Phase 3 Multicenter, Randomized, Double-blind, Placebo-controlled Study of BOTOX (Botulinum Toxin Type A) for the Prevention of Migraine in Subjects With Episodic Migraine
Phase: PHASE3
Conditions: Episodic Migraine
Sponsor: AbbVie



 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
TABLE OF CONTENTS 
1 
SYNOPSIS 
5 
2 
INTRODUCTION 
7 
2.1 
BACKGROUND AND RATIONALE 
7 
2.2 
BENEFITS AND RISKS TO SUBJECTS 
7 
3 
OBJECTIVES AND ENDPOINTS 
8 
3.1 
OBJECTIVES, HYPOTHESES, AND ESTIMANDS 
8 
3.2 
PRIMARY ENDPOINT 
9 
3.3 
SECONDARY ENDPOINTS 
9 
3.4 
OTHER ENDPOINTS 
10 
3.5 
SAFETY ENDPOINTS 
12 
3.6 
BIOMARKER RESEARCH 
12 
4 
INVESTIGATIONAL PLAN 
12 
4.1 
OVERALL STUDY DESIGN AND PLAN 
12 
4.2 
DISCUSSION OF STUDY DESIGN 
14 
5 
STUDY ACTIVITIES 
15 
5.1 
ELIGIBILITY CRITERIA 
15 
5.2 
CONTRACEPTION RECOMMENDATIONS 
19 
5.3 
PROHIBITED MEDICATIONS AND THERAPY 
20 
5.4 
PRIOR AND CONCOMITANT THERAPY 
21 
5.5 
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY 
22 
5.6 
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY 
23 
5.7 
STUDY DRUG 
24 
5.8 
RANDOMIZATION/DRUG ASSIGNMENT 
24 
5.9 
PROTOCOL DEVIATIONS 
25 
5.10 DATA MONITORING COMMITTEE 
25 
6 
SAFETY CONSIDERATIONS 
26 
6.1 
COMPLAINTS AND ADVERSE EVENTS 
26 
Page 2 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
6.2 
OTHER SAFETY DATA COLLECTION 
29 
7 
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE 
30 
7.1 
STATISTICAL AND ANALYTICAL PLANS 
30 
7.2 
DEFINITION FOR ANALYSIS POPULATIONS 
30 
7.3 
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND KEY SECONDARY ENDPOINTS 
31 
7.4 
STATISTICAL ANALYSES FOR EFFICACY 
31 
7.5 
STATISTICAL ANALYSES FOR SAFETY 
33 
7.6 
INTERIM ANALYSIS 
34 
7.7 
OVERALL TYPE I ERROR CONTROL 
35 
7.8 
SAMPLE SIZE DETERMINATION 
35 
8 
ETHICS 
36 
8.1 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB) 
36 
8.2 
ETHICAL CONDUCT OF THE STUDY 
36 
8.3 
SUBJECT CONFIDENTIALITY 
37 
9 
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION 
37 
10 DATA QUALITY ASSURANCE 
37 
11 COMPLETION OF THE STUDY 
37 
12 REFERENCES 
37 
LIST OF FIGURES 
FIGURE 1. 
STUDY SCHEMATIC 
14 
FIGURE 2. 
SCHEMATIC OF THE MULTIPLICITY METHOD TO CONTROL OVERALL TYPE I ERROR RATE 
35 
LIST OF APPENDICES 
APPENDIX A. 
STUDY-SPECIFIC ABBREVIATIONS AND TERMS 
39 
APPENDIX B. 
RESPONSIBILITIES OF THE INVESTIGATOR 
41 
Page 3 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
APPENDIX C. 
LIST OF PROTOCOL SIGNATORIES 
42 
APPENDIX D. 
ACTIVITY SCHEDULE 
43 
APPENDIX E. 
PROTOCOL SUMMARY OF CHANGES 
46 
APPENDIX F. 
OPERATIONS MANUAL 
48 
 
 
 
Page 4 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
2 INTRODUCTION 
2.1 Background and Rationale 
Why Is This Study Being Conducted 
Migraine is a multifactorial, disabling neurological disease characterized by recurrent and often 
debilitating headaches of moderate to severe intensity and accompanied by symptoms that can include 
nausea, vomiting, and/or sensitivity to light or sound.1  It is one of the most common neurologic 
disorders, affecting 12% of the general population, and ranked second among the causes of disability 
worldwide.2,3   
Migraine with/without aura can be further categorized according to the frequency of attacks as episodic 
migraine (EM) or chronic migraine (CM).1  The definition of CM and EM is based on the frequency of 
days with headache; however, this does not cover the complexity of the disorder.1  In fact, EM and CM 
are both part of the migraine disease spectrum that is nonbinary and manifests as a continuum of 
disease severity; this is evidenced by frequent and spontaneous fluctuations between CM and EM and 
similar levels of disability associated with CM and high frequency EM.4,5 
Botulinum Toxin Type A Purified Neurotoxin Complex (United States and Canada adopted name is 
onabotulinumtoxinA; referred to hereafter as BOTOX) for injection is currently indicated for the 
prophylaxis of headaches in adults with CM.6  Individuals who experience less frequent migraines, 
including those categorized as having EM, are not covered in the current indication. 
The economic burden of migraine, the overall impact of migraine on quality of life, and the continued 
need for treatment alternatives, support the rationale to develop appropriate management and 
treatment choices for the population suffering from EM.  Therefore, AbbVie is evaluating BOTOX for the 
prophylaxis of EM, which has the potential to expand treatment options available to patients in the 
pursuit of headache freedom. 
2.2 Benefits and Risks to Subjects 
BOTOX is approved in over 90 countries for the prophylaxis or symptom relief of headaches in adults 
with CM.  The similar disease characteristics, along with the established efficacy of BOTOX in adults with 
CM, supports the assumption that the benefit/risk profile in EM will be favorable.   
The results of the safety analyses of the Phase 3 CM population support the known safety and 
tolerability profile of BOTOX seen in a large number of other clinical applications, when BOTOX is 
administered every 12 weeks.  Overall, no safety findings emerged from the CM safety database, or 
from Phase 4 studies and the postmarketing database, that raise concerns over the use of BOTOX at 
doses of 155 or 195 U administered intramuscularly every 12 weeks in the target population of adults 
with migraine. 
In the Phase 3 CM studies, the most frequently reported adverse drug reactions occurring in ≥ 5% of 
patients following injection of BOTOX were neck pain reported in 8.7% of patients.  Additional adverse 
drug reactions that were reported in ≥ 2% of BOTOX-treated patients were headache (4.7%), migraine 
Page 7 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
(3.8%), eyelid ptosis (3.6%), musculoskeletal stiffness (3.6%), muscular weakness (3.5%), injection site 
pain (3.3%), myalgia (3.1%), musculoskeletal pain (2.6%), and facial paresis (2.2%). 
The doses and dosing paradigm confirmed in the Phase 3 CM studies will be utilized in this Phase 3 EM 
Study, M21-307.  
Known risks associated with BOTOX administration are pre-existing neuromuscular disorders, 
immunogenicity, distant spread of toxin, and dysphagia in chronic migraine patients. 
Based on the collective evidence from the Phase 3 CM studies, observational studies, and clinical 
experience, international consensus guidelines recommend BOTOX as both effective and safe in subjects 
with CM.7-9  The lack of need for slow dose escalation, the relatively rapid onset of therapeutic benefits, 
and the positive tolerability of injectable therapies such as BOTOX contribute to a favorable benefit-risk 
profile.10 
Further details, including findings from completed studies and other safety data, are provided in the 
current Investigator's Brochure for BOTOX. 
Considering the coronavirus disease  2019 (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study have been re-evaluated.  Based on the limited information to date, no 
additional risk to study subjects is anticipated with the use of BOTOX.  Based on the population and 
disease being studied and the anticipation that COVID-19 related risks are not expected to differ 
substantially between study subjects and the broader population of subjects receiving treatment for 
migraine, no change to the benefit/risk balance for subjects in this study is expected. 
3 OBJECTIVES AND ENDPOINTS 
3.1 Objectives, Hypotheses, and Estimands 
Primary 
The objective of this study is to evaluate the efficacy and safety of 2 dose levels of BOTOX compared 
with placebo as migraine prevention in subjects with EM. 
The estimand corresponding to the primary objective of this study is displayed in the table below.  It 
defines the primary endpoint as the change from baseline in the frequency of monthly migraine days 
(i.e., migraine or probable migraine headache days) across Months 5 and 6 in the BOTOX groups and the 
placebo group for subjects in the intent-to-treat (ITT) population, which includes all subjects who are 
randomized.  The primary analysis assumes that missing data are missing completely at random or 
missing at random.   
Page 8 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
ESTIMAND 
Target Study Population: 
Patients with EM as constrained by the study inclusion and 
exclusion criteria; most notably < 15 headache days and 6 to 14 
migraine days during the 28-day baseline period that ends the 
day before randomization.  The population of inference will be 
further constrained by baseline ranges that are narrower or less 
inclusive than the eligibility criteria (e.g., too few males 
compared with the target population epidemiology). 
Endpoint of Interest: 
Change from baseline in the frequency of 
monthly migraine days across Months 5 and 
6, which are defined as the 28-day daily 
diary periods ending with Days 56 and 84 
after the second study treatment 
intervention day with BOTOX or placebo 
injections, for subjects in the ITT population. 
Intercurrent Events: 
Study discontinuation, especially those due to lack of efficacy or 
due to AEs.  Also, any significant protocol deviation that could 
affect the primary endpoint, such as taking rescue medication or 
not receiving the Week 12 treatment.  A sensitivity analysis will 
impute scores differently for such intercurrent events (e.g., 
reversion toward baseline) and will be described in the SAP. 
Population-Level Summary of Variable:  
Between-treatment comparison of the 
change from baseline in monthly migraine 
days across Months 5 and 6. 
 
