above are 1-sided, these hypotheses will operationally be evaluated 
via 2-sided tests. 
9.1.1. 
Multiplicity Adjustment 
The statistical comparisons for the primary efficacy endpoint and the key secondary endpoints 
will be carried out in the hierarchical order as indicated in Section 3. This means that statistically 
significant results for the comparison in the higher rank (primary, then ranked secondary 
variables) are required to initiate the testing of the next comparison in the lower rank. Since a 
step-down procedure is used, each comparison will be tested at a significance level of 0.05 and 
an overall alpha level of 0.05 will be preserved. 
The order of objectives/comparisons may change (with the exception of the primary objective). 
Should such a change take place, the final hierarchical order used/multiplicity adjustment 
approach employed to ensure overall 0.05 alpha-level control will be documented within an 
approved final SAP prior to study unblinding. 
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9.2. 
Analyses Sets 
Participant Analysis Set 
Description 
Intention to Treat (ITT) set 
All randomized participants and receive at least 1 dose of study 
intervention. Participants will be included in the analyses 
according to their randomized treatment. 
Safety analysis set 
All participants who are exposed to study intervention. 
Participants will be analyzed according to the treatment they 
actually received. 
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
Statistical analysis of this study will be the responsibility of Lilly or its designee. Details of 
statistical analysis methods will be described in the SAP with the final SAP approved prior to 
study unblinding being the official version for this study.  
Unless otherwise specified, analyses will be conducted on the ITT population for efficacy 
analyses and on the safety population for safety analyses (see Section 9.2). When change from 
baseline is assessed, the participant will be included in the analysis only if he/she has a baseline 
and a postbaseline measurement. 
Binary efficacy variables with repeated measures will be analyzed using a GLIMMIX as pseudo-
likelihood-based mixed effects repeated measures analysis. The GLIMMIX model will include 
the fixed, categorical effects of treatment, month, and treatment-by-month interaction, as well as 
the continuous, fixed covariate of baseline monthly migraine headache days value. 
For binary efficacy variables without repeated measures, comparisons between treatment groups 
will be performed using logistic regressions with LOCF imputation being used. This model will 
include the main effects of treatment and a continuous effect for baseline monthly migraine 
headache days.  
Continuous efficacy variables with repeated measures will be analyzed using MMRM methods. 
The MMRM will include the fixed categorical effects of treatment, month, and treatment-by-
month interaction, as well as the continuous fixed covariates of baseline and baseline-by-month 
interaction. Wherever possible an unstructured covariance matrix will be used to model the 
correlation structure among repeated measures. A list of other covariance structures to be used in 
case of nonconvergence will be given within the SAP. 
For continuous efficacy variables without repeated measures, an ANCOVA model with LOCF 
imputation will be used, which contains the main effects of treatment, and the continuous fixed 
covariate of baseline. Type III sum-of-squares for the LSMeans will be used for the statistical 
comparisons. 
For continuous safety variables with repeated measures, MMRM methods will be used, as well 
as an ANCOVA model with LOCF imputation if deemed appropriate. When an ANCOVA 
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model is used for safety measures, the model will contain the main effect of treatment, as well as 
the continuous fixed covariate of baseline. Type III sum-of-squares for the LSMeans will be used 
for the statistical comparisons. 
For categorical safety variables (such as AEs and other categorical changes of interest), 
comparisons between treatment groups will be performed using Fisher’s exact test. 
Treatment effects will be evaluated based on a 2-sided significance level of 0.05 for all the 
efficacy and safety analyses unless otherwise stated. The 95% confidence intervals for the 
difference in LSMeans between treatment groups will be presented. Type I error due to multiple 
comparisons for the primary and key secondary objectives will be controlled using sequential 
gating procedure (see Section 9.1.1). There will be no adjustments for multiplicity for analyses 
of other data (other secondary objectives or tertiary objectives).  
9.3.2. 
Primary Endpoint(s)/Estimand(s) Analysis 
The primary endpoint is based on the percentage of participants showing a 50% response on each 
month, defined as showing 50% or fewer migraine headache days within the month than was 
seen during the baseline period. The primary estimand of interest is the overall mean monthly 
50% response rate across the 3-month double-blind period attributable to the randomized 
treatment based on all available data as estimated from the GLIMMIX model. Here all available 
monthly migraine headache data will contribute to analysis as long as baseline monthly migraine 
headache day values are available. Any migraine headache day data collected after study 
intervention discontinuation but within the double-blind period will still be used within the 
analysis. 
The primary analysis method will be the GLIMMIX given in Section 9.3.1 above for binary data. 
If the sample size is increased as a result of the interim analysis, the CHW procedure (Cui et al. 
1999) will be applied to the primary endpoint to control the type I error at a one-sided α = 0.025 
significance level. The CHW method ensures strong control of type I error when the sample size 
is increased in a data dependent manner. 
If the sample size is increased as a result of the interim analysis, an unadjusted point estimate for 
the primary efficacy analysis will be calculated and reported. A median unbiased point estimate 
and a stage-wise adjusted confidence interval for the primary efficacy analysis will be calculated 
and reported based on the approach described by Brannath et al. (2009) to assess sensitivity of 
the point estimate. 
9.3.3. 
Secondary Endpoints/Estimands Analysis 
For all secondary endpoints, a similar estimand to the one used for the primary analysis will be 
employed. That is, the estimand of interest will be based on mean monthly estimates 
across/within the double-blind period and will be based on all available data during that period 
(even if collected after study intervention discontinuation). Additionally, baseline values must 
also be available.  
The corresponding analyses for each of these endpoints will be as stated within Section 9.3.1 
based on the type of endpoint measured (that is, binary or continuous).  
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If the sample size is increased, the CHW test statistic will be calculated for the key secondary 
endpoints before applying multiple testing procedure. 
9.3.4. 
Safety Analyses 
The safety and tolerability of treatment will be assessed by summarizing the following: 
 TEAEs 
 SAEs 
 AEs leading to discontinuation 
 AEs related to injection sites  
 vital signs  
 laboratory measurements  
Unless specified otherwise, the categorical safety analyses will include both scheduled and 
unscheduled visits. Comparisons between treatment groups for all categorical safety measures 
will be made using Fisher’s exact test within the safety population.  
9.3.4.1. 
Treatment-Emergent Adverse Events 
TEAEs are defined as the reported AEs that first occurred or worsened during the postbaseline 
period compared with the baseline period. For each TEAE, the reported severity level of the 
event (mild, moderate, or severe) will be determined by physician opinion. The MedDRA LLT 
will be used in the treatment-emergent computation. For each LLT, the maximum severity at 
baseline will be used as the baseline severity. If the maximum severity during postbaseline is 
greater than the maximum baseline severity, the event is considered to be treatment-emergent for 
the specific postbaseline period. Safety analyses for each study period will use all visits up 
through the last scheduled visit in the prior study period as baseline. For each participant and 
TEAE, the maximum severity for the MedDRA level being displayed (preferred term, High-
Level Term, or System Organ Class [SOC]) is the maximum postbaseline severity observed from 
all associated LLTs mapping to that MedDRA level. 
For events that are sex-specific, the denominator and computation of the percentage will include 
only participants from the specific sex. 
9.3.4.2. 
Vital Signs 
Vital signs collected during the study include systolic and diastolic blood pressure, pulse, and 
temperature. For vital signs procedures see Section 8.2.2.  
The number and percentage of participants meeting criteria for treatment-emergent abnormalities 
in vital signs at any time during study will be summarized. Treatment group comparisons will be 
performed using Fisher’s exact test. 
9.3.4.3. 
Laboratory Tests 
The incidence rates of participants with treatment-emergent abnormal, high, or low laboratory 
values at any time postbaseline will be assessed using Fisher’s exact test for each laboratory test. 
