Clinical trial NCT02191579
Conditions: Migraine Disorders
Sponsor: Allergan
Start date: 2014-08-05; Completion date: 2017-09-01
Enrollment: 282 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy, safety and tolerability of prophylactic (preventative) treatment with BOTOX® (onabotulinumtoxinA) compared to topiramate in adults with chronic migraine.

Detailed description:

Arms: arm 1: 155U onabotulinumtoxinA (BOTOX®) total dose per treatment by intramuscular injection every 12 weeks for up to 3 treatments. arm 2: Topiramate starting at a daily oral dose of 25 mg/day titrated up to a maximum dose of 100 mg/day for 36 weeks. Participants who discontinue topiramate are eligible to receive treatment with BOTOX®.
Interventions: intervention 1: onabotulinumtoxinA intervention 2: Topiramate
Intervention descriptions: intervention 1: 155U onabotulinumtoxinA (BOTOX®) total dose per treatment by intramuscular injection every 12 weeks. intervention 2: Topiramate up to a maximum oral dose of 100 mg/day.

Protocol documents:
Prot_001.pdf: 
NCT02191579 
 
 
GMA-US-NEU-0206 
 
Title: A Multicenter, Prospective, Randomized, Open-label Study to Compare the Efficacy, 
Safety, and Tolerability of BOTOX® and Topiramate for Headache Prophylaxis in 
Adults with Chronic Migraine 
 
 
Protocol Date: May 27, 2014 
 
 
Statistical Analysis Plan (SAP) Date: July 17, 2017 






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INVESTIGATOR SIGNATURE PAGE
INVESTIGATOR:
I agree to:

Implement and conduct this study diligently and in strict compliance with the protocol,
good clinical practices and all applicable laws and regulations.

Maintain all information supplied by Allergan in confidence and, when this information
is submitted to an Institutional Review Board (IRB), Independent Ethics Committee
(IEC) or another group, it will be submitted with a designation that the material is
confidential.

Ensure that all persons assisting with the trial are adequately informed about the protocol,
the investigational product(s), and their trial-related duties and functions.
I have read this protocol in its entirety and I agree to all aspects.
Investigator Printed Name
Signature
Date


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Table of Contents
Table of Contents ...................................................................................................................... 4
List of Tables............................................................................................................................. 7
List of Figures........................................................................................................................... 7
Protocol Summary .................................................................................................................... 8
1.
Background and Clinical Rationale................................................................................. 16
2.
Study Objectives and Clinical Hypotheses...................................................................... 17
2.1
Study Objectives .................................................................................................... 17
2.2
Clinical Hypotheses ............................................................................................... 17
3.
Study Design.................................................................................................................... 18
3.1
Structure................................................................................................................. 18
3.2
Visit Schedule......................................................................................................... 19
3.3
Study Treatments.................................................................................................... 20
3.4
Schedule for Data Collection ................................................................................. 21
4.
Study Population and Entry Criteria................................................................................ 21
4.1
Number of Patients................................................................................................. 21
4.2
Study Population Characteristics ........................................................................... 21
4.3
Inclusion Criteria.................................................................................................... 22
4.4
Exclusion Criteria................................................................................................... 22
4.5
Permissible and Prohibited Medications/Treatments............................................. 24
4.5.1
Permissible Medications/Treatments ......................................................... 24
4.5.2
Prohibited Medications/Treatments ........................................................... 25
4.5.3
Special Diet or Activities ........................................................................... 26
5.
Study Treatments ............................................................................................................. 26
5.1
Study Treatments and Formulations ...................................................................... 26
5.2
Treatment Allocation Ratio and Stratification ....................................................... 27
5.3
Method for Assignment to Treatment Groups/Randomization .............................. 27
5.4
Treatment Regimen and Dosing............................................................................. 27
5.4.1
BOTOX Treatment..................................................................................... 27
5.4.2
Topiramate Treatment ................................................................................ 29
5.5
Storage of Study Medications ................................................................................ 30
5.6
Preparation of Study Medications.......................................................................... 30


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5.7
Treatment Administration ...................................................................................... 30
6.
Response Measures and Summary of Data Collection Methods..................................... 31
6.1
Efficacy Measures.................................................................................................. 31
6.1.1
Primary Efficacy Measure.......................................................................... 32
6.1.2
Secondary Efficacy Measures.................................................................... 33
6.1.3
Other Efficacy Measures............................................................................ 33
6.2
Safety Measures ..................................................................................................... 36
6.3
Examination Procedures, Tests, Equipment, and Techniques ................................ 38
6.4
Other Study Supplies ............................................................................................. 38
6.5
Summary of Methods of Data Collection .............................................................. 39
7.
Statistical Procedures....................................................................................................... 41
7.1
Analysis Populations.............................................................................................. 41
7.2
Collection and Derivation of Primary and Secondary Efficacy Assessments........ 42
7.2.1
Primary Efficacy Variable .......................................................................... 43
7.2.2
Secondary Efficacy Variables..................................................................... 43
7.2.3
Other Efficacy Variables ............................................................................ 44
7.3
Hypothesis and Methods of Analysis..................................................................... 45
7.3.1
Primary Efficacy Analyses......................................................................... 45
7.3.2
Secondary Efficacy Analyses..................................................................... 46
7.3.3
Safety Analyses.......................................................................................... 47
7.4
Subgroup Analyses................................................................................................. 47
7.5
Sample Size Calculation ........................................................................................ 47
7.6
Interim Analysis ..................................................................................................... 48
8.
Study Visit Schedule and Procedures .............................................................................. 48
8.1
Patient Entry Procedures........................................................................................ 48
8.1.1
Overview of Entry Procedures................................................................... 48
8.1.2
Informed Consent and Patient Privacy....................................................... 48
8.2
Washout Intervals/Run-in....................................................................................... 49
8.3
Procedures for Final Study Entry........................................................................... 49
8.4
Visits and Associated Procedures........................................................................... 49
8.4.1
Screening (Office Visit) ............................................................................. 49
8.4.2
Day 1 (Office Visit; Randomization/Treatment)........................................ 50
8.4.3
Week 6 (eCOA).......................................................................................... 51
8.4.4
Week 12 (Office Visit) ............................................................................... 51


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8.4.5
Week 18 (eCOA)........................................................................................ 52
8.4.6
Week 24 (Office Visit) ............................................................................... 52
8.4.7
Week 30 (eCOA)........................................................................................ 53
8.4.8
Week 36 (Office Visit) ............................................................................... 53
8.4.9
Week 42 (eCOA for Patients Remaining in the Study).............................. 54
8.4.10 Week 48 (Office Visit for Patients Remaining in the Study) ..................... 54
8.5
Instructions for the Patients.................................................................................... 55
8.6
Unscheduled Visits................................................................................................. 56
8.7
Compliance with Protocol...................................................................................... 56
8.8
Early Discontinuation of Patients .......................................................................... 56
8.9
Withdrawal Criteria................................................................................................ 57
8.10 Study Termination.................................................................................................. 57
9.
Adverse Events ................................................................................................................ 57
9.1
Definitions.............................................................................................................. 58
9.1.1
Adverse Event ............................................................................................ 58
9.1.2
Serious Adverse Event ............................................................................... 58
9.1.3
Severity ...................................................................................................... 59
9.1.4
Relationship to Study Drug or Study Procedure ........................................ 59
9.2
Procedures for Reporting Adverse Events ............................................................. 59
9.3
Procedures for Reporting a Serious Adverse Event ............................................... 60
10. Administrative Items ....................................................................................................... 61
10.1 Protection of Human Patients................................................................................. 61
10.1.1 Compliance with Informed Consent Regulations (US 21 CFR Part 50) and
Relevant Country Regulations ................................................................... 61
10.1.2 Compliance With IRB Regulations............................................................ 61
10.1.3 Compliance With Good Clinical Practice .................................................. 61
10.1.4 Compliance With Electronic Records; Electronic Signatures Regulations
(US 21CFR Part 11) ................................................................................... 61
10.2 Changes to the Protocol ......................................................................................... 61
10.3 Patient Confidentiality ........................................................................................... 62
10.3.1 Patient Privacy ........................................................................................... 62
10.4 Documentation ....................................................................................................... 62
10.4.1 Source Documents ..................................................................................... 62
10.4.2 Case Report Form Completion .................................................................. 63
10.4.3 Study Summary.......................................................................................... 63
10.4.4 Retention of Documentation ...................................................................... 64