Clinical Hypotheses 
• 
At least 1 dose level of BOTOX is more effective than placebo, as measured by the difference 
between treatment groups in the change from baseline in the frequency of migraine days per 
28day period 
• 
BOTOX has an acceptable safety profile 
 
3.2 Primary Endpoint 
The primary endpoint is the change from baseline in the frequency of monthly migraine days across 
Months 5 and 6. 
3.3 Secondary Endpoints 
The secondary efficacy endpoints will be as follows (and will be evaluated in the stated order): 
1. Change from baseline in the frequency of monthly headache days across Months 5 and 6  
2. Responder status of 50% reduction from baseline in the frequency of monthly migraine days 
across Months 5 and 6 
3. Change from baseline in the frequency of monthly acute headache medication days across 
Months 5 and 6  
4. Change from baseline in Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) 
Role Function  Restrictive (RFR) domain score at Month 6 
Page 9 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
5. Change from baseline in the Activity Impairment in Migraine  Diary (AIM-D) Physical 
Impairment domain score across Months 5 and 6 (total 6-item Headache Impact Test [HIT-6] 
score in Europe) 
 
3.4 Other Endpoints 
The other endpoints include the following: 
Page 10 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Page 11 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
The primary and secondary efficacy measures will also be evaluated at monthly time points. 
3.5 Safety Endpoints 
Measures of safety and tolerability for the entire study duration include adverse event (AE) monitoring, 
clinical laboratory testing (hematology, chemistry, and urinalysis), vital sign measurements, and 
Columbia-Suicide Severity Rating Scale (C-SSRS) scores. 
3.6 Biomarker Research  
Biospecimens (whole blood DNA, plasma, and serum) will be collected at specified time points 
(Appendix D) throughout the study to evaluate known and/or novel disease-related or drug-related 
biomarkers in circulation or at tissue sites.  All samples will be optional.  Types of biomarkers may 
include nucleic acids, proteins, lipids, and/or metabolites, either free or in association with particular cell 
types.  The analyses may include but are not limited to: biomarkers associated with mechanisms of 
migraine, such as calcitonin gene-related peptide (CGRP) and its degradants.  This research may be 
exploratory in nature and the results may not be included with the clinical study report.  Further details 
regarding the biomarker research rationale and collection time points are located in the Operations 
Manual, Section 3.9 and Appendix D. 
4 INVESTIGATIONAL PLAN 
4.1 Overall Study Design and Plan 
This is a multicenter, randomized, double-blind placebo-controlled, parallel-group study with an 
open-label extension phase in adults with EM.  Approximately 777 subjects who meet study enrollment 
eligibility criteria will be randomized in this study.  Subjects in this study will be male or female adults 18 
to 65 years of age at Visit 1 with a history of migraine headache disorder meeting ICHD-3 diagnostic 
criteria for migraine with aura or migraine without aura (1.1 and 1.2) for ≥ 12 months, with onset before 
50 years of age.  Specifically, subjects will have 6 to 14 migraine days and < 15 headache days per month 
in each of the 3 months prior to the screening visit (Visit 1) and during the 4-week screening/baseline 
phase.  See Section 5 for information regarding eligibility criteria. 
Randomization will be stratified by 
 (yes/no) and 
≥  monthly migraine days at baseline (yes/no).  Enrollment will be monitored to target at least
% of 
randomized subjects having taken at least 
 with proven efficacy 
(see Section 8.1 of the Operations Manual, Appendix F, for the list of medications) and at least 
% of 
randomized subjects having ≥  monthly migraine days during baseline.  The population of subjects who 
have failed 
 preventive treatments will be monitored throughout the trial.  The target is to enroll 
no less than 
% of the study population who have failed 
 preventive treatments.  This may result 
in enrollment restrictions for subjects who failed fewer than  preventive treatments.  The study will 
aim to enroll no more than 
% of subjects meeting criteria for medication overuse per the 
investigator's discretion based on regular overuse of acute headache medication as defined in the 
Operations Manual Section 8.2 in the 3 months prior to Visit 1 OR history of medication overuse 
Page 12 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
headache diagnosis per ICHD-3 8.2.1  The study will aim to enroll approximately 
% males in order to 
obtain a representative proportion of males with EM.11  Enrollment restrictions may be implemented in 
order to achieve these enrollment targets. 
Screening/baseline phase 
Study participation will begin with a 4-week screening/baseline phase, during which subjects will use an 
electronic diary (e-Diary).  Subjects will complete daily e-Diary entries on a handheld device provided to 
them at home to report headache data, including the absence of headache, as well as acute medication 
use.  On a weekly basis, the subject will also be asked to enter the number of migraine attacks he or she 
experienced over the past 7 days.  Subjects must complete at least 20 out of 28 days in the e-Diary 
during the screening/baseline phase to continue in the study. 
Subjects who complete the 4-week screening/baseline phase and meet all entry criteria will proceed to 
the double-blind placebo-controlled treatment phase at Visit 2 (randomization visit).  The 
screening/baseline phase may be extended due to COVID-19-related circumstances (see Section 5.4).  
Re-screening is permitted in certain situations, such as COVID-19 related circumstances, with permission 
from AbbVie.  However, subjects with a positive result on the urine drug and alcohol test unless 
explained by permitted concomitant medication use (e.g., opioids prescribed for migraine pain) are not 
allowed to be re-screened. 
Double-blind, placebo-controlled phase 
At Visit 2 (Day 1/Randomization Visit), subjects will be randomized 1:1:1 to receive BOTOX 195 U, 
BOTOX 155 U, or placebo, and will be administered the first treatment.  Telephone visits will occur at 
Week 4 (Visit 3), Week 8 (Visit 4), Week 16 (Visit 6), and Week 20 (Visit 7); clinic visits will occur at 
Week 12 (Visit 5) and Week 24 (Visit 8).  At Week 12 (Visit 5), subjects will be administered the second 
blinded treatment.  Subjects will complete daily e-Diary entries and patient-reported outcome (PRO) 
questionnaires on the handheld device provided to them. 
Open-label phase 
Subjects who complete the double-blind, placebo-controlled phase may be eligible to continue to the 
open-label treatment phase of the study at Week 24 (Visit 8).  All subjects in the open-label phase will 
receive BOTOX 195 U at 12-week intervals for up to 2 treatment cycles.  Telephone visits will occur at 
Week 28 (Visit 9), Week 32 (Visit 10), Week 40 (Visit 12), and Week 44 (Visit 13); clinic visits will occur at 
Week 36 (Visit 11) and Week 48 (Visit 14).  Subjects will complete daily e-Diary entries and patient-
reported outcome questionnaires on the handheld device provided to them.  The total duration of the 
study will be up to 52 weeks.   
The schematic of the study is shown in Figure 1.  The study procedures by visit and associated visit 
windows are listed in the Schedule of Activities (Appendix D).  The screening visit window is Day −35 to 
Day −28 and all post-randomization visits have a window of ± 3 days.  Further details regarding study 
procedures are provided in the Operations Manual. 
Page 13 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Figure 1. 
Study Schematic 
 
 
4.2 Discussion of Study Design 
Choice of Control Group 
The double-blind phase of the study is placebo-controlled.  Given the substantial placebo effects 
observed in migraine trials, especially those involving injections, the placebo not only controls for the 
actual placebo response, it also controls for other nonspecific effects such as natural history and 
regression to the mean.12-14   
Appropriateness of Measurements 
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy 
measurements in this study are standard for assessing disease activity in subjects with migraine.  All 
clinical and laboratory procedures in this study are standard and generally accepted. 
Suitability of Subject Population 
Development of the inclusion and exclusion criteria for the Phase 3 EM study were based on the recent 
guidelines put forth by the International Headache Society for controlled trials of preventive treatment 
of migraine attacks in adults with EM.15   
Page 14 of 85

STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Considering the spontaneous fluctuations in migraine frequency, requiring at least 12 months of attacks 
meeting ICHD criteria for EM will ensure that subjects enrolled into a clinical trial are less likely to enter 
a spontaneous remission period.4,16  Further, since EM with onset after 50 years of age is very unusual, 
and the risk of secondary headache increases with age of onset, only subjects who have EM prior to this 
age threshold will be enrolled in this study.
The study will enroll subjects with 6 to 14 migraine days per month in each of the 3 months prior to the 
screening visit and during the 4-week screening/baseline phase.  This population is appropriate based on 
available evidence from prior studies and the literature, which suggests that subjects with 6 to 
14 migraine days per month have a similar response to BOTOX as subjects with CM. 
The study will require subjects to have less than 15 headache days per month in each of the 3 months 
prior to screening and in the 4-week screening/baseline phase.  
The study will exclude subjects with CM and other confounding headache disorders as listed above.  
Subjects who have failed more than 4 prophylactic treatments for migraine, 2 with different 
mechanisms, will be excluded as these subjects may be treatment-refractory.  To reduce potential 
confounding factors for efficacy, the study will exclude subjects with prior 
 treatment in 
protocol treatment areas, prohibit the concurrent use of prophylactic treatments for migraine 
(e.g., CGRP monoclonal antibodies), and exclude the use of gepants in the double-blind phase.
Selection of Doses in the Study
The doses of BOTOX for this study in EM (155 U and 195 U) were selected to be consistent with the 
doses and dosing paradigm that demonstrated efficacy in the Phase 3 CM studies.  The selection of the 
 dose and dosing paradigm in EM as in CM is considered appropriate as subjects with EM and CM 
are part of a migraine spectrum with similar disease burden and response to treatment.  
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent
1. Subjects must voluntarily sign and date an informed consent approved by an independent 
ethics committee (IEC)/institutional review board (IRB), prior to the initiation of any screening or 
study-specific procedures.
Demographic and Laboratory Assessments
2. Adult male or female, 18 to 65 years of age at Visit 1.
3. Completed at least 20 out of 28 days in the e-Diary during the screening/baseline phase.
Page 15 of 85

STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
4. Able to read, understand, and complete study questionnaires and e-Diary per investigator's 
judgment.
5. Willing and able to comply with procedures required in this protocol.
6. Negative result on the urine drug and alcohol screen at Visit 1 unless explained by permitted 
concomitant medication use (e.g., opioids prescribed for migraine pain).
Disease/Condition Activity
7. History of migraine headache disorder meeting ICHD-3 diagnostic criteria for migraine with 
aura or migraine without aura (1.1 and 1.2) for ≥12 months.
8. Onset of migraine before 50 years of age.
9. History of 6 to 14 migraine days/month in each of the 3 months prior to Visit 1.
10. Six to 14 migraine days during the 4-week screening/baseline phase. 
11. < 15 headache days/month in each of the 3 months prior to Visit 1 and during the 4-week 
screening/baseline phase.
Subject History
12. No current diagnosis of chronic migraine (1.3) according to ICHD-3
13. No history of or current diagnosis of the following headache disorders according to ICHD-3:
a.
Migraine with brainstem aura (1.2.2) or retinal migraine (1.2.4)
b.
Complications of migraine (1.4), chronic tension-type headache (2), trigeminal 
autonomic cephalalgias (3), hypnic headache (4.9), 
 (3.4) or new 
daily persistent headache (4.10)
14. No history of headache attributed to another disorder (e.g., cervical dystonia, craniotomy, 
head/neck trauma) with exception that medication overuse headache per ICHD-3 criteria (8.2) is 
allowed.
15. No history of inadequate response to > 4 prophylactic treatment for migraine, 2 of which 
have different mechanisms of action (see Section 8.1 of the Operations Manual for the list of 
medications and criteria for determining inadequate response).
16. No unremitting headache lasting continuously throughout the 4-week baseline period.
17. No concurrent pain condition that may significantly impact current headache disorder 
(e.g., fibromyalgia, craniofacial pain, TMD/TMJ).
18. Subject must not have Patient Health Questionnaire (PHQ-9) score ≥ 15 at Visit 1 (or 
potentially confounding depression per the investigator's discretion).
Page 16 of 85

STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
19. No significant risk of self-harm, based on clinical interview and responses on the C-SSRS, or 
of harm to others in the opinion of the investigator; subject must be excluded if they report 
suicidal ideation with intent, with or without a plan or suicidal behavior (i.e., yes response to 
Question 4 or 5 in the suicidal ideation section or yes to any question in the suicidal behavior 
section of the C-SSRS) in the past 6 months prior to Visit 1.
20. No concurrent psychiatric conditions including bipolar disorder, schizophrenia, dementia, or 
other significant neurological disorders.
21. No presence or history of any medical condition that may place the subject at increased risk 
following exposure to BOTOX or interfere with the study evaluation, including:
a.
Diagnosed myasthenia gravis, Lambert-Eaton syndrome, amyotrophic lateral sclerosis, 
or any other significant disease that might interfere with neuromuscular function.
b.
Facial nerve palsy. 
c.
Infection or dermatological condition at the site of study intervention injection.
d.
Any significant eyebrow or eyelid ptosis at Day 1 as determined by the investigator.
22. No history of clinically significant (per investigator's judgment) drug or alcohol abuse within 
6 months of Visit 1.  
23. Must not have a condition or be in a situation which, in the investigator's opinion, may put 
the subject at significant risk, may confound the study results, or may interfere significantly with 
the subject's participation in the study.
24. No known active Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection.  
If a subject has signs/symptoms suggestive of SARS‑CoV‑2 infection, the subject must have a 
negative molecular (e.g., polymerase chain reaction [PCR]) test result. 
25. No unremitting symptoms of "Long COVID" due to prior SARS-CoV-2 infection or any other 
lasting symptoms that, in the investigator's opinion, may put the patient at significant risk, may 
confound the study results, or may interfere significantly with the patient's participation in the 
study. 
26. Subjects who do not meet SARS-CoV-2 infection eligibility criteria must be screen failed and 
may only rescreen after they meet the following SARS-CoV-2 infection viral clearance criteria:
a.
At least 14 days since first negative PCR test result have passed in asymptomatic 
patients or 14 days since recovery, defined as resolution of fever without use of 
antipyretics and improvement in symptoms.
27. If the subject has received a SARS-CoV-2 vaccination, the subject must have completed their 
final dose of the vaccine at least 14 days prior to Day 1 (study drug administration).  Subjects 
who receive an initial SARS-CoV-2 vaccine during the screening/baseline period may remain in 
the study, as long as a minimum 14-day interval between the vaccine administration and study 
drug administration is maintained.  Subjects who are unvaccinated are eligible for this study (see 
Section 5.4 for additional guidance).
Page 17 of 85

STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
28. Subject has not received any investigational product within 30 days or 5 half-lives of the drug 
(whichever is longer) before the first dose of study drug or is currently enrolled in another 
clinical study. This will be confirmed via Verified Clinical Trials (VCT) for US subjects only.  
Simultaneous enrollment in a non-interventional study not for a headache or migraine 
condition, may be permitted as long as the study is not overly burdensome, is not anticipated to 
impact performance on key study endpoints, and is unlikely to trigger subject discontinuation 
pending approval by AbbVie.
29. No known allergy or sensitivity to the study medication or its components.
Contraception
30. For all females of childbearing potential; a negative serum pregnancy test at Visit 1 and a 
negative urine pregnancy test at Visit 2 prior to the first dose of study drug.
31. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control, that is effective from Visit 1 through at least 90 days after the last dose of study 
drug.  Female subjects of nonchildbearing potential do not need to use birth control.
32. Female who is not pregnant, breastfeeding, or considering becoming pregnant during the 
study or within 90 days after the last dose of study drug.
Concomitant Medications
33. No use of any opioids or barbiturates >  days/month or any gepant in the 3 months prior to 
Visit 1 per investigator's judgment, or during the baseline or screening phase.
34. No prior use of ANY 
 injections in the 
head, face, and/or neck in the subject's lifetime.
35. No prior use of ANY botulinum toxin (any serotype, therapeutic or cosmetic), regardless of 
location, in the 6 months prior to Visit 1.
36. No concurrent use or use of any migraine prophylactic treatment in the 4 weeks prior to 
Visit 1 nor during the baseline or screening phase.
37. No use of CGRP monoclonal antibody in the 6 months prior to Visit 1. 
38. No concurrent use or use of acupuncture, TENS (e.g., Cefaly Dual), cranial traction, 
nociceptive trigeminal inhibition or occipital nerve block treatments, or injection of anesthetics 
or steroids into the study target muscles in the 4 weeks prior to Visit 1.
39. Euthyroid based on investigator review of relevant medical information at screening, 
laboratory results, physical exam, concomitant medication, and medical history.  Thyroid 
medication must be stable for at least 3 months prior to Visit 1 and remain unchanged during 
the study.
40. Subject must not have received immunization for any botulinum toxin serotype nor have a 
history of botulism. 
Page 18 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
5.2 Contraception Recommendations 
Contraception Requirements for Females 
Subjects must follow the following contraceptive guidelines as specified: 
• 
Females, Non-Childbearing Potential 
Females do not need to use birth control during or following study drug treatment if considered 
of non-childbearing potential due to meeting any of the following criteria: 
1. Premenopausal female with permanent sterility or permanent infertility due to one of the 
following: 
• 
Permanent sterility due to a hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy 
• 
Non-surgical permanent infertility due to Mullerian agenesis, androgen insensitivity, or 
gonadal dysgenesis; investigator discretion should be applied to determining study entry 
for these individuals. 
2. Postmenopausal female 
• 
Age > 55 years with no menses for 12 or more months without an alternative medical 
cause. 
• 
Postmenopausal, Age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND a follicle-stimulating hormone level > 30 IU/L. 
• 
Females, of Childbearing Potential 
• 
Females of childbearing potential must avoid pregnancy during the study and for at least 
90 days after the last dose of study drug.   
• 
Females must commit to one of the following methods of birth control: 
• 
Combined (estrogen and progestogen containing) hormonal birth control (oral, 
intravaginal, transdermal, injectable) associated with inhibition of ovulation initiated at 
least 30 days prior to study baseline Day 1. 
• 
Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to study Day 1. 
• 
Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure). 
• 
Intrauterine device (IUD). 
• 
Intrauterine hormone-releasing system (IUS). 
• 
Vasectomized partner (provided the partner has received medical confirmation of the 
surgical success of the vasectomy and is the sole sexual partner of the trial subject). 
• 
Practice true abstinence, defined as:  Refraining from heterosexual intercourse when 
this is in line with the preferred and usual lifestyle of the subject (periodic abstinence 
Page 19 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are 
not acceptable). 
 