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9.3.5. 
Other Analyses 
Details of analyses of other endpoints not falling under either efficacy or safety will be provided 
within the SAP. 
9.4. 
Interim Analysis 
One interim analysis is planned for this study. The interim analysis will occur during Study 
Period III (double-blind treatment); this may result in increasing the sample size or continuing 
with the planned sample size. Details will be documented in the SAC SAP and ERB supplement. 
To minimize the potential bias that results from performing an interim analysis, the interim 
analysis for this study will be conducted by a SAC external to the study team. 
Only the SAC is authorized to evaluate unblinded interim analyses results to make an informed 
decision. Study sites will receive information about interim results ONLY if they need to know 
for the safety of their patients. 
Unblinding details will be specified in the unblinding plan section of the SAP or a separate 
unblinding plan document. 
9.5. 
Sample Size Determination 
The study will screen an estimated 1150 potential study participants to ensure a minimum of 
approximately 575 randomized participants. Based on the assumption of treatment difference of 
12%, the minimum sample size of approximately 575 provides more than 85% power at a two-
sided significance level of 5% and a dropout rate of no more than 10%, with the opportunity to 
increase the final sample size at the interim analysis if indicated to maintain a well-powered 
study. To preserve blinding, details of the sample size and power calculations are omitted from 
this protocol and are provided to the ERB in a separate document. If the interim is not 
performed, then the trial will enroll to a sample size as specified in the ERB document. 
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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: 
○ Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines 
○ Applicable ICH GCP Guidelines 
○ Applicable laws and regulations 
● The protocol, protocol amendments, ICF, IB, and other relevant documents (for 
example, 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. 
● Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
● The investigator will be responsible for the following: 
○ 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. 
○ Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures. 
○ Providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 Code of Federal Regulations (CFR), ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations. 
● Investigator sites are compensated for participation in the study as detailed in the 
CTA. 
10.1.2. 
Informed Consent Process 
● The investigator or his/her representative will explain the nature of the study, 
including the risks and benefits, to the participant, and answer all questions 
regarding the study. 
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● 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, privacy and data 
protection 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 entered 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 reconsented 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 and is kept on file.  
Participants who are rescreened are required to sign a new ICF. 
10.1.3. 
Data Protection 
● Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets or tissue samples that are transferred to the sponsor 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 sponsor 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 his/her 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. 
● The sponsor has processes in place to ensure data protection, information security 
and data integrity. These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach. 
10.1.4. 
Committees Structure 
Potential cardiovascular events will be adjudicated by an external CEC. The role of the CEC is to 
adjudicate defined clinical events in a blinded, consistent, and unbiased manner throughout the 
course of a study. The purpose of the CEC for adjudication of cardiovascular events is to ensure 
that all reported events are evaluated uniformly by a single group.  
Death, resuscitated cardiac arrest, and potential treatment-emergent cardiovascular events from 
the CRF will be identified using a search strategy based on the 9 MedDRA SMQs listed below. 
Narrow terms from these SMQs will be adjudicated if they are reported as a SAE. Potential non-
serious cardiovascular events may be selected for adjudication following blinded medical review. 
Details of membership, operations, recommendations from the Committee, and the 
communication plan will be documented in the charter.  
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Narrow terms in the following SMQs will be adjudicated: 
 Cardiac arrhythmias (includes sub SMQs; SMQ 20000049) 
 Cardiac failure (SMQ 20000004) 
 Cardiomyopathy (SMQ 20000150) 
 Central nervous system vascular disorders (includes sub SMQs; SMQ 20000060) 
 Embolic and thrombotic events (includes sub SMQs; SMQ 20000081) 
 Hypertension (SMQ 20000147) 
 Ischemic heart disease (includes sub SMQs; SMQ 20000043) 
 Pulmonary hypertension (SMQ 20000130) 
 Torsade de pointes/QT prolongation (SMQ 20000001) 
Case unblinding may be performed for above reviews, only if necessary 
10.1.5. 
Dissemination of Clinical Study Data 
A clinical study report will be provided for this study and a summary of study information 
provided on publicly available websites. 
10.1.6. 
Data Quality Assurance 
● All participant data relating to the study will be recorded on electronic CRFs 
unless transmitted to the sponsor or designee electronically (for example, 
laboratory data). The investigator is responsible for verifying that data entries are 
accurate and correct by 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. 
● QTLs will be pre-defined to identify systematic issues that can impact participant 
safety and/or reliability of study results. These pre-defined parameters will be 
monitored during the study and important excursions from the QTLs and remedial 
actions taken will be summarized in the clinical study report. 
● Monitoring details describing strategy (for example, 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 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. 
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● The sponsor assumes accountability for actions delegated to other individuals (for 
example, 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 the time period outlined in the CTA 
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 records may be transferred to another location or 
party without written notification to the sponsor. 
● In addition, sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study 
may be audited by sponsor or its representatives, and/or regulatory agencies at 
any time. Investigators will be given notice before an audit occurs. 
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
An EDC system will be used in this study for the collection of CRF data. The investigator 
maintains a separate source for the data entered by the investigator or designee into the 
sponsor-provided EDC system. The investigator is responsible for the identification of any data 
to be considered source and for the confirmation that data reported are accurate and complete by 
signing the CRF. 
Additionally, eCOA data (participant-focused outcome instrument) will be directly recorded by 
the participant into an instrument (handheld smart phone and/or tablet). The eCOA data will 
serve as the source documentation and the investigator does not maintain a separate, written or 
electronic record of these data. 
Data collected via the sponsor-provided data capture system(s) will be stored at third parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture systems. Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports or electronic transfers will be provided to the 
investigator for review and retention. Data will subsequently be transferred from the central 
vendor to the sponsor data warehouse. 
Data from complaint forms submitted to sponsor will be encoded and stored in the global PC 
management system. 
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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 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. 
● Definition of what constitutes source data can be found in Section 10.1.6.  
10.1.8. 
Study and Site Start and Closure 
First Act of Recruitment 
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 participant visit and will be the study start date. 
Study or Site Termination 
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: 
For study termination: 
● 
Discontinuation of further study intervention development 
For site termination: 
● 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 (evaluated after a reasonable amount of time) of 
participants by the investigator 
● Total number of participants included earlier than expected 
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. 
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10.1.9. 
Publication Policy 
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal. 
10.1.10. 
Investigator Information 
Physicians with a specialty in neurology, headache specialist, or other physicians with 
experience in headache clinical trials and diagnosing and treating migraine participants will 
participate as investigators in this clinical trial. 
 