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10.5 Labeling, Packaging, and Return or Disposal of Study Medications/Treatments . 64
10.5.1 Labeling/Packaging.................................................................................... 64
10.5.2 Clinical Supply Inventory .......................................................................... 64
10.5.3 Return or Disposal of Study Medications/Treatments and/or Supplies ..... 64
10.6 Monitoring by the Sponsor..................................................................................... 64
10.7 Handling of Biological Specimens ........................................................................ 65
10.8 Publications............................................................................................................ 65
11. References........................................................................................................................ 65
12. Attachments ..................................................................................................................... 69
12.1 BOTOX Treatment Administration........................................................................ 69
12.2 Glossary of Abbreviations...................................................................................... 77
List of Tables
Table 1
Schedule of Visits and Procedures.................................................................. 13
Table 2
Required BOTOX Dose Using Fixed-site, Fixed-dose Injection Paradigm ... 28
Table 3
Recommended Topiramate Dose Titration Schedule...................................... 29
List of Figures
Figure 1
Study Design................................................................................................... 18
Figure 2
Fixed-site, Fixed-dose BOTOX Injection Site Locations:  (A) Corrugators,
(B) Procerus, (C) Frontalis, (D) Temporalis, (E) Occipitalis, (F) Cervical
Paraspinal, and (G) Trapezius Muscle Injection Sites .................................... 28
Figure 3
Corrugator Muscle FSFD Injection Sites........................................................ 70
Figure 4
Procerus Muscle FSFD Injection Sites ........................................................... 71
Figure 5
Frontalis Muscle FSFD Injection Sites........................................................... 72
Figure 6
Temporalis Muscle FSFD Injection Sites ....................................................... 73
Figure 7
Occipitalis Muscle FSFD Injection Sites........................................................ 74
Figure 8
Cervical Paraspinal Muscle Group FSFD Injection Sites............................... 75
Figure 9
Trapezius Muscle FSFD Injection Sites.......................................................... 76


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Protocol Summary
Study Compound(s): BOTOX® (onabotulinumtoxinA) Botulinum Toxin Type A Purified Neurotoxin
Complex (hereafter referred to as BOTOX) and topiramate (Topamax®; Janssen Pharmaceuticals, Inc.)
Phase: 4
Study Objective(s): To compare the efficacy, safety, and tolerability of prophylactic treatment with BOTOX
and topiramate in adults with chronic migraine
Clinical Hypotheses
BOTOX is more effective than topiramate as measured by the difference between treatment groups in a 50%
responder rate (defined as the proportion of patients with a ≥50% reduction from baseline in the number of
headache days over a 28-day period).
BOTOX has a superior tolerability profile than topiramate as measured by the difference between treatment
groups in the rates of adverse events and discontinuations due to adverse events.
BOTOX has an acceptable safety profile.
Study Design
Structure: Multicenter, randomized, open-label, parallel-group, post-authorization, prospective study
Duration: Up to 54 weeks (includes a 28-day run-in period within a 6-week window, followed by up to
36 weeks of study treatment, followed by up to 12 weeks of posttreatment follow up)
Study Treatment Groups: BOTOX or topiramate
Controls: None, as this is an open-label study of 2 active treatments
Dosage/Dose Regimen: BOTOX 155 U will be administered approximately every 12 weeks as 31 fixed-site,
fixed-dose intramuscular injections across 7 specific head/neck muscle areas for up to 36 weeks. Patients
randomized to BOTOX will receive 3 treatment sessions of BOTOX. The final/exit visit for these patients will
be at week 36 (or approximately 12 weeks after the last injection).
Topiramate will be administered as oral tablets given daily for up to 36 weeks. The topiramate dose will be
titrated to a minimum of 50 mg/day and maximum of 100 mg/day taken twice daily. The final/exit visit for
patients who complete topiramate treatment will be at week 36.  Patients who discontinue topiramate treatment
on or before week 36 will return to the office at the next scheduled office visit and approximately every
12 weeks up to and including the week 36 visit to receive BOTOX 155 U, for a maximum of 3 BOTOX
treatment sessions in the study.  The final/exit visit for these patients who discontinue topiramate and
subsequently receive BOTOX will be at week 48 (or approximately 12 weeks after the last injection).
Randomization/Stratification: On day 1, qualified patients will be randomly assigned with 1:1 treatment
allocation ratio to receive either BOTOX or topiramate. There is no stratification factor.
Visit Schedule: Up to 6 office visits and up to 4 electronic clinical outcome assessments (eCOA) at home are
planned for each patient:
1)
Screening (Office Visit):  Visit occurs within 6 weeks prior to day 1. The time period between screening
and day 1 will include a 28-day run-in period.
2)
Day 1 (Office Visit):  Randomization and first administration of study drug (BOTOX or topiramate)
3)
Week 6 (eCOA)
4)
Week 12 (Office Visit)
5)
Week 18 (eCOA)
6)
Week 24 (Office Visit)






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General Statistical Methods and Types of Analyses: Efficacy analysis will be performed on the Intent-to-
Treat (ITT) analysis set.  A sensitivity analysis will be performed using a subset of the ITT analysis set.
Patients will be analyzed according to the treatment arm to which they were randomized for all efficacy
analyses. The primary efficacy endpoint (proportion of patients with a ≥50% responder rate at week 32) is a
dichotomous variable, and this will be analyzed using a logistic regression model with treatment as a factor, and
baseline value as a covariate. A worst case imputation method will be utilized to impute missing values for this
analysis. This type of imputation replaces the missing value (ie, frequency of headache days during the 28-day
run-in period) with the baseline value.  Thus, if a patient has a missing responder value at week 32 for any
reason (eg, discontinuation due to adverse events, loss to follow-up, lack of efficacy), then the patient will be
considered as a nonresponder and baseline value data will be utilized. Patient(s) randomized to topiramate who
discontinue treatment and subsequently cross over to BOTOX will be considered nonresponder(s) for the
efficacy analyses thus baseline value data will be utilized. A two-sided test with p-value less than or equal to
0.05 will be considered as statistically significant. If there are convergence issues with the logistic regression
due to small cell counts, the same logistic regression model will be implemented using exact (conditional)
logistic regression analysis.
The 3 secondary efficacy variables are ranked in a hierarchical order of clinical importance.  To control for
Type I error rate for multiple secondary endpoints, a hierarchical testing gatekeeping procedure will be used,
starting with the first secondary endpoint in the ranking order, followed by the next, and so on, in a sequential
fashion. The change from baseline in frequency of headache days will be compared between BOTOX and
topiramate groups via analysis of covariance (ANCOVA) with baseline headache day count as the covariate.
The HIT-6 score will be compared between treatment groups using a nonparametric rank analysis of covariance
(rank ANCOVA), with treatment as a factor, and adjusting for the baseline value. The proportion of patients
with ≥70% responder rate will be analyzed similarly as the primary endpoint, using a logistic regression model
adjusted by the baseline frequency of headache days.


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All safety analyses will be performed using the safety population, consisting of all patients who received at least
one dose of either study medication. Safety data will be summarized by treatment actually received.
Sample Size Calculation: Approximately 400 patients (200 per group) are required to provide 90% statistical
power to detect an expected treatment difference of 16%.  This calculation assumes a topiramate responder rate
of 28% and a BOTOX responder rate of 44% at the primary timepoint of week 32.  A responder is defined as
having a ≥ 50% decrease from baseline in the frequency of headache days per 28-day period.  The above
calculations were based on a two-sided test at alpha = 0.05, using the commercial software nQuery Advisor
version 6.01 (Elashoff, 2005), procedure PTT1 for a two-group continuity corrected Chi-squared test of equal
proportions, with equal sample sizes.