Contraception recommendations related to the use of concomitant therapies prescribed should be 
based on the local label. 
5.3 Prohibited Medications and Therapy 
In addition to the medications listed in the eligibility criteria, the following medications/therapies are 
prohibited during the study:  
• 
Monoclonal antibodies blocking the CGRP pathway (e.g., erenumab, fremanezumab, 
galcanezumab, eptinezumab) 
• 
Oral CGRP antagonists (e.g., rimegepant and atogepant; during the double-blind and open-label 
phases) except ubrogepant, which is prohibited during the double-blind phase but allowed 
during the open-label phase with restricted use of no more than  days per month 
• 
Medications with demonstrated efficacy for the prophylactic treatment of migraine (e.g., 
amitriptyline, topiramate, propranolol) (see Section 8.1 of the Operations Manual for the list of 
medications) 
• 
Benzodiazepines 
• 
Botulinum toxin type A or other serotypes except for the investigational product 
• 
Homeopathic or herbal remedies for migraine headaches (e.g., feverfew, valerian, belladonna) 
• 
Marijuana, CBD oil, or other cannabinoid derivatives 
• 
Any therapy intended for preventive treatment of migraine 
 
Opioids and barbiturates are allowed but their use is restricted to no more than  days/month.  Therapy 
considered necessary for the subject's welfare may be given at the discretion of the investigator.  The 
decision to administer a prohibited medication/treatment is made with the safety of the study subject 
as the primary consideration.  When possible, AbbVie should be notified before the prohibited 
medication/treatment is administered.   
Coadministration of aminoglycosides or agents that could interfere with neuromuscular transmission 
(e.g., curare-like agents) or muscle relaxants should be used with caution, as the effects of the toxin 
could be potentiated. 
Page 20 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
5.4 Prior and Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the subject is receiving at the time of enrollment or receives during the study 
from 6 months prior to study drug administration through the exit visit (Week 48) must be recorded. 
Concomitant prophylactic medications are not allowed in the study; however, the following medications 
for the acute treatment of migraine are allowed during the study and use of these medications must be 
documented in the e-Diary: 
• 
Acute migraine-specific medication (any triptan, ditan, or ergot) 
• 
Any other form of analgesic (including acetaminophen) 
• 
Any NSAID agent 
• 
Any antiemetic agent 
• 
Any opioid ≤  days/month 
• 
Any barbiturate ≤  days/month 
 
Ubrogepant is an acute migraine-specific medication and is allowed during the open-label phase only 
with restricted use of no more than  days per month.  Any questions regarding concomitant or prior 
therapy should be raised to the AbbVie emergency contact.  Information regarding potential drug 
interactions with BOTOX can be located in the Investigator's Brochure.  
COVID 19 Pandemic Related Vaccination Guidance 
Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g., mRNA, non-replicating viral 
vector, protein subunit, etc.) to prevent SARS-CoV-2 infection may be administered during the 
treatment period, as long as components of the vaccine are not contraindicated.  The decision to receive 
a locally available vaccine should be based on local guidance and an individual discussion between the 
treating physician and the subject.  The potential impact of BOTOX on SARS-CoV-2 vaccination is 
unknown.   
If the subject has received a SARS-CoV-2 vaccination prior to screening, the subject must have 
completed their final dose of the vaccine at least 14 days prior to Day 1 (study drug administration).  
Subjects who receive an initial SARS-CoV-2 vaccine during the screening/baseline period may remain in 
the study, as long as a minimum 14-day interval between the vaccine administration and study drug 
administration is maintained.  If this is not possible, the timing of the Day 1 visit for eligible subjects may 
be extended by a maximum of 14 days or the subject may need to withdraw from the study and be re-
screened after receiving their final dose of vaccine, pending approval by the Sponsor. 
Throughout the study, study drug, when possible, is preferred to be given at least 14 days before or 
after SARS-CoV-2 vaccine administration.  
Note:  The above guidance applies to all SARS-CoV-2 vaccine doses given as part of the complete 
treatment course. 
Page 21 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
These recommendations may be subject to change based on the evolving knowledge around the use of 
SARS-CoV-2 vaccines and as more data are collected in real-world scenarios and clinical trials. 
Any SARS-CoV-2 vaccine information must be documented on the COVID-19 vaccine electronic case 
report form (eCRF).  Refer to Section 4.2 of the Operations Manual for instructions on reporting any AEs 
associated with the COVID-19 vaccine. 
5.5 Withdrawal of Subjects and Discontinuation of Study 
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons including, 
but not limited to, the following:   
• 
The subject responds "Yes" to questions 4 or 5 in the suicidal ideation section or to any question 
in the suicidal behavior section of the C-SSRS. 
• 
Clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the investigator or the AbbVie medical contact. 
• 
The investigator believes it is in the best interest of the subject. 
• 
The subject requests withdrawal from the study. 
• 
Eligibility criteria violation is noted after the subject started study drug and continuation of the 
study drug may place the subject at risk. 
• 
Introduction of prohibited medications or dosages and continuation of the study drug may place 
the subject at risk. 
• 
The subject is significantly noncompliant with study procedures, which may put the subject at 
risk for continued participation in the trial. 
• 
Any female subject who becomes pregnant while participating in the study will not be eligible to 
receive further study intervention.  However, the subject should remain in the study to ensure 
adequate follow-up of safety and efficacy data through the end of the respective treatment 
cycle, and then be exited from the study.  See "Pregnancy" subsection under Section 6.1 for 
more information. 
 
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made, and 1 certified 
letter must be sent and documented in the subject's source documentation. 
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The investigator may 
also stop the study at their site if they have safety concerns.  If AbbVie terminates the study for safety 
reasons, AbbVie will promptly notify the investigator. 
COVID 19 Pandemic Related Acceptable Protocol Modification 
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care.  Acceptable mitigation strategies are 
identified and included in the Operations Manual in Appendix F. 
Page 22 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
The investigator should contact the AbbVie medical contact before discontinuing a subject from the 
study for a reason other than described in the protocol to ensure all acceptable mitigation steps have 
been explored. 
Refer to the Operations Manual in Appendix F for details on how to handle study activities/procedures. 
Interruption/Discontinuation of Study Drug Due to COVID 19 Infection 
During the study drug dosing period, a subject with confirmed (viral test positive) or suspected 
COVID-19 infection can only be dosed with study drug if the following COVID-19 viral clearance criteria 
are met: 
• 
Symptomatic subjects:  At least 2 negative viral tests in a row, ≥ 24 hours apart after at least 
10 days have passed since recovery, defined as resolution of fever without use of antipyretics 
and improvement in respiratory symptoms (e.g., cough, shortness of breath) 
• 
Asymptomatic subjects:  At least 2 negative viral tests in a row, ≥ 24 hours apart after at least 
10 days have passed since prior positive result (note:  subjects who develop symptoms will 
follow guidance above for symptomatic subjects) 
 