 
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10.2. 
Appendix 2: Treatments Allowed and Treatments not Allowed as 
Concomitant Therapy 
 
A. Medications allowed for the ACUTE treatment of migraine headaches or other pain 
or injury: 
Acetaminophen (paracetamol), NSAIDs; Triptans; Ergotamine and derivatives; aspirin, caffeine, and 
acetaminophen combination; or combinations thereof. For acetaminophen, the maximal allowed dose will be 
3 g/day from all acetaminophen-containing medicinal products. 
 
The following medications are allowed with restrictions: 
1. Opioid and barbiturates no more than 4 days/month. 
2. Single dose of injectable steroids allowed only once during the study, in an emergency setting (SP II and III). 
 
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B. Medications, procedures or devices not allowed for any reason/indication during SP II 
and III: 
Acetazolamide 
Acupuncture 
Anticonvulsants/Antiepilepticsa  
Antipsychotics  
Beta-blockers  
Botulinum toxin applied to head/neck area for therapeutic use  
Cannabis/Cannabinoidsb 
Chiropractic procedures, physiotherapy, TENS or other electric devices on head and neck 
Corticosteroids for oral usec 
CYP3A4: Moderate and strong inhibitors of CYP3A4 (includes Paxlovid)d  
CYP3A: Moderate and strong inducers of CYP3A 
Efflux transporters: Inhibitors of P-gp and BCRP  
Flunarizine 
Herbals with anti-inflammatory effect (feverfew, willow bark, petasites/butterbur), herbals with sympathomimetic 
effect (ma huang, ephedra, bitter orange, synephrine) and herbals with catecholamine transmitter reuptake 
inhibition (St. John’s Wort) 
Migravent 
Monoamine oxidase inhibitors (MAOIs) 
Memantine 
Neurotropin® 
Nerve block in head/neck area 
Serotonin 5HT2a/2c antagonists, for example: nefazodone 
Tizanidine 
Tricyclic antidepressants (TCAs) 
Triptans for prophylaxis of menstrual-related migraine  
Venlafaxine and desvenlafaxine 
Verapamil 
C. Restricted medication during SP II and III: Use of the following medications for 
indications other than migraine prevention is allowed providing the dose is stable 
2 months prior to Visit 2 and is expected to remain stable during Visit 2 through 6.  
ACE inhibitors  
Angiotensin receptor blockers (ARBs) 
Benzodiazepines 
Bupropion  
Calcium-channel blockers (except verapamil and flunarizine) 
Clonidine  
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Gabapentin 
Guanfacine  
Mirtazapine 
Pregabalin  
SSRIs/NRIs/SNRIs (other than venlafaxine)  
Stimulants (prescription strength), for example: methylphenidate, dextroamphetamine, mixed amphetamine salts 
Trazadone (for sleep only and must be taken in a stable fashion) 
Use of electric devices (that is, TENS), physiotherapy, chiropractic procedures on low back and extremities 
 
D. Restricted medication during SP II-III: Use of the following medications for 
indications other than migraine prevention is allowed: 
Beta-blockers, ophthalmic 
Cyproheptadine 
Melatonin 
 
Abbreviations: 5HT = 5-hydroxytryptamine; ACE = angiotensin-converting enzyme; NRI = norepinephrine 
reuptake inhibitor; NSAID = nonsteroidal anti-inflammatory drug; SNRI = serotonin-norepinephrine reuptake 
inhibitor; SP = Study Period; SSRI = selective serotonin reuptake inhibitor; TENS = transcutaneous electrical 
nerve stimulation. 
a 
Gabapentin and pregabalin may be allowed if the criteria in Part C are met. 
b It may be allowed in the study if prescribed for a condition other than migraine or headache, as long as the use of 
Cannabis/Cannabinoids is not expected to affect the interpretation of study results or the safety of the participant. 
The usage should remain consistent for the duration of the study and criteria in exclusion 23ii are met. 
c Topical and inhaled corticosteroids allowed for conditions other than migraine or headache. 
d 
Paxlovid is authorized by the FDA for emergency use for treatment of mild-to-moderate COVID-19 and contains 
ritonavir - a strong CYP3A4 inhibitor; thus, is excluded in CGBD. 
 