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1.
Background and Clinical Rationale
Migraine is a debilitating headache disorder. Because there are no biological markers for
migraine, diagnosis is based on clinical history and the exclusion of other headache
disorders. Chronic migraine (CM) is recognized as a complication of migraine, and CM
sufferers experience ≥15 headache days per month (Olesen et al, 2006). CM is a disabling,
underdiagnosed, and undertreated disorder (Bigal et al, 2008). Approximately 1.3% of the
US population (~ 3 million people) and 1.3% to 2.4% of the European population suffer from
CM. Females are 2.5 to 6.5 times more likely to suffer from the disorder than males
(Scher et al, 1998; Castillo et al, 1999; Lanteri-Minet et al, 2003; Natoli et al, 2010). Studies
have established that those suffering from CM have impaired quality of life and that they
suffer substantial socio-economic burden due to increased medical needs, referral to medical
specialists, drug utilization, work absenteeism, and reduced effectiveness at work
(Blumenfeld et al, 2011; Munataka et al, 2009).
BOTOX® (Botulinum Toxin Type A Purified Neurotoxin Complex [US Adopted Name is
onabotulinumtoxinA], henceforth referred to as BOTOX) has been approved by the United
States Food and Drug Administration (US FDA) and global regulatory agencies for
prophylaxis of headaches in adult patients with CM and is increasingly included in guidelines
globally as a prophylactic option in this difficult to treat chronic migraine population.
Results from 2 phase 3 multicenter, double-blind, placebo-controlled pivotal trials
demonstrated that BOTOX treatment resulted in significant improvements compared with
placebo for multiple headache symptom measures, including the frequency of headache-free
days (Aurora et al, 2010; Diener et al, 2010). Intramuscular (IM) administration of BOTOX
at doses of 155 to 195 U every 12 weeks for 56 weeks resulted in clinically meaningful and
statistically significant improvements in functioning, vitality, psychological distress, and
overall quality of life. Repeat treatment with BOTOX was safe and well tolerated with few
systemic adverse effects. The most frequently reported adverse events (occurring in ≥5% of
patients) following injection of BOTOX were neck pain and headache (BOTOX® US
package insert, 2013).
A number of other drug classes have been used clinically for the prevention of headache in
patients suffering from chronic migraine, despite not being specifically labeled for use in this
patient population, eg, antiepileptic drugs, antihypertensive agents, antidepressants, and
calcium channel blockers. Topiramate (Topamax®, Janssen Pharmaceuticals, Inc., Titusville,
NJ), an antiepileptic agent, is approved by the US FDA for adults for the prophylaxis of
migraine headaches.  Topiramate has shown efficacy in several clinical trials with daily oral
doses of 100 to 200 mg (Brandes et al, 2004; Silberstein et al, 2007; Diener et al, 2007;


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Silberstein et al, 2012).  The 100 mg daily dose was used in the pivotal clinical trials for
topiramate and is the FDA-approved dose for migraine prophylaxis (Topamax® US
package insert, 2012).  However, despite being listed in a number of guidelines as a first line
therapy option for prophylaxis in patients with chronic migraine, topiramate has been
associated with systemic adverse events such as paresthesia, anorexia, weight decrease,
fatigue, dizziness, somnolence, nervousness, psychomotor slowing, difficulty with memory,
concentration, and attention, cognitive problems, and confusion. Adverse events most often
associated with the use of topiramate relate to the central nervous system. Clinical studies
with topiramate have demonstrated high discontinuation rates due to adverse events and low
tolerability.  Many patients who begin migraine prophylaxis with antiepileptics are no longer
taking these medications at 6 months (Berger et al, 2012).
Two double-blind randomized studies of headache prophylaxis compared BOTOX
(maximum 200 U) and topiramate (maximum 200 mg/day) in 119 CM patients
(Mathew and Jaffri, 2009; Cady et al, 2011).  Both studies demonstrated positive benefit for
both BOTOX and topiramate in the reduction of headache days from baseline.  In the
9-month study by Mathew and Jaffri, patients receiving BOTOX had fewer adverse events
than topiramate, and fewer patients in the BOTOX group discontinued the study due to
adverse events.
2.
Study Objectives and Clinical Hypotheses
2.1
Study Objectives
To compare the efficacy, safety, and tolerability of prophylactic treatment with BOTOX and
topiramate in adults with CM
2.2
Clinical Hypotheses

BOTOX is more effective than topiramate as measured by the difference between
treatment groups in a 50% responder rate (defined as the proportion of patients with a
≥50% reduction from baseline in the number of headache days over a 28-day period).

BOTOX has a superior tolerability profile than topiramate as measured by the difference
between treatment groups in the rates of adverse events and discontinuations due to
adverse events.

BOTOX has an acceptable safety profile.


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3.
Study Design
3.1
Structure
This is a prospective, multicenter, randomized, open-label, parallel-group, post-authorization
study to evaluate the efficacy, safety, and tolerability of BOTOX versus topiramate in adult
patients with CM. The study consists of a pretreatment period lasting 4 weeks, a treatment
period with BOTOX or topiramate treatment lasting up to 36 weeks, and a posttreatment
follow-up period lasting 12 weeks (for patients receiving BOTOX) (Figure 1). All
randomized patients are to remain in the study until week 36.  However, patients who
discontinue topiramate treatment on or before week 36 will crossover to treatment with
BOTOX and remain in the study until week 48. Therefore, a patient could remain in the
study for a maximum of 54 weeks. Patients are required to maintain a daily electronic
headache diary (e-diary) the during the entire study period (ie, screening visit to exit visit).
Figure 1
Study Design
The pretreatment period consists of a screening visit that occurs within 6 weeks prior to day 1
and a prospective 28-day run-in period. The prospective run-in period should begin as soon
as the patient completes the screening procedures. Patients who complete the run-in period


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and meet the prespecified entry criteria will be randomized on day 1 in a 1:1 ratio to receive
BOTOX or topiramate. For data analysis purposes, the number of headache days during the
first 28 continuous days of the run-in period will serve as the “baseline” for calculating
change from baseline for 28-day periods subsequent to each office visit.
The treatment period consists of patients receiving either IM injections of BOTOX 155 U
approximately every 12 weeks or up to 100 mg/day of oral topiramate administered daily up
to week 36. Patients randomized to BOTOX will receive 3 treatment sessions of BOTOX
155 U (at day 1, week 12 ± 7 days, and week 24 ± 7 days) according to the fixed-site, fixed-
dose injection paradigm. The final/exit visit for these patients will be at week 36 (or
approximately 12 weeks after the last injection) (see Section 5.4.1 for details).
Patients randomized to receive topiramate treatment will receive up to 36 weeks of daily
topiramate treatment. A stable topiramate dose of at least 50 mg/day is required (maximum
100 mg/day) (see Section 5.4.2 for details). The final/exit visit for patients who complete
topiramate treatment will be at week 36.  Patients who discontinue topiramate treatment
before the week 36 visit will return to the office approximately every 12 weeks up to and
including the week 36 visit to receive BOTOX 155 U, for a maximum of 3 BOTOX
treatment sessions in the study. The final/exit visit for these patients who discontinue
topiramate and subsequently receive BOTOX will be at week 48 (or approximately 12 weeks
after the last injection).
3.2
Visit Schedule
Up to 6 office visits and up to 4 electronic clinical outcomes assessment (eCOAs) at home
are planned for each patient:
1)
Screening (Office Visit): Visit occurs within 6 weeks prior to day 1.  The time period
between screening and day 1 will include a 28-day run-in period.
2)
Day 1 (Office Visit):  Randomization and first administration of study drug (BOTOX or
topiramate)
3)
Week 6 (eCOA)
4)
Week 12 (Office Visit)
5)
Week 18 (eCOA)
6)
Week 24 (Office Visit)
7)
Week 30 (eCOA)
8)
Week 36 (Office Visit/Study Exit*)