Delays in study drug dosing due to the above COVID-19 testing guidance for subjects must be discussed 
with the AbbVie medical contact, along with the possibility of premature discontinuation (PD) from the 
study drug dosing period.  Follow subsequent protocol Section 5.6 for subjects who discontinue study 
drug.  Frequency or timing of COVID-19 testing and intervals between testing for the above viral 
clearance criteria may be adjusted to account for epidemiologic trends, updated information regarding 
infectivity, and local/institutional guidelines. 
5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study 
To minimize missing data for efficacy and safety assessments, subjects who prematurely discontinue 
study drug treatment should continue to be followed for all regularly scheduled visits, unless subjects 
have decided to discontinue study participation entirely (withdrawal of informed consent).  Subjects 
should be advised on the continued scientific importance of their data even if they discontinue 
treatment with study drug early. 
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the exit/PD visit (Week 48/Visit 14) should be completed as soon as possible, 
preferably within 2 weeks.  In addition, if subject is willing, a 30-day follow-up phone call after the last 
dose of study drug may be completed to ensure all treatment-emergent AEs (TEAEs)/SAEs have been 
resolved. 
In the event a subject withdraws consent from the clinical study, biomarker research will continue 
unless the subject explicitly requests analysis to be stopped.  When AbbVie is informed the patient has 
withdrawn and no longer wishes biomarker samples research to continue, samples will not be analyzed, 
and no new biomarker analysis data will be collected for the withdrawn subject or added to the existing 
Page 23 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
data or database(s).  Data generated from biomarker research, before subject withdrawal of consent, 
will remain part of the study results. 
5.7 Study Drug  
BOTOX (195 U or 155 U) or matching placebo will be administered by a trained injector at Day 1 (Visit 2) 
and Week 12 (Visit 5) of the double-blind phase.   
All subjects who continue to the open-label treatment phase of the study will receive open-label BOTOX 
195 U at Week 24 (Visit 8) and Week 36 (Visit 11). 
Each site will keep an accurate record that specifies the amount of study drug administered to each 
subject and the date of administration.  This information will be recorded in the subject's eCRF. 
AbbVie provided study drug should not be substituted or alternately sourced unless otherwise directed 
by AbbVie.   
BOTOX 100 U and matching placebo vials manufactured by AbbVie will be packaged in quantities 
sufficient to accommodate the study design.  Each kit will be labeled per local requirements and this 
label must remain affixed to the kit.  Upon receipt, study drug should be stored as specified on the label 
and kept in a secure location.  Each kit will contain a unique kit number.  This kit number is assigned to a 
subject via interactive response technology (IRT) and encodes the appropriate study drug to be 
dispensed at the subject's corresponding study visit.  Study drug will only be used for the conduct of this 
study. 
An independent drug reconstitutor (IDR) will add preservative-free saline to each vial and draw the 
study drug into syringes to be injected.  Instructions for drug preparation are provided in the Pharmacy 
Manual, which will be provided separately from the protocol and operations manual.  
Digital Health Tools Accountability  
The investigator or their representative will verify that the digital health tools are received intact and in 
the correct amounts.  A proof of receipt or similar document will be kept in the site files as a record of 
what was received. 
In addition, sites will maintain records of traceability, accountability, and return including but not limited 
to date received/dispensed/returned, subject number, and the identification of the person 
dispensing/returning the digital health tools. 
5.8 Randomization/Drug Assignment 
All subjects will be assigned a unique identification number by the IRT at the screening visit.  For 
subjects who rescreen, the screening number assigned by the IRT at the initial screening visit should be 
used.  The IRT will assign a randomization number that will encode the subject's treatment group 
assignment according to the randomization schedule at Visit 2. 
Page 24 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Eligible subjects will be randomized to BOTOX 155 U, BOTOX 195 U, or placebo in a 1:1:1 ratio.  
Randomization in this study will be performed at the country level, and randomization stratification 
factors will include 
 (yes/no), and ≥ monthly 
migraine days at baseline (yes/no).  
 is based on 
medical history and patient interview.  The monthly migraine days count at baseline is generated in the 
full eligibility report using e-Diary data of the 28 days prior to Visit 2; no manual calculation is required.  
All AbbVie personnel with direct oversight of the conduct and management of the trial (with the 
exception of AbbVie Drug Supply Management Team), the investigator, study site personnel, and the 
subject will remain blinded to each subject's treatment throughout the study.  To maintain the blind, the 
BOTOX and placebo vials provided for the study will be identical in appearance.  In addition, an IDR will 
add preservative-free saline to each vial and draw the study drug into syringes to be injected.  To further 
facilitate blinding, all subjects will receive 39 injections in the prespecified injection sites at all treatment 
cycles during the double-blind phase (BOTOX 155 U: 31 sites with active study drug and 8 sites with 
placebo; BOTOX 195 U: 39 sites with active study drug; placebo: 39 sites with placebo).   
When necessary for the safety and proper treatment of the subject, the investigator can unmask the 
subject's treatment assignment to determine which treatment was assigned and institute appropriate 
follow-up care.  The IRT will provide unrestricted and immediate access to unblinded subject treatment 
information.  The responsibility to break the treatment code in emergency situations resides solely with 
the investigator.  The investigator should inform the AbbVie medical contact of the unmasking.  The 
reason for breaking the code must be recorded in the subject's eCRF.  
All subjects who are eligible to continue to the open-label treatment phase of the study at Week 24 
(Visit 8) will receive open-label BOTOX 195 U at 12-week intervals for up to 2 treatment cycles.   
5.9 Protocol Deviations 
AbbVie does not allow intentional/prospective deviations from the protocol, except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified, including those that may be due to the COVID-19 pandemic), 
the investigator is responsible for notifying independent ethics committee (IEC)/independent review 
board (IRB), regulatory authorities (as applicable), and AbbVie. 
5.10 Data Monitoring Committee 
No data review committee is planned for this study.   
Page 25 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
6 SAFETY CONSIDERATIONS  
6.1 Complaints and Adverse Events 
Complaints  
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie. 
Product Complaint 
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s). 
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues. 
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event.  Product complaints occurring during the 
study will be followed up to a satisfactory conclusion. 
Medical Complaints/Adverse Events and Serious Adverse Events:  BOTOX 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product. 
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
"special situations" such as accidental or intentional overdose, medication error, occupational or 
accidental exposure, off-label use, drug abuse, drug misuse, or drug withdrawal, all which must be 
reported whether associated with an AE or not.  Any worsening of a pre-existing condition or illness is 
considered an AE.  Worsening in severity of a reported AE should be reported as a new AE.  Laboratory 
abnormalities and changes in vital signs are considered to be AEs only if they result in discontinuation 
from the study, necessitate therapeutic medical intervention, and/or if the investigator considers them 
to be AEs. 
The investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion. 
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and/or the surgery/procedure has 
Page 26 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
been pre-planned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE. 
If an AE, whether associated with study drug or not, meets any of the following criteria, it is to be 
reported to AbbVie clinical pharmacovigilance or contract research organization (as appropriate) as a 
serious AE within 24 hours of the site being made aware of the serious AE (or sooner, depending on 
local requirements; refer to Section 4.2 of the Operations Manual for reporting details and contact 
information): 
Death of Subject 
An event that results in the death of a subject. 
Life-Threatening 
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if it 
had occurred in a more severe form. 
Hospitalization or 
Prolongation of 
Hospitalization 
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not include 
an emergency room visit or admission to an outpatient facility. 
Congenital Anomaly 
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss. 
Persistent or Significant 
Disability/Incapacity 
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle). 
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome 
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life-threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event along with any suspected transmission of an 
infectious agent via a medicinal product if no other serious criterion 
is applicable.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse. 
 
Page 27 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
All AEs reported from the time of consent through the last study visit (i.e., 12 weeks after the last study 
drug administration) or through 30 days after the last study drug administration (for subjects who 
discontinue prematurely) will be collected, whether solicited or spontaneously reported by the subject.  
In addition, study procedure-related serious and nonserious AEs will be collected from the time the 
subject signs the study-specific informed consent. 
The following definitions will be used for Serious Adverse Reactions (SAR) and Suspected Unexpected 
Serious Adverse Reaction (SUSAR): 
SAR 
Defined as all noxious and unintended responses to an IMP related to any dose 
administered that result in an SAE as defined above. 
SUSAR 
Refers to individual SAE case reports from clinical trials where a causal 
relationship between the SAE and the IMP was suspected by either the sponsor 
or the investigator, is unexpected (not listed in the applicable Reference Safety 
Information), and meets one of the above serious criteria. 
 
AbbVie will be responsible for SUSAR reporting for the Investigational Medicinal Product (IMP) in 
accordance with global and local requirements. 
All AEs will be monitored throughout the study to identify any of special interest that may indicate a 
trend or risk to subjects. 
Adverse Events of Special Interest 
Possible distant spread of toxin (PDSOT) is defined as a possible pharmacologic effect of botulinum toxin 
at sites noncontiguous and distant from the site of injection.  Utilizing a standardized methodology to 
assess for PDSOT, Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) that may 
be associated with botulinum toxin effects have been prospectively identified (see the statistical analysis 
plan [SAP] for a complete list of these PTs).  Adverse events reporting any of these terms will be 
medically reviewed on a regular basis throughout the duration of the study and will be summarized in 
the study CSR. 
Adverse Event Severity and Relationship to Study Drug 
The investigators will rate the severity of each AE as mild, moderate, or severe. 
The investigator will use the following definitions to rate the severity of each AE: 
Mild 
The AE is transient and easily tolerated by the subject. 
Moderate 
The AE causes the subject discomfort and interrupts the subject's usual 
activities. 
Severe 
The AE causes considerable interference with the subject's usual activities 
and may be incapacitating or life-threatening. 
 