 
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10.3. 
Appendix 3: Adverse Events and Serious 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 participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. 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 a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.  
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition 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.  
 Lack of efficacy or failure of expected pharmacological action per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE.  
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that 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 (for example, endoscopy and appendectomy): the 
condition that leads to the procedure is the AE. 
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 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.  
10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets 1 or 
more of the criteria listed: 
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 admitted to hospital or 
emergency ward (usually involving at least an overnight stay) 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. 
 Hospitalization for elective treatment of a preexisting 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 (for example, 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 
 Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, and ectopic pregnancy) are considered SAEs. 
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f. 
Other situations: 
 Medical or scientific judgment should be exercised by the investigator 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  
For PCs, see Section 8.3.  
AE and SAE Recording 
 When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (for example, hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
 The investigator will then record all relevant AE/SAE information in the participant’s 
medical records, in accordance with the investigator’s normal clinical practice. 
AE/SAE information is reported on the appropriate CRF or paper form, respectively. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to sponsor or designee in lieu of completion of the CRF page or paper form, 
respectively, for AE/SAE. 
 There may be instances when copies of medical records for certain cases are requested 
by sponsor or designee. 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 to sponsor or designee. 
 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: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
 Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
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discomfort but poses no significant or permanent risk of harm to the research 
participant. 
 Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. An AE that is 
assessed as severe should not be confused with an 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 pre-defined 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. The investigator will use clinical judgment to 
determine the relationship. 
 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. 
 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 IB and/or Product Information 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 to sponsor or designee. 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 to sponsor or designee. 
 The investigator may change his/her opinion of causality in light of follow-up 
information and send an 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 by sponsor or 
designee 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 healthcare professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide sponsor or designee with a copy of any 
post-mortem findings including histopathology.  
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10.3.4. 
Reporting of SAEs 
SAE Reporting via Paper Form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the sponsor or designee. 
 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 site training documents.  
10.3.5. 
Regulatory Reporting Requirements 
SAE Regulatory Reporting 
Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities toward 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, 
IRBs/IECs, and investigators. 
● An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (for example, summary or listing of SAEs) 
from the sponsor will review and then file it along with the IB or Product 
Information and will notify the IRB/IEC, if appropriate according to local 
requirements.  
 
 
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10.4. 
Appendix 4: Clinical Laboratory Tests 
● The tests detailed in the table below will be performed by the central laboratory 
unless specified otherwise. 
● Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study intervention administration and/or 
response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time, if feasible. Additionally, if the 
local laboratory results are used to make either a study intervention decision or 
response evaluation, the results must be recorded. 
● In circumstances where the sponsor allows the use of local laboratory testing in 
lieu of central laboratory testing (in the table below), the local laboratory must be 
qualified in accordance with applicable local regulations. 
● Protocol-specific laboratory result requirements for inclusion or exclusion of 
participants are detailed in Section 5. 
● Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
● Investigators must document their review of the laboratory safety results.  
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Clinical Laboratory Tests 
Hematology 
Clinical Chemistrya 
Hemoglobin 
Serum Concentrations of: 
Hematocrit 
Sodium 
Erythrocyte count (RBC) 
Potassium 
Mean cell volume 
Total bilirubin (TBL) 
Mean cell hemoglobin concentration 
Direct bilirubin 
Leukocytes (WBC) 
Alkaline phosphatase (ALP) 
Neutrophils, segmented 
Alanine aminotransferase (ALT) 
Lymphocytes 
Aspartate aminotransferase (AST) 
Monocytes 
Blood urea nitrogen (BUN) 
Eosinophils 
Creatinine 
Basophils 
Uric acid 
Platelets 
Calcium 
 
Glucose 
 
Albumin 
Urinalysis 
Total cholesterol 
Specific gravity 
Creatine kinase (CK) 
pH 
 
Protein 
Pregnancy Test (females only)b 
Glucose 
Serum pregnancy or FSH 
Ketones 
Urine pregnancy test (local) 
Blood 
 
Urine leukocyte esterasec 
 
 
 
UDSb
 
Abbreviations: FSH = follicle stimulating hormone; RBC = red blood cells; UDS = urine drug screen; WBC = white 
blood cells. 
a Fasting not required. 
b May be repeated during the study at the discretion of the investigator. 
c A positive urine leukocyte esterase result will require a follow-up sample with microscopic analysis and possibly 
a urine culture. 
 
 
 
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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments  
10.5.1. 
Hepatic Evaluation Testing 
See Sections 10.5.2 and 10.5.3 below for guidance on appropriate test selection. 
The Lilly-designated central laboratory must complete the analysis of all selected testing except 
for microbiology testing. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
Results will be reported if a validated test or calculation is available. 
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs - red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs - white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
    Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
    Lymphocytes 
Creatine kinase (CK) 
    Monocytes 
Other Chemistry 
    Basophils 
Acetaminophen 
    Eosinophils 
Acetaminophen protein adducts 
Platelets 
ALP isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl alcohol (EtOH) 
Prothrombin time, INR (PT-INR) 
Haptoglobin 
Serology 
Immunoglobulin (Ig)A (quantitative) 
Hepatitis A virus (HAV) testing: 
IgG (quantitative) 
    HAV total antibody 
IgM (quantitative) 
    HAV IgM antibody 
Phosphatidylethanol (PEth) 
Hepatis B virus (HBV) testing: 
Urine Chemistry 
    Hepatitis B surface antigen (HBsAg) 
Drug screen 
    Hepatitis B surface antibody (anti-HBs) 
Ethyl glucuronide (EtG) 
    Hepatitis B core total antibody (anti-
HBc) 
Other Serology 
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    Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA) 
    Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA)a 
    HBV DNAb 
Anti-actin antibodyc 
Hepatis C virus (HCV) testing: 
Epstein-Barr virus (EBV) testing: 
    HCV antibody 
    EBV antibody 
    HCV RNAb 
    EBV DNAb 
Hepatitis D virus (HDV) testing: 
Cytomegalovirus (CMV) testing: 
    HDV antibody 
    CMV antibody 
Hepatitis E virus (HEV) testing: 
    CMV DNAb 
    HEV IgG antibody 
Herpes simplex virus (HSV) testing: 
    HEV IgM antibody 
    HSV (Type 1 and 2) antibody  
    HEV RNAb 
    HSV (Type 1 and 2) DNAb 
Microbiologyd 
Liver kidney microsomal type 1 (LKM-1) 
antibody 
Culture: 
    Blood 
    Urine 
 