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9)
Week 42 (eCOA; only for patients remaining in the study)*
10) Week 48 (Office Visit; only for patients remaining in the study)*
*For patients randomized to topiramate who receive BOTOX injection(s) in the study, an
additional eCOA will be made at week 42 and the final/exit visit will occur in the office at
week 48.
The primary efficacy timepoint is the 28-day period ending at week 32.
3.3
Study Treatments
Study medication will be administered for up to 48 weeks. Following a 28-day run-in period,
patients meeting the inclusion/exclusion criteria will receive their first treatment on day 1.
Patients will be randomized in a 1:1 ratio to receive IM injections of BOTOX 155 U
administered approximately every 12 weeks, or topiramate administered orally at doses up to
100 mg/day (minimum 50 mg/day), until week 36. Patients who discontinue topiramate
treatment on or before the end of the week 36 visit will crossover to BOTOX treatment for
the remainder of the study. All patients receiving BOTOX will be followed for
approximately 12 weeks after the last injection.
Patients randomized to receive BOTOX treatment will receive 3 treatment sessions of
BOTOX over the course of the treatment period, ie, at day 1, week 12 ± 7 days, and week
24 ± 7 days.  During each of the treatment sessions, each patient will receive a dose of 155 U
BOTOX administered as 31 fixed-site, fixed-dose IM injections across 7 specific head/neck
muscle areas (ie, the US labeled injection paradigm; BOTOX® US package insert, 2013).
The follow-the-pain injection paradigm should not be used. Patients who complete BOTOX
treatment at week 24 will be exited from the study at the week 36 visit.
Patients randomized to receive topiramate will receive up to 36 weeks of daily treatment.
There will be a 4-week titration phase starting on day 1, followed by a dose maintenance
phase for the remainder of topiramate treatment. At the day 1 office visit, patients will
receive an initial dose of topiramate 25 mg/day and will be instructed to continue this dose
for 1 week. Patients will be instructed that, during the next 3 weeks of the titration phase, the
topiramate dose should be increased in weekly increments of 25 mg/day until a dose of
100 mg/day (or a lower maximum tolerated dose) is reached. Upon discussion with the
investigator, the patient may also decrease the dose until the topiramate dose is optimized.
Starting at week 2, topiramate will be administered in 2 divided doses. Starting at week 4
(ie, the maintenance phase), a stable topiramate dose of at least 50 mg/day is required. As
per the recommended topiramate dose for migraine prophylaxis, the topiramate dose must


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not exceed 100 mg/day (Topamax® US package insert, 2012). At the next scheduled office
visit (ie, week 12), the investigator, at his/her discretion, may adjust the topiramate dose
(upward or downward) to be within the range of 50 to 100 mg/day; the patient should remain
on this dose for the remainder of topiramate treatment in the study. For all patients
completing topiramate treatment or those who discontinue from treatment, a dose taper
period of up to 2 weeks is recommended. Refer to Section 5.4.2 for further details.
Patients who complete topiramate treatment at week 36 will be exited from the study at
week 36. Patients who discontinue topiramate treatment at any time up to or including
week 36 will crossover to receive treatment with BOTOX 155 U for the remainder of the
study. The first BOTOX treatment will be administered at the next scheduled office visit,
and the patient will return every 12 weeks up to and including the week 36 visit to receive
BOTOX treatments, with a final exit visit at week 48. BOTOX treatment can be initiated
during the topiramate dose tapering period.
All patients receiving BOTOX in the study will be followed for 12 weeks after the last
injection.
3.4
Schedule for Data Collection
Office visit data (ie, non-diary data) for this study will be collected using electronic case
report forms (eCRFs) or eCOA at the screening visit, the day 1 (randomization/treatment)
visit, and at 12-week intervals thereafter, coinciding with each office visit.  Patient diary data
will be collected daily via an e-diary during the 28-day run-in period and daily throughout
the duration of the study. Patient-reported and clinician-reported outcomes will be collected
via an eCOA. Follow-up data will be collected up to week 48, or up to 12 weeks after the
last BOTOX injection.
4.
Study Population and Entry Criteria
4.1
Number of Patients
Approximately 400 patients (200 patients per arm) will be enrolled at approximately 40 US
sites.
4.2
Study Population Characteristics
Diagnosis of chronic migraine






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4.5
Permissible and Prohibited Medications/Treatments
4.5.1
Permissible Medications/Treatments
Therapy considered necessary for the patient's welfare may be given at the discretion of the
investigator.  If the permissibility of a specific medication/treatment is in question, please
contact Allergan or Allergan designee. In addition, any concern regarding drug-drug
interactions should be addressed with Allergan or designee prior to administering the study
treatment.
The use of any concurrent medication including vitamins and herbal remedies, dietary
supplements and prescription or over-the-counter (OTC) medication, is to be recorded on the
patient’s eCRF along with the reason the medication was taken.
Patients may use medication(s) with a known headache prophylactic effect if, in the opinion
of the investigator, the dose has been stable and the medication(s) has been well tolerated for
at least 12 weeks prior to screening. Any medication with a known headache prophylactic
effect used by the patient should be maintained at a stable dose and dosage regimen during
the study.
Patients may also take prescription or OTC acute headache pain medications as prescribed
and/or directed by the investigator. The specific medication class used each day should be
recorded by the patient in the e-diary.
Any concurrent medication should be maintained at a stable dose and dosage regimen during
the study.


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4.5.1.1
Definition of Females of (Non-)Childbearing Potential and/or
Acceptable Contraceptive Methods
Women who are not of childbearing potential are considered as postmenopausal (at least
12 consecutive months without menstruation) or permanently sterilized (eg, tubal occlusion,
hysterectomy, bilateral salpingectomy). For women of childbearing potential who may
participate in the study, the following methods of contraception, if properly used, are
generally considered reliable: 1) the use of 2 of the following methods at the same time: oral
contraceptives, patch contraceptives, injection contraceptives, male condom with intravaginal
spermicide, diaphragm or cervical cap with spermicide, vaginal contraceptive ring,
intrauterine device; or 2) surgical sterilization (bilateral tubal ligation); or 3) vasectomized
partner; or 4) sexual abstinence.
The investigator and each patient will determine the appropriate methods of contraception for
the patient and/or partner during the participation in the study. Patients should be instructed
that the maximum topiramate dose of 100 mg/day in the current study has not been shown to
cause decreased contraceptive efficacy (Topamax® US package insert, 2012).
If a pregnancy is reported during the study, the investigator will notify the Allergan
immediately after the pregnancy is confirmed and the patient will be exited from the study
after appropriate safety follow-up. To report a pregnancy, use the Allergan Pregnancy
Communication Form. The Pre-Delivery Information Form (initial) (GSE-SIMR-F-005)
reports initial information and the Post-Delivery (follow-up) information Form (GSE-SIMR-
F-005) reports follow-up information and outcome. These forms are completed following
signing of additional informed consents by the patient and partner. Fax the Pregnancy
Communication Form to Allergan Safety Information Management and Reporting using the
fax number found on the cover page of protocol. The investigator will then (1) notify the
patient’s physician that the patient was being treated with an investigational drug BOTOX or
topiramate, if appropriate, and (2) follow the progress of the pregnancy. The investigator
should record the date of the last menstrual period so that the approximate time of
completion of the pregnancy can be estimated. Allergan will conduct follow -up.
4.5.2
Prohibited Medications/Treatments
The decision to administer a prohibited medication/treatment is done with the safety of the
study participant as the primary consideration.  When possible, Allergan or designee should
be notified before the prohibited medication/treatment is administered.


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Patients should not receive acupuncture, TENS, cranial traction, dental splints for headache,
or injection of steroid or anesthetics into the study target muscles at any time during the
study. Coadministration of aminoglycosides or other agents that could interfere with
neuromuscular transmission (eg, curare-like agents) should only be used with caution as the
effects of toxin theoretically could be potentiated.
Patients should be advised that any of the following medications may interact with
topiramate during the study: antiepileptic drugs (eg, phenytoin, carbamazepine, valproic
acid, lamotrigine), topical anticholinergic or sympathomimetic dilating drops, tricyclic
antidepressants, monoamine oxidase inhibitors, antihistamines, antiparkinsonian drugs,
antipsychotic medications, antispasmolytic agents, sulfonamide-containing medications,
metformin, carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide,
dichlorphenamide), lithium, alcohol, and all central nervous system depressants.
Administration of botulinum toxin of any serotype or topiramate for any indication during
the study is prohibited, except as directed by the study.
Concurrent enrollment in another clinical investigational medicinal product or device study is
prohibited.
4.5.3
Special Diet or Activities
Throughout the study, patients should maintain the same or similar level of caffeine
ingestion. Per the exclusion criteria, patients on a ketogenic diet should not be enrolled.
5.
Study Treatments
5.1
Study Treatments and Formulations
BOTOX® (onabotulinumtoxinA, Formulation Number 9060X) contains 200 U of
Clostridium botulinum toxin type A, 1 milligram (mg) of albumin (human), and 1.8 mg of
sodium chloride in a sterile, vacuum dried form without preservative. One unit corresponds
to the calculated median lethal intraperitoneal dose in mice.
BOTOX will be reconstituted with 4 mL sterile, non-preserved 0.9% sodium chloride
injection USP for the 200 U vial.
Topiramate will be provided for oral administration as 25 mg tablets in 60 tablet count
bottles. Sufficient supply will be provided to ensure a 13-week supply.