Page 28 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
treatment: 
Reasonable 
Possibility 
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship. 
No Reasonable 
Possibility 
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
insufficient evidence (information) to suggest a causal relationship. 
 
Pregnancy 
If a pregnancy occurs in a study subject, information regarding the pregnancy and the outcome will be 
collected.  While not an AE, pregnancy in a study subject must be reported to AbbVie within 24 hours 
after the site becomes aware of the pregnancy.  Any female subject who becomes pregnant while 
participating in the study will not be eligible to receive further study intervention but should remain in 
the study to ensure adequate follow-up of safety and efficacy data through the end of the respective 
treatment cycle, and then be exited from the study. 
The study subject will be followed to determine the outcome of the pregnancy.  The investigator will 
collect follow-up information on the study subject and the neonate, and the information will be 
forwarded to the Sponsor.  Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  The pregnancy outcome of an 
elective or spontaneous abortion, stillbirth, or congenital anomaly is considered an SAE and must be 
reported to AbbVie within 24 hours after the site becomes aware of the event. 
6.2 Other Safety Data Collection 
Columbia Suicide Severity Rating Scale (C SSRS) 
The C-SSRS reports the severity of both suicidal ideation and behavior.  Suicidal ideation is classified on a 
5-item scale: 1 (wish to be dead), 2 (nonspecific active suicidal thoughts), 3 (active suicidal ideation with 
any methods [not plan] without intent to act), 4 (active suicidal ideation with some intent to act, 
without specific plan), and 5 (active suicidal ideation with specific plan and intent).  The C-SSRS also 
captures information about the intensity of ideation, specifically the frequency, duration, controllability, 
deterrents, and reasons for the most severe types of ideation.  Suicidal behavior is classified on a 5-item 
scale: 0 (no suicidal behavior), 1 (preparatory acts or behavior), 2 (aborted attempt), 3 (interrupted 
attempt), and 4 (actual attempt).  More than one classification can be selected provided they represent 
separate episodes.  For actual attempts only, the actual or potential lethality is classified for the initial, 
most lethal, and most recent attempts.  Any subject who has suicidal ideation with intent (with or 
without plan), either via answering "yes" to question 4 and/or question 5 to the suicidal ideation section 
or "yes" to any question in the suicidal behavior section of the C-SSRS, or via clinical interview, will be 
evaluated immediately by the investigator and discontinued from the study.  The AbbVie medical 
contact will also be notified.  The subject should receive appropriate follow-up as in routine clinical 
practice.  In addition, if the subject expresses suicidal ideation at any time during the study, the 
Page 29 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
investigator and the AbbVie medical contact should be notified immediately.  Under no circumstances 
should a subject who has positively endorsed or expressed suicidal ideation be left alone, be allowed to 
exit the site, or go home before a qualified medical professional has evaluated the subject's risk.  
The C-SSRS is administered by the clinician or trained personnel via subject interview in person or over 
the telephone, as applicable, at all study visits.  At Visit 1 (screening), the C-SSRS will be completed for 
the subject's lifetime history and for the 6 months prior to screening.  At all other visits the C-SSRS will 
be completed for ideation and behavior since the previous visit. 
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE 
7.1 Statistical and Analytical Plans 
The statistical methods provided in this protocol will be focused on primary and key secondary analyses.  
Complete and specific details of the statistical analysis will be described in the SAP, which must be in 
place before randomization codes are unmasked for any analysis. 
A primary analysis will be performed at the end of the double-blind phase and a final analysis at the end 
of the open-label phase.  A database lock will occur, and randomization data will be released when all 
subjects have completed the double-blind phase through the Week 24 visit.  The planned primary 
analysis will be performed at that time.  The final database will be locked when all subjects have 
completed the open-label phase of the study.  For analysis purposes, subjects who complete the Week 
24 visit and remain in the study regardless of whether or not they receive further treatment, will be 
considered as having entered the open-label phase.  The planned final analysis will be performed after 
the final database is locked.  The final analysis will include data from both the double-blind phase and 
the open-label phase of the study. 
7.2 Definition for Analysis Populations 
The following analysis populations are defined for this study: 
• 
The intent-to-treat (ITT) population includes all subjects who are randomized.  This will be used 
as the full analysis set (FAS) population.  Subjects will be summarized according to their 
randomization assignment (i.e., as randomized), regardless of study intervention received.  (All 
subjects will have non-missing baseline data for the primary efficacy variable because it is a 
condition of randomization, and therefore, the ITT population is not being modified with such a 
constraint.)  
• 
The safety population includes all randomized subjects who have at least 1 study treatment 
intervention (i.e., BOTOX or placebo).  Subjects will be summarized according to the study 
intervention received (i.e., as treated), regardless of their randomization assignment. 
 
Page 30 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
7.3 Handling Potential Intercurrent Events for the Primary and Key 
Secondary Endpoints 
The estimand corresponding to the primary objective of this study is displayed in Section 3.1.  Among 
intercurrent events, it includes study discontinuations, especially if due to lack of efficacy or due to AEs.  
Also included are any significant protocol deviations that could affect the primary endpoint, such as 
taking rescue medication or not receiving the Week 12 treatment.  A sensitivity analysis will impute 
scores differently for such intercurrent events (e.g., reversion toward baseline).   
The primary analysis assumes that missing data are missing completely at random or missing at random.  
A sensitivity analysis will use the same model as the primary analysis after imputation of missing data by 
the modified last observation carried forward (mLOCF) rate-change method, which adjusts the most 
recent observation by the average change since that observation within the same treatment regimen.  
An additional sensitivity analysis, which is aimed at intercurrent events, will instead impute missing data 
by reversion toward baseline for subjects who have intercurrent events that could affect the primary 
endpoint.  These sensitivity analyses will be described in more detail in the SAP. 
7.4 Statistical Analyses for Efficacy 
The efficacy analyses will be based on the ITT population, in general.  Baseline for efficacy analyses is 
defined as the last non-missing efficacy assessment before randomization.  For the primary efficacy 
variable and similar variables based on headache diary data, baseline will be the count of affected days 
during the 4 weeks ending the day before randomization. 
Summary and Analysis of the Primary Endpoint 
The primary efficacy endpoint is defined in Section 3.2.  The primary efficacy analysis will test the null 
hypothesis that BOTOX (each dose group separately) and placebo are equally effective, as measured by 
the change from baseline in monthly migraine days across Months 5 and 6. 
A mixed model repeated measures (MMRM) analysis will be used for the primary analysis, using data for 
baseline and each month of the double-blind, placebo-controlled phase (i.e., months ending with Weeks 
4, 8, 12, 16, 20, and 24).17  The statistical model will include treatment (BOTOX 195 U, BOTOX 155 U, and 
placebo), month, country, strata of 
, and 
treatment group-by-month interaction as fixed effects, with the baseline number of monthly migraine 
days as a covariate, included as a continuous variable rather than as the binomial stratification variable.  
Subject and residual errors will be random effects.  The primary comparisons of interest will be the 
pairwise comparisons of each BOTOX dose (195 U and 155 U) versus placebo across Months 5 and 6.   
Each dose comparison will be analyzed across primary and secondary endpoints in the order described 
in Section 7.7, using a ranked-order serial gatekeeping approach to control the overall type I (false-
positive) error rate.  For each BOTOX dose versus placebo, each variable/dose pair will be examined for 
significance only if significance was determined for all variable/dose pairs ranked ahead of it.  
The primary analysis assumes that missing data are missing completely at random or missing at random.  
Details of the sensitivity analyses will be provided in the SAP.  A 2-sided test with a P value ≤ 0.05 will be 
Page 31 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
considered as statistically significant for the treatment group comparisons of each BOTOX dose (195 U 
and 155 U) versus placebo.   
Interaction effects will be examined at the 0.10 level by including treatment group-by-country 
interaction in a separate expansion of the primary MMRM model.  If there is a significant interaction 
(P ≤ 0.10) in the expanded MMRM model, the relevant reduced model will be examined for 
interpretation (i.e., by country). 
Secondary analyses of covariance (ANCOVAs) of the primary efficacy variable (monthly migraine days) 
will be made for each month of the double-blind, placebo-controlled phase (i.e., months ending with 
Weeks 4, 8, 12, 16, 20, and 24), using the same model as for the primary MMRM analysis, but without 
repeat measures (i.e., omitting fixed effect of month and treatment group-by-month interaction). 
A sensitivity analysis will use the same MMRM model after imputation of missing data by the mLOCF 
rate-change method, which adjusts the most recent observation by the average change since that 
observation within the same treatment regimen.  This method has been chosen for consistency with 
methods used for the Phase 3 CM studies of BOTOX.  Additional sensitivity analyses, including those 
using other imputation methods, will be described in the SAP (e.g., reversion toward baseline).   
Subgroup Analysis of the Primary Endpoint 
The primary effectiveness analysis (MMRM of change in monthly migraine days without the fixed effect 
of the corresponding subgroup variable) will be repeated for subgroups defined by each randomization 
stratification subgroup (monthly migraine days at baseline ≥  [yes/no] and 
 