a Not required if anti-actin antibody is tested. 
b Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c Not required if anti-smooth muscle antibody (ASMA) is tested. 
d Assayed ONLY by investigator-designated local laboratory; no central testing available. 
10.5.2. 
Close Hepatic Monitoring 
Laboratory tests (Section 10.4), including ALT, AST, ALP, TBL, D. Bil, GGT, and CK, should 
be repeated within 48 to 72 hours to confirm the abnormality and to determine if it is increasing 
or decreasing, if 1 or more of these conditions occur: 
For participants enrolled with normal or near normal hepatic biochemical tests 
If a participant with baseline 
results of ...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN 
ALP <1.5x ULN 
ALP ≥2x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants with 
Gilbert’s syndrome) 
For participants enrolled with elevated baseline hepatic biochemical tests 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
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TBL ≥1.5x ULN 
TBL ≥1.5x baseline (except for participants 
with Gilbert’s syndrome) 
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, history of alcohol 
drinking and other substance abuse.  
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and laboratory results stabilize. Monitoring of ALT, AST, ALP, 
and TBL should continue until levels normalize or return to approximate baseline levels. 
Comprehensive hepatic evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of these conditions occur: 
For participants enrolled with normal or near normal hepatic biochemical tests 
If a participant with baseline 
results of...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN with hepatic signs/symptomsa, or  
ALT or AST ≥5x ULN 
ALP <1.5x ULN 
ALP ≥3x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants with Gilbert’s 
syndrome) 
For participants enrolled with elevated baseline hepatic biochemical tests  
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline with hepatic signs/symptomsa, or 
ALT or AST ≥3x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥2x baseline (except for participants with Gilbert’s 
syndrome)  
aHepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant 
abdominal pain, fever, rash, and/or eosinophilia >5%. 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for PT-INR; tests for viral hepatitis A, B, C, or E; tests 
for autoimmune hepatitis; and an abdominal imaging study (for example, ultrasound or CT scan).  
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus 
(HDV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), acetaminophen levels, 
acetaminophen protein adducts, urine toxicology screen, Wilson’s disease, blood alcohol levels, 
urinary ethyl glucuronide, and blood phosphatidylethanol. Based on the circumstances and the 
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investigator’s assessment of the participant’s clinical condition, the investigator should consider 
referring the participant for a hepatologist or gastroenterologist consultation, magnetic resonance 
cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), 
cardiac echocardiogram, or a liver biopsy.  
10.5.3. 
Additional Hepatic Data Collection (Hepatic Safety CRF) in Study Participants 
Who Have Abnormal Liver Tests During the Study 
Additional hepatic safety data collection in hepatic safety CRFs should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
1. Elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5x ULN) 
➢ In participants with baseline ALT ≥1.5x ULN, the threshold is ALT ≥3x baseline 
on 2 or more consecutive tests 
2. Elevated TBL to ≥ 2x ULN (if baseline TBL <1.5x ULN) (except for cases of known 
Gilbert’s syndrome) 
➢ In participants with baseline TBL ≥1.5x ULN, the threshold should be TBL ≥2x 
baseline 
3. Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5x ULN) 
➢ In participants with baseline ALP ≥1.5x ULN, the threshold is ALP ≥2x baseline 
on 2 or more consecutive blood tests 
4. Hepatic event considered to be an SAE 
5. Discontinuation of study intervention due to a hepatic event  
Note: the interval between the 2 consecutive blood tests should be at least 2 days. 
 
 
 
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10.6. 
Appendix 6: Provisions for Changes in Study Conduct During 
Exceptional Circumstances 
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations. 
After approval by local Ethical Review Boards, regulatory bodies and any other relevant local 
authorities, implementation of these exceptional circumstance changes will not typically require 
additional notification to these groups, unless they have specific requirements in which 
notification is required (for example, upon implementation and suspension of changes). All 
approvals and notifications must be retained in the study records.  
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with GCP, enabling 
participants to continue safely in the study and maintaining the integrity of the study. 
Informed Consent 
Additional consent from the participant will be obtained, if required, for:  
 participation in remote visits, as defined in Section “Remote Visits,” 
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities. 
Changes in Study Conduct During Exceptional Circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 
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Remote visits 
Types of remote visits 
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments. Assessments to be completed in this manner include, 
but are not limited to: AE and concomitant medications. 
Mobile healthcare: Healthcare visits may be performed by a mobile healthcare provider at 
locations other than the study site when participants cannot travel to the site due to an 
exceptional circumstance if written approval is provided by the sponsor. Procedures 
performed at such visits include, but are not limited to: vital signs, 12-lead ECG, 
collection of central laboratory blood and urine samples including serum pregnancy, 
collection of MSQ v2.1, MIDAS, and PGI-S via Slate, distribution and collection of the 
ePRO diary and paper headache medication log, and collection of unused study 
intervention and ancillary supplies. 
Additionally, procedures listed above as telemedicine may be performed in the mobile 
healthcare setting. 
Other alternative locations: Procedures that may be done at an alternate location, other 
than listed above, include local safety labs, if applicable.  
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and PCs remain unchanged.  
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing. The local 
laboratory must be qualified in accordance with applicable local regulations.  
 