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5.2
Treatment Allocation Ratio and Stratification
On day 1, qualified patients will be randomly assigned with 1:1 treatment allocation ratio to
1 of 2 treatment arms: 155 U BOTOX given IM or up to 100 mg/day of oral topiramate.
There is no stratification factor.
5.3
Method for Assignment to Treatment Groups/Randomization
At the screening visit, once informed consent is signed, the site staff will log onto the
interactive web response system (IWRS) to obtain a unique patient number, which will be
used as identification for the electronic patient e-diary, eCRFs, eCOAs, and all source
documentation throughout the study.
The IWRS system will provide the site with the treatment assignment to which the patient is
assigned.  Sites will dispense study medication according to the IWRS instructions.  Sites log
onto the IWRS at subsequent visits to dispense additional study medication as needed.  Sites
will receive the IWRS confirmation notifications for each transaction.  All notifications are to
be maintained with the study source documents.
5.4
Treatment Regimen and Dosing
5.4.1
BOTOX Treatment
During each of the BOTOX treatment sessions, each patient will receive a dose of 155 U
BOTOX administered as 31 fixed-site, fixed-dose IM injections across 7 specific head/neck
muscle areas (Table 2 and Figure 2). The follow-the-pain injection paradigm should not be
used. No dose adjustments will be made.
Detailed instructions for the administration of study medication are provided in
Attachment 12.1.


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Table 2
Required BOTOX Dose Using Fixed-site, Fixed-dose Injection Paradigm
Head/Neck Area
LEFT
Number of units per
muscle (number of
injection sitesa)
RIGHT
Number of units per
muscle (number of
injection sitesa)
TOTAL
Number of units per
muscle (number of
injection sitesa)
Procerus
-
-
5 (1 site)
Corrugator
5 (1 site)
5 (1 site)
10 (2 sites)
Frontalis
10 (2 sites)
10 (2 sites)
20 (4 sites)
Temporalis
20 (4 sites)
20 (4 sites)
40 (8 sites)
Occipitalis
15 (3 sites)
15 (3 sites)
30 (6 sites)
Cervical Paraspinal
Muscle Group
10 (2 sites)
10 (2 sites)
20 (4 sites)
Trapezius
15 (3 sites)
15 (3 sites)
30 (6 sites)
Total Dose
-
-
155 U (31 sites)
a
1 injection site = 0.1 milliliter (mL) = 5 U of BOTOX
Figure 2
Fixed-site, Fixed-dose BOTOX Injection Site Locations: (A) Corrugators,
(B) Procerus, (C) Frontalis, (D) Temporalis, (E) Occipitalis, (F) Cervical
Paraspinal, and (G) Trapezius Muscle Injection Sites


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5.4.2
Topiramate Treatment
Patients randomized to topiramate treatment will receive daily oral administration of
topiramate tablets.
Because of the bitter taste, topiramate tablets should not be broken.  Topiramate can be taken
without regard to meals.
There will be a 4-week titration phase starting on day 1, followed by a dose maintenance
phase for the remainder of topiramate treatment.
5.4.2.1
Dose Titration
At the day 1 office visit, patients will receive an initial dose of topiramate 25 mg/day taken
once daily and will be instructed to continue this dose for 1 week. Patients will be instructed
that, during the next 3 weeks, the topiramate dose should be increased in weekly increments
of 25 mg/day until a dose of 100 mg/day (or a lower maximum tolerated dose) is reached.
Upon discussion with the investigator, the patient may also decrease the dose until the
topiramate dose is optimized. Starting at week 2, topiramate will be administered in
2 divided doses. As per the recommended topiramate dose for migraine prophylaxis, the
topiramate dose must not exceed 100 mg/day (Topamax® US package insert, 2012).
The recommended topiramate dose titration schedule is presented in Table 3.
Table 3
Recommended Topiramate Dose Titration Schedule
Morning Dose
Evening Dose
Week 1
None
25 mg
Week 2
25 mg
25 mg
Week 3
25 mg
50 mg
Week 4
50 mg
50 mg
Source: Topamax® US package insert, 2012
Note, during the 4-week titration period, the topiramate dose should be increased or decreased in weekly
increments of 25 mg/day until a dose of 100 mg/day (or a lower maximum tolerated dose) is reached.
5.4.2.2
Dose Maintenance
Starting at week 4 (ie, the maintenance phase), the patient should remain on a stable
topiramate dose of at least 50 mg/day. As per the recommended topiramate dose for
migraine prophylaxis, the topiramate dose must not exceed 100 mg/day (Topamax® US
package insert, 2012).  At the next scheduled office visit (ie, week 12), the investigator, at


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his/her discretion, may adjust the topiramate dose (upward or downward) to be within the
range of 50 to 100 mg/day; the patient should remain on this dose for the remainder of
topiramate treatment in the study.
For all patients who complete topiramate treatment or who discontinue from treatment, a
dose taper period of up to 2 weeks is recommended. The investigator will determine the
duration of the taper, which is based on the maximum dose received during the maintenance
phase.
Patients who discontinue topiramate at any time up to or including week 36 will crossover to
receive treatment with BOTOX 155 U for the remainder of the study. The first BOTOX
treatment will be administered at the next scheduled office visit, and the patient will return
every 12 weeks up to and including the week 36 visit to receive BOTOX treatments, with a
final exit visit at week 48. BOTOX treatment can be initiated during the topiramate dose
tapering period.
5.5
Storage of Study Medications
The study medications must be stored in a secure area and administered only to patients
entered into the clinical study, at no cost to the patient, in accordance with the conditions
specified in this protocol.
Upon receipt, BOTOX MUST be stored immediately in a refrigerator at 2° to 8° Celsius (°C)
until used. Reconstituted BOTOX that is not administered immediately should not be
withdrawn from the vial, and the vial must be stored in a refrigerator (2° to 8°C).  If not used
within 4 hours of reconstitution, study medication vials may not be used.
5.6
Preparation of Study Medications
BOTOX will be reconstituted with 4 mL sterile, non-preserved 0.9% sodium chloride
injection USP for the 200 U vial. Detailed instructions for the preparation of study
medication are provided in the Pharmacy Manual.
5.7
Treatment Administration
Following a 28-day run-in period, patients meeting the inclusion/exclusion criteria will
receive their first treatment at visit 2 (day 1). On day 1, patients will be randomized in a 1:1
ratio to receive IM BOTOX 155 U administered approximately every 12 weeks or up to
100 mg/day oral topiramate administered daily, up to week 36. Patients who discontinue
topiramate treatment on or before the week 36 visit will receive treatment with BOTOX for
the remainder of the study.


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Patients randomized to receive BOTOX treatment will receive 3 treatment sessions of
BOTOX according to the US labeled injection paradigm (see Section 5.4.1) over the course
of the study, ie, at day 1, week 12 ± 7 days, and week 24 ± 7 days.
Patients randomized to receive topiramate treatment will receive up to 36 weeks of
topiramate administered orally at doses starting at 25 mg/day given once daily and tapered up
to 100 mg/day given twice daily. Patients will continue to receive daily doses of topiramate
until week 36 or early discontinuation (with dose tapering to commence at the time of
discontinuation).
Patients who discontinue topiramate treatment prior to week 36 will be asked to return to the
office at the next scheduled visit to receive treatment with BOTOX.  These patients will
receive IM injections of BOTOX 155 U approximately every 12 weeks up to and including
the week 36 visit, for a maximum of 3 BOTOX treatment sessions during the course of the
study. BOTOX treatment can initiated during the topiramate dose tapering period.
All patients receiving BOTOX in the study will be followed for approximately 12 weeks
after the last injection.
6.
Response Measures and Summary of Data Collection Methods
6.1
Efficacy Measures
Data required for the evaluation of the primary and some secondary efficacy measures will
be recorded by patients using an e-diary. Patients are required to maintain the daily e-diary
for the entire duration of the study, ie, from the screening visit to the exit visit.  The following
efficacy parameters will be collected with the daily e-diary.  Patient instructions and training
for completion of e-diary will be provided.