[yes/no]), for medication overuse subgroup [yes/no] (see Section 8.2 in 
the Operations Manual), for each gender, and for each country. Additional subgroup analyses will be 
described in the SAP. 
Summary and Analysis of Secondary Endpoints 
The secondary efficacy endpoints are defined in Section 3.3; Each dose comparison will be analyzed 
across primary and secondary endpoints in the order described in Section 7.7, using a ranked-order 
serial gatekeeping approach to control the overall type I (false-positive) error rate.  For each BOTOX 
dose versus placebo, each variable/dose pair will be examined for significance only if significance was 
determined for all variable/dose pairs ranked ahead of it. 
The comparisons of interest for each of these secondary endpoints will be the pairwise comparisons of 
each BOTOX dose (195 U and 155 U) versus placebo, with no statistical comparison between the BOTOX 
doses.   
The analysis results of the change from baseline in monthly headache days, MSQ v2.1 RFR domain score, 
monthly acute headache medication days, and AIM-D Physical Impairment domain score (or HIT-6 score 
[for Europe]) across Months 5 and 6 will come from the same type of MMRM analysis of observed data 
used for the primary efficacy endpoint, except that the baseline covariates will be monthly headache 
days, MSQ v2.1 RFR domain score, monthly acute headache medication days, and AIM-D Physical 
Impairment domain score (or HIT-6 score [for Europe]), respectively.   
Page 32 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Logistic regression will be used to analyze responder variables using the same ANCOVA analysis model 
described for the primary variable (i.e., the MMRM model used for the primary analysis, but without 
repeat measures).  The proportion of subjects with 50% reduction in the change from baseline in 
monthly migraine days across Months 5 and 6 will be summarized, along with p-values from the logistic 
regression.  The primary assessment will be the pairwise comparison of each BOTOX dose versus 
placebo.  A sensitivity analysis will use the same logistic model after imputation of missing data for the 
underlying primary variable by the mLOCF rate-change method, as described above.  Alternatively, 
GLIMMIX models for repeated measures of binary data might be used in place of MMRM models; if so, 
the methodology will be described in the SAP.  
Summary and Analysis of Other Endpoints 
The other endpoints are defined in Section 3.4.  These endpoints are not planned to be included in the 
multiplicity control.  Hence, results will be considered descriptive and potentially supportive of the 
results for the primary and secondary endpoints.   
The comparisons of interest for each of the other endpoints will be the pairwise comparisons of each 
BOTOX dose (195 U and 155 U) versus placebo, with no statistical comparison between the BOTOX 
doses.  Specific details of the statistical analysis of other efficacy endpoints will be described in the SAP.  
In general, though, for continuous and ordinal variables, the change from baseline analysis will be done 
with the same type of MMRM or ANCOVA analyses described for the primary efficacy endpoint, except 
that the baseline covariate will be for the variable being analyzed.  For 
 which is recorded as 
change score postbaseline, the 
 baseline score will be used as a surrogate baseline covariate, to 
adjust for variation in response that is due to baseline differences between treatment groups. 
In general, for responder variables, analysis of the responder status will be done with the same methods 
described for the secondary variable of 50% responder status.  
For 
, the change from baseline analysis will be done with the same 
type of MMRM or ANCOVA analyses described for the primary efficacy endpoint, except that the model 
will use 
.  The counts for a given week will be prorated to 28-day counts before 
calculating the change from baseline. 
7.5 Statistical Analyses for Safety 
The safety analysis will be performed using the safety population and will be fully defined in the SAP.  
The safety parameters will include AEs, clinical laboratory test results (hematology, chemistry, and 
urinalysis), vital signs, C-SSRS, and concomitant medications and procedures.  The safety endpoints will 
be summarized using response frequencies and descriptive statistics, as applicable.   
Any AEs that may occur before randomization will be listed but not summarized.  An AE will be 
considered a TEAE if the AE began or worsened (increased in severity or became serious) on or after the 
date (and time, if known) of the first study intervention.  An AE will be considered a TESAE if it is a TEAE 
that additionally meets any SAE criterion. 
Page 33 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
The incidence of TEAEs will be presented for each BOTOX dose group and the placebo group by the 
following: 
• 
descending order of incidence rate 
• 
primary system organ class (SOC) and PT 
• 
primary SOC, PT, and maximum severity  
• 
primary SOC, PT, and maximum duration 
 
The number and percentage of subjects with treatment-related TEAEs in the treatment and placebo 
groups will similarly be tabulated by descending order of incidence rate, by SOC and PT and, separately, 
by SOC, PT, and severity. 
If more than 1 AE is coded to the same PT for the same subject, the subject will be counted only once for 
that PT using the most severe and most related occurrence for the summarizations by severity and by 
relationship to study intervention. 
Summary tables will be provided separately for subjects with TESAEs, for subjects with TEAEs leading to 
discontinuation, and for subjects with AEs of special interest (e.g., PDSOT, as defined in Section 6.1) if 
5 or more subjects report such events.  Note that MedDRA PTs for PDSOT will be provided in the SAP.  
Listings of all AEs, SAEs, and AEs leading to discontinuation by subject will be presented. 
The analyses described above for treatment versus placebo groups will be for AEs occurring during the 
24-week double-blind, placebo-controlled phase.  The analyses will be repeated to summarize AE results 
for treated subjects over the open-label phase for subjects who receive open-label BOTOX. 
All safety endpoints and analyses will be fully defined in the SAP. 
Subgroup Analysis of Key Safety Endpoint(s) 
The analysis of treatment-related TEAEs (by descending order of PT incidence) will be repeated for 
subgroups defined by each randomization stratification group (monthly migraine days at baseline ≥  
[yes/no] and 
 [yes/no]), for medication overuse 
subgroup [yes/no] (see Section 8.2 in the Operations Manual), for each gender, and for each country. 
Additional subgroup analyses will be described in the SAP. 
7.6 Interim Analysis 
There is no interim analysis planned for this study.  However, to assess the validity of the assumptions 
for powering this Phase 3 trial, a blinded sample size re-estimation will be performed when 
approximately 33% of the subjects have reached the Week 24 visit (i.e., with diary data available for the 
primary endpoint of migraine days during Months 5 and 6).  This will allow for a potential increase to the 
study sample size if the assumptions around data variability are inaccurate.  Sample size adjustment 
within 25% of the current sample size per treatment arm of 259 participants per group is allowed 
without the need for a protocol amendment.  
Page 34 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
Under a 1:1:1 randomization ratio, 259 subjects in each of the BOTOX dose groups and the placebo 
group at the primary time point will provide 90% power to detect a mean difference of 
 days 
between the groups for tests at alpha 0.05 and to detect a mean difference of 
 days for any tests 
done at alpha 0.025.  These power calculations used a standard deviation estimate of 
, based on data 
for the month ending with Day 180 in EM Phase 2 studies for the subgroup of subjects with 8 to 
14 migraine/probable migraine days at baseline (AbbVie data on file, Study 191622-037/509).  Thus, the 
sample size is based on an effect size of 
.    
With approximately 125 investigational sites planned, it is recommended that no site randomize more 
than approximately 12 subjects (i.e., twice the proportional share of 1 more site = 2 × [777/126]).   
Calculations were done by using the commercial software nQuery Advisor® version 7.0, using a 2-sample 
Student's t-test with equal variances. 
8 ETHICS  
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB) 
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved. 
8.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation (ICH) guidelines, applicable regulations, and guidelines governing clinical study 
conduct and the ethical principles that have their origin in the Declaration of Helsinki.  Responsibilities of 
the investigator are specified in Appendix B. 
In the event a significant disaster/crisis (e.g., epidemic/pandemic, natural disaster, conflict/combat) 
occurs leading to difficulties in performing protocol-specified procedures, AbbVie may engage with 
study site personnel in efforts to ensure the safety of subjects, maintain protocol compliance, and 
minimize risks to the integrity of the study while trying to best manage subject continuity of care.  This 
may include alternative methods for assessments (e.g., phone contacts or virtual site visits), alternative 
locations for data collection (e.g., use of a local laboratory instead of a central laboratory), and shipping 
investigational product and/or supplies direct to subjects to ensure continuity of treatment where 
allowed.  In all cases, these alternative measures must be allowed by local regulations and permitted by 
IRB/IEC.  Investigators should notify AbbVie if any urgent safety measures are taken to protect the 
subjects against any immediate hazard. 
Page 36 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
8.3 Subject Confidentiality 
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie. 
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s). In the event of a significant disaster/crisis (e.g., epidemic/pandemic, natural disaster, 
conflict/combat), remote review/verification of data may be employed if allowed by the local regulatory 
authority, IRB/IEC, and the study site. 
10  DATA QUALITY ASSURANCE 
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements. 
11  COMPLETION OF THE STUDY 
The end-of-study is defined as the date of the last subject's last visit. 
12  REFERENCES 
1. 
Headache Classification Committee of the International Headache Society (IHS) The 
International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211. 
2. 
Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden, and the need for 
preventive therapy. Neurology. 2007;68(5):343-9. 
3. 
Steiner TJ, Stovner LJ, Jensen R, et al. Migraine remains second among the world's causes of 
disability, and first among young women: findings from GBD2019. J Headache Pain. 
2020;21(1):137. 
4. 
Serrano D, Lipton RB, Scher AI, et al. Fluctuations in episodic and chronic migraine status over 
the course of 1 year: implications for diagnosis, treatment and clinical trial design. J Headache 
Pain. 2017;18(1):101. 
Page 37 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
5. 
Torres-Ferrus M, Quintana M, Fernandez-Morales J, et al. When does chronic migraine strike? A 
clinical comparison of migraine according to the headache days suffered per month. 
Cephalalgia. 2017;37(2):104-13. 
6. 
BOTOX® (onabotulinumtoxinA) Prescribing Information. (Revised May, 2018): Allergan, Inc;  
[Available from: http://www.allergan.com/assets/pdf/botox_pi.pdf. 
7. 
Bendtsen L, Sacco S, Ashina M, et al. Guideline on the use of onabotulinumtoxinA in chronic 
migraine: a consensus statement from the European Headache Federation. J Headache Pain. 
2018;19(1):91. 
8. 
Simpson DM, Hallett M, Ashman EJ, et al. Practice guideline update summary: Botulinum 
neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and 
headache: Report of the Guideline Development Subcommittee of the American Academy of 
Neurology. Neurology. 2016;86(19):1818-26. 
9. 
Frampton JE, Silberstein S. Correction to: OnabotulinumtoxinA: A Review in the Prevention of 
Chronic Migraine. Drugs. 2018;78(6):715. 
10. 
The American Headache Society Position Statement On Integrating New Migraine Treatments 
Into Clinical Practice. Headache. 2019;59(1):1-18. 
11. 
Katsarava Z, Schneeweiss S, Kurth T, et al. Incidence and predictors for chronicity of headache in 
patients with episodic migraine. Neurology. 2004;62(5):788-90. 
12. 
Macedo A, Baños JE, Farré M. Placebo response in the prophylaxis of migraine: a meta-analysis. 
Eur J Pain. 2008;12(1):68-75. 
13. 
Shamliyan TA, Choi JY, Ramakrishnan R, et al. Preventive pharmacologic treatments for episodic 
migraine in adults. J Gen Intern Med. 2013;28(9):1225-37. 
14. 
Fillingim RB, Price DD. What is controlled for in placebo-controlled trials? Mayo Clin Proc. 
2005;80(9):1119-21. 
15. 
Diener HC, Tassorelli C, Dodick DW, et al. Guidelines of the International Headache Society for 
controlled trials of preventive treatment of migraine attacks in episodic migraine in adults. 
Cephalalgia. 2020;40(10):1026-44. 
16. 
Bigal ME, Lipton RB. Migraine chronification. Curr Neurol Neurosci Rep. 2011;11(2):139-48. 
17. 
Mallinckrodt CH, Tamura RN, Tanaka Y. Recent developments in improving signal detection and 
reducing placebo response in psychiatric clinical trials. J Psychiatr Res. 2011;45(9):1202-7. 
 