Study intervention and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the sponsor to determine appropriate actions. These actions may 
include:  
 
asking the participant to go to the site and receive study supplies from site staff without 
completion of a full study visit,  
 
asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf,  
 
arranging delivery of study supplies, and  
These requirements must be met before action is taken: 
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 
Alternate delivery of study intervention should be performed in a manner that does not 
compromise treatment blinding and ensures product integrity. The existing protocol 
requirements for product accountability remain unchanged, including verification of 
participant’s receipt of study supplies. 
 
When delivering supplies to a location other than the study site (for example, 
participant’s home), the investigator, sponsor, or both should ensure oversight of the 
shipping process to ensure accountability and product quality (that is, storage conditions 
maintained and intact packaging upon receipt). 
 
Instructions may be provided to the participant or designee on the final disposition of any 
unused or completed study supplies. 
Screening period guidance 
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at the screening visit are valid for a maximum of 45 days. The following rules will be applied for 
active, non-randomized participants whose participation in the study must be paused due to 
exceptional circumstances: 
 If screening is paused for 15 days beyond what is allowed for the screening period 
(30 days): the participant will proceed to the next study visit per the usual SoA, 
provided that Visit 2 must be conducted within 45 days from Visit 1.  
o The site should conduct the next visit if the participant’s Visit 1 eligibility 
criteria are confirmed, and the site should document the reason for delay. 
o Due to the pause in screening, sites should also reconfirm the impacted 
participant’s consent and document this confirmation in the source 
documentation. 
 If screening is paused for more than 15 days beyond what is allowed for the screening 
period (30 days): The participant must be discontinued because of screening 
interruption due to an exceptional circumstance. This is documented as a screen 
failure in the CRF. The participant can reconsent and be rescreened as a new 
participant. This rescreen is in addition to the one allowed by the main protocol. The 
screening and prospective baseline procedures per the usual SoA should be followed, 
starting at Visit 1 to ensure participant eligibility or ineligibility is confirmed by Visit 
3. 
Adjustments to Visit Windows 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA. To maximize the possibility that these visits can be conducted as 
on-site visits, the windows for visits may be adjusted, upon further guidance from the sponsor. 
This minimizes missing data and preserves the intended conduct of the study. 
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This table describes the allowed adjustments to visit windows. 
 
Visit 
Number 
Tolerance 
Visits 4 and 5 
For telephone assessments only, from the intended date: 
 
Up to 2 days prior  
o Participants should be instructed to self-
administer study intervention prior to telephone 
visit. 
 
Up to 7 days after 
o Participants should be instructed to self-
administer study intervention per the original 
schedule. 
Visit 6 
For study procedures per SoA from the intended date: 
 
Up to 2 days prior 
 
Up to 15 days after 
The participant should be instructed to discontinue ODT as 
per the schedule in normal circumstances (eg. approximately 
90 days after Visit 3).  
Abbreviation: ECG = electrocardiogram.  
Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visits types, and conducted 
activities were affected by exceptional circumstances. Dispensing/shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
Source documents at alternate locations 
Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner.  
 
 
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10.7. 
Appendix 7: Abbreviations and Definitions 
Term 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase  
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BCRP 
Breast cancer resistant protein 
blinding  
A single-blind study is one in which the investigator and/or staff are aware of the treatment 
but the participant is not, or vice versa, or when the sponsor is aware of the treatment but the 
investigator and/his staff and the participant are not. 
A double-blind study is one in which neither the participant nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received. 
CEC 
Clinical Events Committee 
CGRP 
Calcitonin gene-related peptide 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Creatine kinase 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, purity, durability, reliability, safety or effectiveness, or performance 
of a drug or drug delivery system. 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
CRF 
Case report form 
CTA 
Clinical Trial Agreement 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
eCOA 
Electronic Clinical Outcome Assessment 
EDC 
Electronic data capture 
enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the study 
are those who have been assigned to a treatment. 
enter 
Participants entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives. 
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ET 
early termination  
GCP 
Good clinical practice 
GGT 
Gamma-glutamyl transferase 
GLIMMIX 
Generalized linear mixed model 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICHD 
International Classification of Headache Disorders 
IHS 
International Headache Society 
IMP 
Investigational Medicinal Product 
informed 
consent 
A process by which a participant voluntarily confirms his or her willingness to participate in 
a particular study, after having been informed of all aspects of the study that are relevant to 
the participant’s decision to participate. Informed consent is documented by means of a 
written, signed and dated informed consent form. 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, that 
is conducted before the final reporting database is created/locked. 
INR 
International normalized ratio 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
ITT 
Intention to treat: The principle that asserts that the effect of a treatment policy can be best 
assessed by evaluating on the basis of the intention to treat a participant (that is, the planned 
treatment regimen) rather than the actual treatment given. It has the consequence that 
participant allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of treatment. 
IWRS 
Interactive web-response system 
LLT 
Lowest Level Term 
LOCF 
Last observation carried forward 
LSMeans 
Least Squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-model repeated measures 
NIMP 
Non-investigational Medicinal Product 
ODT 
Oral disintegrating tablet 
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participant 
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, either 
as recipient of an investigational medicinal product or as a control. 
PC 
Product complaint 
P-gp 
P-glycoprotein 
PK/PD 
Pharmacokinetics/Pharmacodynamics 
PPS 
Per-protocol set: The set of data generated by the subset of participant who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the effects of 
treatment, according to the underlying scientific model. 
PRO/ePRO 
Patient-reported outcomes/Electronic patient-reported outcomes 
PT-INR 
Prothrombin time – international normalized ratio 
QOD 
Every other day 
QTc 
Corrected QT interval 
QTcF 
Fridericia-corrected QT interval 
QTLs 
Quality tolerance limits 
SAC 
Statistical Analysis Center 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
screen 
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SMQ 
Standardized MedDRA queries 
SIB 
Suicidal ideation and behavior 
study 
intervention 
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form. 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event: An untoward medical occurrence that emerges during a 
defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment. 
ULN 
Upper limit of normal 
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USPI 
United States package insert 
WOCBP 
Women of childbearing potential 
 