Frequency of headache days

Headache duration (ie, whether the headache lasted more than 4 hours)

Frequency of severe headache days

Days of acute headache pain medication use

Migraine Interictal Burden Scale (MIBS-4)


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The following patient-reported and clinician-reported outcome measures will be collected via
eCOA:

Headache Impact Test (HIT-6TM)

Assessment of Chronic Migraine – Impact (ACM-I)

Controlled Oral Word Association Test (COWAT)

Patient Health Questionnaire (PHQ-9) Quick Depression Assessment

Work Productivity and Activity Impairment Questionnaire – Specific Health Problem
(WPAI-SHP)

Patient Treatment Satisfaction (PTS)

Clinician Treatment Satisfaction (CTS)
6.1.1
Primary Efficacy Measure
The primary efficacy measure is the proportion of patients with a ≥ 50% decrease from
baseline in the frequency of headache days.
A headache day will be defined as a calendar day (00:00 to 23:59) with 4 or more hours of
headache and/or headache of any duration with the use of migraine-specific acute headache
medication(s) (ie, ergot alkaloids, ergot combinations, opioids, triptans, combination
analgesics [simple analgesics combined with opioids or barbiturate with or without
caffeine]).
A worst case imputation (WCI) method will be utilized to impute missing values for this
analysis. This type of imputation replaces the missing value (ie, frequency of headache days
during the 28-day run-in period) with the baseline value.  Thus, if a patient has a missing
responder value at week 32 for any reason (eg, discontinuation due to adverse events, loss to
follow-up, lack of efficacy), then the baseline value data will be utilized and the patient will
be considered a nonresponder.  Patient(s) randomized to topiramate who discontinue
treatment and subsequently cross over to BOTOX will be considered nonresponder(s) for the
primary and secondary analyses thus baseline value data will be utilized.


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6.1.2
Secondary Efficacy Measures

Frequency of headache days

Headache Impact Test (HIT-6):
The HIT-6 is a valid disease-targeted measure used to assess the impact of headaches
(Yang et al, 2011). It is a reliable measure that is also responsive to changes in physical
activity, irritability, and limitations in daily activities due to headaches. The HIT-6
comprises 6 items that assess pain, role functioning, social functioning, cognitive
functioning, vitality, and psychological distress. A total score is created by summing
across all items, and ranges from 36 (no impact) to 78 (severe impact) reflecting a “best
to worst” scoring. Score categories are based on the total score and include “little to no
impact” (total score 36 to 49), “some impact” (total score 50 to 55), “substantial impact”
(total score 56 to 59) and “severe impact” (total score 60 to 78).
The HIT-6 questionnaire will be completed by the patient at day 1 and weeks 6, 18, and
30.  Data will additionally be completed at week 42 for patients who discontinue
topiramate and cross over to BOTOX. The developer’s scoring algorithm will be used.

Proportion of patients with a ≥70% decrease from baseline in the frequency of headache
days


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.






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6.3
Examination Procedures, Tests, Equipment, and Techniques
Study evaluations and treatment should be performed by the same investigator or sub-
investigator throughout the study whenever possible.  If it is not possible to use the same
individual to follow the patient, then an attempt should be made to have visits overlap
(examine the patient together and discuss findings) for at least 1 visit. Study treatment with
BOTOX must be administered by a clinician investigator or clinician sub-investigator who
has been trained on the protocol injection paradigm.
6.4
Other Study Supplies
The following may be provided by Allergan or Allergan designee:

Laboratory kits for the collection and shipment of blood samples, urine pregnancy
kits, and urine illicit drug test kits will be provided by a vendor (eg, central
laboratory) contracted by Allergan or Allergan designee.


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
Shipping materials for shipment of laboratory samples to central laboratory

Calibrated temperature recorder for monitoring freezer and refrigerator temperatures
(if not already present at the site).
The following will be provided by the investigator:

Needles for study treatment reconstitution (22 gauge, 1.5 inch) and injection
(30 gauge, 0.5 inch)

Syringes for study treatment reconstitution (5 cc) and injection (1 mL tuberculin type
with 0.1 mL gradations, plastic, disposable with removable needles)

Alcohol swabs

Preservative-free 0.9% 0.9% sodium chloride injection USP for study treatment
reconstitution

Surgical gloves for study treatment reconstitution and study treatment administration

Adhesive bandages

Refrigerator to store dry/reconstituted study medication at a temperature of
2C to 8C

Access to a computer with internet connection (high-speed connection for eCRF
completion)

Body weight scale with height measure

Centrifuge for processing laboratory samples

Covered hazardous medical waste container
6.5
Summary of Methods of Data Collection
An IWRS will be used to randomize patients and manage study medication inventory. All
office visit data (ie, non-diary data) for this study will be collected using eCRFs via an
electronic data capture system.  Source documents will be used at the sites and may include a
patient’s medical record, hospital charts, clinic charts, the investigator’s patient study files, as
well as the results of diagnostic tests such as laboratory tests, X-rays, etc.  A centralized
clinical laboratory will be used for the analysis of all blood samples. Additional information
on the collection and handling of samples is detailed in the Lab Procedure Manual.


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Data required for the evaluation of the primary and some secondary efficacy measures will
be recorded by patients using a daily e-diary. Patients will be asked to report data at
approximately the same time each day, preferably at the beginning and end of the day, during
the 28-day baseline period and throughout the study duration. The following data will be
collected with the e-diary (patient instructions and training for completion of the e-diary will
be provided):

Estimated total duration of all headache(s) that day (if no headache, patient will report
0 hours)

Maximum severity of headache(s) that day (mild, moderate or severe) (only for
patients who report a headache duration of > 0)

Any acute headache pain medication(s) used that day

The dose of topiramate taken that day (only for patients receiving topiramate)

MIBS-4 (only for patients who report a headache duration of 0)
Questionnaire data required to be directly collected from patients will be obtained at
protocol-specified study visits using an electronic device. Questionnaires are to be
completed by the patient and the answers to the questions on the questionnaires should come
from the patients directly, not from family, friends, or the study support personnel.  The
patient may elect not to answer some or all of the questions. The patient questionnaires for a
specific study visit should only be completed at that specific study visit. The patient will not
have access to previously completed questionnaires.
Questionnaire data required to be directly collected from clinicians will be obtained at
protocol-specified office visits and recorded on the eCOA.
If the patient reports an AE of cognitive impairment, in addition to completing the detailed
questions on the AE eCRF, the clinician should indicate the patient’s response on the Global
Cognitive Impairment Assessment (GCIA) eCRF. This assessment aims to provide context
for the complex symptoms associated with cognitive impairment.
The C-SSRS will be conducted as a clinical interview at each office visit, and the scores will
be collected from the designated site staff via an electronic device.


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7.
Statistical Procedures
A detailed statistical analysis plan (SAP) describing analyses for all study endpoints will be
developed subsequent to study launch and content finalized prior to database lock. The SAP
will include a more technical and detailed elaboration of the principal features stated in the
protocol and detailed procedures for executing the statistical analysis of the primary and
secondary variables and other data as appropriate (ICH E9 [Statistical Principles for Clinical
Trials], 1998). All analyses will be completed in accordance with the finalized SAP.  A
clinical summary will be prepared when all patients have completed the primary timepoint at
week 32 (or exited the study prior to such completion).  A final analysis will also be
conducted after completion of all planned data analyses following the final posttreatment
follow-up visit.
7.1
Analysis Populations
Four analysis populations are defined for this study.

The intent-to-treat (ITT) population will consist of all randomized patients and analysis
based on ITT will be the primary evidence of efficacy.

A subset of the ITT population (ssITT) will exclude patients who discontinue treatment
for any reason other than: adverse events, loss to follow-up, lack of efficacy, C-SSRS
response of “yes” to questions 4 or 5 in the suicidal ideation section or “yes” to any
question in the suicidal behavior section, or noncompliance with the study treatment
regimen. Sensitivity analysis of the primary and secondary efficacy endpoints will be
performed with the ssITT population.  All efficacy endpoints will analyze patients
according to the treatment to which they were randomized.