Page 38 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AIM-D 
Activity Impairment in Migraine – Diary 
ANCOVA 
Analysis of covariance 
 
 
CGRP 
Calcitonin gene-related peptide 
CI 
Confidence interval 
CM 
Chronic migraine 
COVID-19 
Coronavirus disease – 2019 
CRF 
Case report form 
CSR 
Clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition 
eCOA 
Electronic clinical outcome assessment 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
e-Diary 
Electronic diary 
EM 
Episodic migraine 
ePRO 
Electronic patient-reported outcomes 
 
 
FAS 
Full analysis set 
GCP 
Good clinical practice 
HIT-6 
6-item Headache Impact Test 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use 
ICHD 
International Classification of Headache Disorders 
IDR 
Independent drug reconstitutor 
IEC 
Independent ethics committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional review board 
IRT 
Interactive response technology 
ITT 
Intent-to-treat 
Page 39 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
mLOCF 
Modified last observation carried forward 
MMRM 
Mixed model repeated measures 
MSQ v2.1 
Migraine-Specific Quality of Life Questionnaire version 2.1 
NSAID 
Nonsteroidal anti-inflammatory drug 
PCR 
Polymerase chain reaction 
PD 
Premature discontinuation 
PDSOT 
Possible distant spread of toxin 
 
 
 
 
PHQ-9 
Patient Health Questionnaire 
PP 
Per-protocol 
PRO 
Patient-reported outcome 
PT 
Preferred term 
RFR 
Role Function – Restrictive domain of the MSQ 
RSI 
Reference Safety Information 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reactions 
TEAE 
Treatment-emergent adverse event 
UK 
United Kingdom 
VAS 
Visual analogue scale 
VCT 
Verified Clinical Trials 
 
 
 
Page 40 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR 
Protocol M21-307:  Phase 3 Multicenter, Randomized, Double-blind, Placebo-controlled Study of BOTOX 
(Botulinum Toxin Type A) for the Prevention of Migraine in Subjects with Episodic Migraine 
Protocol Date:  03 April 2024 
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) and 
local regulations and guidelines governing the study at the site location.  In signing the Investigator 
Agreement, the investigator is agreeing to the following: 
1. Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm. 
2. Personally conducting or supervising the described investigation(s). 
3. Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments. 
4. Reporting complaints that occur in the course of the investigation(s) to AbbVie. 
5. Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s). 
6. Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments. 
7. Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie. 
8. Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments. 
9. Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie. 
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s). 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Name of Principal Investigator (printed or typed) 
 
 
Page 41 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
APPENDIX C. LIST OF PROTOCOL SIGNATORIES 
Name 
Title 
Functional Area 
Neuroscience 
Data and Statistical Sciences 
 
Page 42 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
APPENDIX E. PROTOCOL SUMMARY OF CHANGES 
Previous Protocol Versions  
Protocol  
Date  
Version 1.0 
18 May 2021 
Version 2.0 
13 July 2021 
Version 3.0 
16 August 2021 
Administrative Change 1 
01 October 2021 
Version 3.1 (Regional VHP) 
06 October 2021 
Version 3.2 (Germany Only) 
04 November 2021 
Administrative Change 2 
09 November 2021 
Version 4.0 
11 February 2022 
Version 4.1 (UK only) 
10 June 2022 
Administrative Change 3 
23 November 2022 
Administrative Change 4 
16 December 2022 
Administrative Change 6 (UK only) 
21 February 2023 
Administrative Change 5 
22 February 2023 
Version 5.0 
04 April 2023 
 
The purpose of this version is to correct minor clerical errors for consistency in addition to the following 
changes made to align with SAP version 2:  
• 
Protocol title page and Operation Manual Section 1 and Section 4.2  Updated the emergency 
medical contact with the information of the current personnel.  
• 
Protocol Section 3.3  Moved the last secondary endpoint of 
 
 to Section 3.4 "Other Endpoints" due to the exploratory nature of this 
endpoint.  
• 
Protocol Section 3.4  Added additional analysis of 
 in 
participants who report at least 1 day of 
 during baseline. 
Removed medication class analysis from change from baseline in the frequency of monthly 
acute headache medication days endpoint due to too few participants taking these medication 
classes at baseline. Added a statement that all primary and secondary endpoints will also be 
analyzed at monthly time points to further evaluate efficacy throughout the study.  
• 
Protocol Section 7.4  Added additional subgroup analyses to align with regulatory guidelines. 
• 
Protocol Section 7.7  Updated schematic of the multiplicity method to control overall Type I 
error rate to reflect changes in secondary endpoints. 
Page 46 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
• 
Protocol Section 9  Replaced COVID-19 pandemic with significant disaster/crisis events to 
clarify that remote verification may be considered for other significant disasters in addition to 
COVID-19 pandemic. 
• 
Operation Manual Section 1 and Section 4.2  SAE reporting contact information was updated. 
 
Page 47 of 85

 
 
 
 
STUDY M21 307  |  Version 6.0  |  EudraCT 2021 001979 16 
CONFIDENTIAL INFORMATION 
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 
APPENDIX F. OPERATIONS MANUAL 
 
 
Page 48 of 85