 
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10.8. 
Appendix 8: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment c: (22-Sep-2022) 
Overall Rationale for the Amendment: 
The purpose of this amendment is to add language regarding an interim analysis with the 
potential for a sample size increase and make minor clarifications. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1. Synopsis and Section 
9.5. Sample Size Determination 
Original planned 
sample size reduced 
to 575 
The sample size was decreased 
to allow for a sample size re-
estimation based on interim 
results that will increase the 
likelihood that the study is 
adequately powered. 
Section 1.3. Schedule of Activities 
(SoA) 
Added footnote “c” to 
Serum pregnancy or 
FSH for female 
participants row 
Updated to align with current 
internal guidance 
Section 5.1. Inclusion Criteria 
In inclusion criterion 
7.b.ii, updated the 
examples of surgical 
sterilization and 
updated definition of 
menopause 
Updated the examples of 
surgical sterilization and 
menopause to align with 
current internal guidance 
Section 5.2. Exclusion Criteria 
In exclusion criterion 
10: deleted “multiple 
drugs” 
Risk was discharged in 
previous clinical trials. History 
of hypersensitivity to “multiple 
drugs” does not pose a safety 
risk for use of galcanezumab. 
Section 6.3. Measures to Minimize 
Bias: Randomization and Blinding 
Updated guidance on 
self-injections during 
telephone visits 
To clarify the timing of 
telephone visit with regards to 
the injection of study 
intervention 
Section 6.4. Study Intervention 
Compliance 
Updated text 
regarding the return of 
unused study 
intervention 
To provide flexibility in the 
type of closed container the 
participants may use to return 
unused study drug 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.1.1. Liver Chemistry 
Stopping Criteria  
Updated language 
based on most recent 
guidance 
Revised due to Lilly protocol 
template update for consistency 
with FDA liver safety 
guidelines 
Section 9.3.2. Primary 
Endpoint(s)/Estimand(s) Analysis 
Added language 
regarding an interim 
analysis with the 
potential for a sample 
size increase and 
language regarding 
potential sample size 
increase 
Addition 
Section 9.3.3. Secondary 
Endpoints/Estimands Analysis 
Added sentence 
regarding sample size 
and CHW test 
Clarity  
Section 9.3.4. Safety Analyses 
Removed “potential 
hypersensitivity 
events” 
Correction 
Section 9.4. Interim Analysis 
Added language 
regarding an interim 
analysis 
Addition 
Section 10.1.4. Committees 
Structure 
Added “resuscitated 
cardiac arrest” 
Addition to match finalized 
CEC charter 
Section 10.2. Appendix 2: 
Treatments Allowed and 
Treatments not Allowed as 
Concomitant Therapy 
Added footnotes “a,” 
“b,” “c,” and “d” 
under Appendix 2 
table; added 
Migravent, 
desvenlafaxine, and 
Paxlovid to table 
Clarification for medications 
not allowed during SP II and III 
Throughout 
Other minor editorial 
changes 
Minor therefore not described 
Amendment b: (18-Feb-2022) 
Overall Rationale for the Amendment: 
The purpose of this amendment is to update SAE/pregnancy reporting via paper forms and make 
minor clarifications for sites and consistency within the document. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.2 Schema 
Clarified footnotes within 
the schema and added 
placebo to each study 
intervention.  
Minor change added for clarity. 
1.2 Schema; 1.3 
Schedule of 
Activities (SoA) 
Clarified that investigators 
have up to 5 additional days 
if needed to schedule 
participant’s Visit 3 
appointment. 
Minor clarification added for clarity and 
added additional flexibility for sites and 
participants. 
1.3 Schedule of 
Activities (SoA) 
Removed neurological 
examination for Visit 6 and 
early termination. 
Based on established safety profiles for 
the study interventions, assessment is not 
required  
1.3 Schedule of 
Activities (SoA); 
10.4 Appendix 4: 
Clinical Laboratory 
Tests 
Separated urine drug screen 
from urinalysis, clarified 
UDS is not required for 
Visit 6 and ET, and 
clarified participants may 
re-test but must be negative 
at or prior to Visit 2. 
Corrected from previous protocol 
versions.  
1.3 Schedule of 
Activities (SoA) 
Clarified the headache 
medication log should be 
returned to site staff at the 
final office visit or early 
termination visit. 
Minor clarification. 
1.3 Schedule of 
Activities (SoA) 
Moved both participant 
training videos lines so they 
are together and clarified 
videos may be viewed at 
either Visit 2 or Visit 3. 
Minor clarification added for additional 
flexibility for sites and participants.  
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Section # and Name 
Description of Change 
Brief Rationale 
4.1.1 Study Period 
I: Screening (Visit 
1); 4.1.2 Study 
Period II: 
Prospective 
Baseline (Visit 2); 
4.1.3 Study Period 
III: Double-Blind 
Treatment (Visits 
3-6) 
Sections were re-formatted. 
Minor changes for clarity. 
4.1.2 Study Period 
II: Prospective 
Baseline (Visit 2) 
Clarified timing of initial 
study intervention shipment 
and eligibility.  
Clarified for sites. 
5.1 Inclusion 
Criteria 
Changed age to 18 to 75 
years of age (inclusive) in 
Inclusion Criterion #1. 
Changed to include older patients 
consistent with recent studies for 
galcanezumab. 
5.2 Exclusion 
Criteria 
Removed “significant 
active or unstable” when 
describing psychiatric 
disease by medical history.  
Minor clarification.  
5.2 Exclusion 
Criteria 
Removed Exclusion 
Criterion #19. 
Changed to be consistent with recent 
studies for galcanezumab. 
5.2 Exclusion 
Criteria 
Revised Exclusion 
Criterion #21 to exclude 
participants who have used 
opioids or barbiturate 
containing analgesic >4 
days per month for the 
treatment of pain in more 
than 2 of the past 3 months. 
Changed to be consistent with recent 
studies for galcanezumab. 