The per protocol (PP) population will include all patients who had no major protocol
deviations during the study.  This will be determined prior to the final database lock
following the completion of the final posttreatment follow-up visit.  This population may
be used in further exploratory analyses of some specified efficacy variables, and patients
will be analyzed as-treated and without any imputation for missing data.  Details will be
provided in the SAP.

The safety population will consist of all patients who received at least one dose of study
medication.  All safety analyses will be performed using the safety population and
patients will be analyzed as treated.


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7.2
Collection and Derivation of Primary and Secondary Efficacy
Assessments
Data required for the evaluation of efficacy measures will be recorded for the duration of the
study using e-diary, eCRFs, and eCOA, which includes patient- and clinician-reported
assessments.
Each patient will establish a baseline frequency of headache days in the e-diary system daily
during the baseline period. Additionally, over the course of active treatment, headache
frequency, severity, and duration, as well as days of use of acute headache pain medications
and dose of topiramate treatment will be recorded daily.  Should a patient skip a day of an
e-diary entry, the patient will be able to provide the missed information for up to 1 calendar
day.  This is defined as a 1-day “missing-recall” window.  Responses reported during
missing-recall time windows will be treated identically to responses reported on the intended
reporting day. The e-diary should not be completed on the day of the office visit; the last
e-diary entry for the preceding period should be completed the day prior to the office visit.
If total hours of headache and/or severity are recorded more than once for the same calendar
day, the maximum number of reported hours for that day and the maximum severity reported
for that day will be used as the patient’s data for analysis. For example, if the patient
reported 4 total hours of headache yesterday and within the 1-day “missing-recall” window
reports 6 total hours of headache for yesterday, then the report of 6 hours will be used as the
patient’s response. This is allowed in case the patient had additional hours of headache after
making an e-diary report yesterday.
The primary efficacy variable is the proportion of patients with a ≥ 50% decrease from
baseline in the frequency of headache days per 28-day period ending with week 32. This
variable is derived from the e-diary reports of total duration of all headaches for a given day.
It is based on the count of days with at least 4 hours total duration of headaches and/or
headache of any duration with the use of migraine-specific acute headache medication(s).
The primary timepoint is week 32, encompassing the last 28-day period ending with week 32
(ie, day 198 to day 225 inclusive following the day 1 office visit).
Following study treatment at day 1, where the randomization and administration of BOTOX
or topiramate take place, there are 8 more assessments (both in-office and eCOAs at home) at
6-week intervals, including 5 visits ending at week 30 (just prior to the primary timepoint of
week 32) and 3 other visits (where the last 2 visits at weeks 42 and 48 only apply to
topiramate patients who receive BOTOX during the study). However, in practice, there may
or may not be an exact 6-week (ie, 42-day) duration between 2 consecutive visits.


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For data analysis purposes, the number of headache days during the first 28 continuous days
of the run-in period will serve as the “baseline” for calculating change from baseline for
28-day periods subsequent to each office visit. If the run-in period (starting with the
screening visit and preceding the first study treatment on day 1) exceeds 28 days, then the
run-in period will only include the first 28 days. In order to be randomized, a patient must
have been in the run-in period for at least 28 continuous days and must have reported e-diary
data for at least 20 days (including “missing recall”) during the 28-day run-in period.
Baseline assessments for non-daily e-diary data (eg, HIT-6, ACM-1, COWAT) will be
collected at the day 1 office visit.
7.2.1
Primary Efficacy Variable
The primary efficacy variable is the proportion of patients with a ≥ 50% decrease from
baseline in the frequency of headache days per 28-day period, at the primary timepoint of
week 32 (defined as the 28-day period ending with week 32).
7.2.1.1
Imputation for Missing Diary Entries
The primary efficacy endpoint is a dichotomous variable (responder /nonresponder), and a
WCI method will be utilized to impute missing values.  If a patient has a missing responder
value at week 32 for any reason (ie, discontinuation), the patient will be considered as a
nonresponder.
Other types of imputation for the analysis of secondary efficacy variables or in sensitivity/
supportive analysis of the primary variable will be detailed in the SAP.
7.2.2
Secondary Efficacy Variables

Change from baseline in the frequency of headache days per 28-day period.  This variable
will be derived from the daily e-diary reports. It will be based on the count of days with
at least 4 continuous hours in total duration of headaches, and/or headache of any
duration with the use of migraine-specific acute headache medication(s).

Change from baseline in total HIT-6 score per 28-day period

Proportion of patients with a ≥ 70% decrease from baseline in the frequency of headache
days per 28-day period.  This responder variable will be derived from the underlying
primary variable of headache days.


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7.2.3.1
Imputation for Missing Values and Scoring Algorithms
For validated questionnaires, scoring will follow the guidelines set forth by the instrument
developers and missing data handled per developer instructions. Imputation methods for
missing values and scoring algorithms for other outcome measures will be detailed in the
SAP.
Over the course of active treatment, each patient receiving topiramate will record the total
daily dose taken in the e-diary system. If a patient skips a dose(s) or fails to take the specific
maintenance dosing regimen, the patient will still be able to continue in the study.
Topiramate dosing compliance will be calculated based on the e-dairy data and if necessary,
corresponding pill counts (number of pills actually taken, number of pills retrieved/returned,
and the number of pills expected to have been taken by the patient while in the topiramate
arm of the study). Topiramate dosing compliance details will be provided in the SAP. If the
patient indicates that no topiramate treatment was taken in the e-dairy system and treatment
discontinuation is reported at the subsequent office visit, then date of last dose taken will be
the reported as date of discontinuation.
7.3
Hypothesis and Methods of Analysis
7.3.1
Primary Efficacy Analyses
The primary efficacy analysis is based on the proportion of responders (patients with a ≥ 50%
decrease from baseline in the frequency of headache days per 28-day period), and the
primary timepoint is defined as the 28-day diary period ending with week 32 (ie, weeks 29 to
32). The primary null hypothesis is that BOTOX and topiramate are equally effective, as
measured by the proportion of patients with a ≥ 50% decrease from baseline in the frequency
of headache days per 28-day period at week 32. The alternative hypothesis is that BOTOX
has a different effect than topiramate.
The primary comparison between treatment groups will be performed using a simple logistic
regression model, adjusted by the baseline number of headache days as a covariate. Missing
values will be estimated according to the imputation method provided in the SAP. All centers
will be pooled for this analysis. A two-sided test with p-value less than or equal to 0.05 will
be considered as statistically significant, with the exception that treatment-by-subgroup
interactions will be examined at the 0.10 level. If there are convergence issues with the
simple logistic regression due to small cell counts, the same logistic regression model will be
implemented using exact (conditional) logistic regression analysis.


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7.3.2
Secondary Efficacy Analyses
A sensitivity analyses of the primary variable will be performed using (1) Fisher’s exact test
based on the imputation method discussed in the SAP, and (2) using a similar logistic
regression analysis but applying another imputation scheme (to be discussed in the SAP) to
impute for missing values when there are less than 20 days of reported data in the e-diary.
Other sensitivity analyses will be described in the SAP.
The 3 secondary efficacy variables (Section 7.2.2) are ranked in a hierarchical order of
clinical importance.  To control for Type I error rate for multiple secondary endpoints, a
hierarchical testing gatekeeping procedure will be used, starting with the first secondary
endpoint in the ranking order, followed by the next, and so on, in a sequential fashion. If the
test of the first secondary endpoint shows statistical significance at the 0.05 level (2-sided),
then there is justification to proceed to test the next endpoint in the ranking order; this
stepwise process continues for all the endpoints listed in the hierarchical order.  However, if
no statistical significance is shown at the 0.05 level (2-sided) for the test of any specified
endpoint in the hierarchical order, then that endpoint and all subsequent endpoints below this
in the ranking order should not be considered statistically significant, regardless of their
nominal p-value.
The change from baseline in frequency of headache days will be compared between BOTOX
and topiramate groups via analysis of covariance (ANCOVA) with baseline headache day
count as the covariate. A treatment-by-investigator site interaction will also be investigated
in a separate ANCOVA model.
The HIT-6 score will be compared between treatment groups using a nonparametric rank
analysis of covariance (rank ANCOVA) (Stokes et al, 2000), with treatment as a factor, and
adjusting for the baseline value.
The ≥70% responder rate will be analyzed similar to the primary endpoint, using a logistic
regression model adjusted by the baseline frequency of headache days. The exact conditional
logistic regression analysis will be performed if there are convergence issues with the default
unconditional analysis.