5.2 Exclusion 
Criteria 
Added exceptions to a 
positive UDS for 
benzodiazepine to 
Exclusion Criterion #23.  
Clarified to keep consistent with 
permitted concomitant medications.  
5.2 Exclusion 
Criteria 
Updated ophthalmoplegic 
to retinal migraine in 
Exclusion Criterion #26. 
To align with current guidance.  
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Section # and Name 
Description of Change 
Brief Rationale 
5.2 Exclusion 
Criteria 
Added Exclusion Criterion 
#33 to exclude participants 
with a history of ≥15 
headache days per month 
during the past 3 months or 
are suspected of suffering 
from chronic migraine as 
defined per IHS ICHD-3. 
To clarify exclusion criteria related to 
chronic migraine. 
5.4 Screen Failures 
Added rescreen allowance 
for Exclusion Criterion #16 
which excludes patients 
with an acute, serious, or 
unstable medical condition 
that in the judgement of the 
investigator precludes study 
participation. 
This change allows for participants to 
rescreen if their acute or unstable illness 
resolves and/or is controlled. 
5.4 Screen Failures 
Added to allow participants 
who have become eligible 
to enroll in the study as a 
result of a protocol 
amendment. 
Clarification. 
6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding 
Clarified in the case of 
emergency unblinding that 
if a participant’s 
intervention assignment is 
unblinded, the sponsor must 
be notified immediately 
after breaking the blind. 
Clarification. 
6.8 Concomitant 
Therapy 
Clarified that botulinum 
toxin A or B in the head or 
neck area for therapeutic 
use is not allowed within 4 
months prior to Visit 2. 
Corrected error. 
7.1 Discontinuation 
of Study 
Intervention 
Clarified if study 
intervention is permanently 
discontinued, the 
participant should remain in 
the study to be evaluated 
for safety and efficacy 
assessments, unless criteria 
in Section 7.2 apply. 
Minor clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
8.2.3 
Electrocardiograms 
Clarified in the event the 
ECG machine does not 
automatically calculate the 
QTcF interval, the QTcF 
interval may be manually 
calculated. 
Clarified for site flexibility.  
8.3 Adverse Events, 
Serious Adverse 
Events, and Product 
Complaints; 8.3.2 
Product 
Complaints; 8.3.2.1 
Time Period for 
Detecting Product 
Complaints; 8.3.2.2 
Follow-Up of 
Product Complaints 
Moved text from Section 
8.3.2, Section 8.3.2.1, and 
Section 8.3.2.2 into Section 
8.3. 
Minor changes for clarity. 
8.3.1 Timing and 
Mechanism for 
Collecting Events; 
10.3.3 Recording 
and Follow-Up of 
AE and/or SAE 
Clarified the mechanism for 
reporting adverse events as 
the AE CRF, severe adverse 
events as the SAE paper 
form, and pregnancy as the 
pregnancy paper form. 
Electronic methods are not used for this 
study. 
10.1.4 Committees 
Structure 
Updated text to include 
terms and events for 
adjudication.  
Minor changes for clarity. 
10.2 Appendix 2: 
Treatments 
Allowed and 
Treatments not 
Allowed as 
Concomitant 
Therapy 
Clarified opioid and 
barbiturates are allowed no 
more than 4 days /month. 
Clarified for flexibility.  
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Section # and Name 
Description of Change 
Brief Rationale 
10.2 Appendix 2: 
Treatments 
Allowed and 
Treatments not 
Allowed as 
Concomitant 
Therapy 
Clarified gabapentin, 
pregabalin, and stimulants 
(prescription strength) are 
restricted during SP II and 
III and may be used for 
indications other than 
migraine prevention 
provided the dose is stable 
2 months prior to Visit 2 
and is expected to remain 
stable during Visit 2 
through 6. 
Changed to be consistent with recent 
studies for galcanezumab. 
10.3.3 Recording 
and Follow-Up of 
AE and/or SAE 
Removed “product 
complaint” and clarified 
CRF. 
To ensure consistency with protocol text. 
10.3.4 Reporting of 
SAEs 
Removed section for SAE 
reporting via an electronic 
data collection tool.  
Not applicable to study. 
10.3.4 Reporting of 
SAEs 
Clarified facsimile 
transmission of the SAE 
paper form to the sponsor 
or designee. 
Align with changes made throughout the 
protocol. 
10.6 Appendix 6: 
Provisions for 
Changes in Study 
Conduct During 
Exceptional 
Circumstances 
Clarified telemedicine and 
mobile healthcare example 
assessments.  
Minor clarification.  
10.6 Appendix 6: 
Provisions for 
Changes in Study 
Conduct During 
Exceptional 
Circumstances 
Clarified at visit windows 
when participants should be 
instructed to self-administer 
study intervention and 
discontinue ODT. 
Minor clarification.  
Throughout 
Reference to Manual of 
Operations was changed to 
Reference Manual. 
Align with current manual.  
Throughout 
Other minor editorial 
changes were made to add 
clarity. 
Minor therefore not described. 
 
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Amendment a: (6-Aug-2021) 
Overall Rationale for the Amendment: 
The current sample size and power estimates assume a scenario where the reduction in migraine 
days across Months 1, 2, and 3 for rimegepant in the current study will be consistent with the 
reduction in migraine days at Month 3 for rimegepant as published for their single phase 2/3 
prevention study. The proposed sample size increase to approximately 700 randomized patients 
assumes a smaller reduction in migraine days with rimegepant during Months 1 and 2 compared 
to Month 3. 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
Added Study Acronym 
Branding. 
1.1. Synopsis 
9.5. Sample Size 
Determination 
Increased sample size and 
updated sample size 
determination. 
Additional power to detect effect. 
6. Study 
Intervention(s) and 
Concomitant 
Therapy 
Added additional definition 
for “study intervention”. 
Clarification. 
Throughout 
Minor editorial corrections. 
Minor therefore not described. 
 
 
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11. 
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