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7.4
Subgroup Analyses
Subgroup analyses of efficacy and/or safety variables will be detailed in the SAP.
7.5
Sample Size Calculation
Approximately 400 patients (200 per group) are required to provide 90% statistical power to
detect an expected treatment difference of 16%. This calculation assumes a
topiramate responder rate of 28% and a BOTOX responder rate of 44% at the primary
timepoint of week 32. A responder is defined as having a ≥ 50% decrease from baseline in
the frequency of headache days per 28-day period. The above calculations were based on a
two-sided test at alpha = 0.05, using the commercial software nQuery Advisor version 6.01
(Elashoff, 2005), procedure PTT1 for a two-group continuity corrected Chi-squared test of
equal proportions, with equal sample sizes.
The assumed responder rates for BOTOX were estimated from 2 Allergan phase 3 double-
blind placebo-controlled studies which reported the observed rates as 43.5% (113/260),
50.5% (141/279), and 47.1% (254/539) for study 191622-079, study 191622-080, and the
pooled/combined data, respectively, at the primary timepoint of week 24 (Aurora et al, 2010;


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Diener et al, 2010). At week 32, the observed rates were 55.7% (141/253), 61.7% (161/261),
and 58.8% (302/514), respectively, for these studies.  The corresponding rates for an ITT
analysis where patients terminating the study are treated as failures are obtained as 41.3%
(141/341), 46.4% (161/347), and 43.9% (302/688), respectively.  Based on these studies, the
BOTOX responder rate for an ITT analysis at week 32 ranges from 41.3% to 46.4%, and the
value of 44% was chosen as reasonable for the purposes of sample size calculation for the
current study.
The topiramate responder rate was estimated from 2 published articles. A double-blind
placebo-controlled study with combination therapies, topiramate + placebo (n = 95) and
topiramate + propranonol (n = 96) is described in Silberstein et al, 2012. The observed
responder rates for ≥ 50% decrease in headache days from baseline reported at week 24 were
28% (23/82) and 31% (26/84), respectively, for the 2 groups. These correspond to 24% and
27%, respectively, for an ITT analysis where patients terminating the study are treated as
failures. Rothrock et al, 2005 also describes an open-label study involving topiramate
(n = 170), where a responder rate (≥50% reduction from baseline) of 38.8% (45/116) was
reported. This rate also corresponds to 29.4% for an ITT analysis where patients terminating
the study are treated as failures.  Thus, the ITT rates for topiramate ranges from 24% to
29.4%, and the value of 28% is deemed reasonable for sample size calculation purposes.
7.6
Interim Analysis
No interim analysis is planned for this study.
8.
Study Visit Schedule and Procedures
Please see Table 1 for a schematic of the schedule of visits and procedures.
8.1
Patient Entry Procedures
8.1.1
Overview of Entry Procedures
Prospective patients as defined by the criteria in Sections 4.3 and 4.4 (inclusion/exclusion
criteria) will be considered for entry into this study.
8.1.2
Informed Consent and Patient Privacy
The study will be discussed with the patient and a patient wishing to participate must give
informed consent prior to any study-related procedures or change in treatment.  The patient
must also give authorization and other written documentation in accordance with the relevant
country and local privacy requirements (where applicable) prior to any study-related


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procedures or change in treatment. If a patient or partner of a patient becomes pregnant, then
appropriate follow-up forms should be completed following signing of additional informed
consents by the patient and partner (see Section 4.5.1.1).
8.2
Washout Intervals/Run-in
There is no protocol-specified washout interval for this study. Patients will be screened at
the screening visit and eligible patients will commence with the 28-day prospective run-in
period.
8.3
Procedures for Final Study Entry
At the screening and day 1 (randomization) visits, patients must meet all of the inclusion
criteria and must not meet any of the exclusion criteria. Also, all females of childbearing
potential must have negative results on the urine pregnancy test on day 1 (prior to the first
administration of study medication).
See Section 5.3 for the method for assignment to treatment groups/randomization.
8.4
Visits and Associated Procedures
The study procedures are listed for each visit below.


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


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


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o


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8.5
Instructions for the Patients
At approximately the same time (preferably at the beginning and end of the day) on a daily
basis during the 28-day run-in period and throughout the study duration, patients are to report
information, using an e-diary, on the total duration of all headaches (in hours), maximum
severity of headaches that occurred that day (as mild, moderate or severe), any acute
headache pain medication(s) used that day, and for those patients taking topiramate, the dose
of topiramate that day.  Patients will be able to report headache data, including absence of
headache, for the day of the e-diary report and for the previous day(s). Patients will be asked
to complete the MIBS-4 questionnaire only on the specific day(s) when a duration of
0 headache hours are reported in the e-diary.
Patient-reported outcome questionnaires (ie, HIT-6, ACM-I, PHQ-9, COWAT, WPAI-SHP,
and PTS) are to be completed by the patient via the eCOA on days specified in the visit
schedule (Table 1), and the answers to the questions on the questionnaires should come from
the patients directly, not from family, friends, or the study support personnel. Patient
instructions and training for completing the e-diary and eCOA will be provided to the site.
Patients receiving topiramate will be instructed on the daily dosing schedule.  At the day 1
office visit, patients will receive an initial topiramate dose of 25 mg/day and will be
instructed to continue this dose for 1 week. Patients will be instructed that, during the next
3 weeks, the topiramate dose should be increased in weekly increments of 25 mg/day until a
dose of 100 mg/day (or a lower maximum tolerated dose) is reached. Upon discussion with
the investigator, the patient may also decrease the dose until the topiramate dose is
optimized.  At the next scheduled office visit (ie, week 12), the investigator may adjust the
topiramate dose (upward or downward) at his/her discretion and the patient will be instructed
to remain on this dose for the remainder of topiramate treatment in the study.  Patients should
report in the daily e-diary the doses of topiramate taken each day. Patients should consult
with the investigator regarding any changes made to their instructed topiramate dosing
schedule. If the patient decides to stop taking topiramate, for any reason, they should contact
their investigator to ensure an appropriate tapering regimen and unused pills should be
returned at next visit.  The patient should continue to complete their daily diary and the
treatment discontinuation eCRF can be completed at the subsequent office visit. The patient
treatment discontinuation eCRF must be completed to determine reason for discontinuation.
Patients may use medication(s) with a known headache prophylactic effect and take
prescription or OTC acute headache pain medications, as prescribed and/or directed by the
investigator. Any medication with a known headache prophylactic effect used by the patient
should be maintained at a stable dose and dosage regimen during the study. Patients should


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not receive acupuncture, TENS, cranial traction, dental splints for headache, or injection of
steroid or anesthetics into the study target muscles at any time during the study. Patients
should be advised of the use of medications that may interact with topiramate during the
study (see Section 4.5.2).
Females of childbearing potential will be counseled on using reliable methods of
contraception during the study. The investigator and each patient will determine the
appropriate methods of contraception for the patient and/or partner (see Section 4.5.1.1).
Throughout the study, patients should maintain the same or similar level of caffeine
ingestion.
8.6
Unscheduled Visits
All procedures and evaluations necessary for the well-being of the patient should be
performed , if necessary at an unscheduled visit, and eCRFs should be completed if
appropriate.
8.7
Compliance with Protocol
Patients will be scheduled for follow-up visits in a timely manner and these should occur as
close as possible to the day specified in the visit schedule (Table 1). At each visit, the patient
will be asked if the patient changed the dose/regimen of any existing concomitant
medications, initiated the use of any new concomitant medications, or had any concurrent
procedures since the last visit to ensure compliance with the protocol. Both BOTOX and
topiramate study treatments should be administered per protocol.  Given topiramate is self-
administered, patients will also record in the daily e-diary if the topiramate treatment was
taken and the specific dose each day to ensure compliance with titration and maintenance
dosing. If the specified dose is not recorded, the patient will be able to continue in the study
and criteria for adequate topiramate compliance will be detailed in the SAP.
8.8
Early Discontinuation of Patients
Patients may voluntarily withdraw consent from the study at any time.  If the patient
withdraws consent due to any reasons other than treatment discontinuation (eg, patient
moved, patient does not complete visits), all of the final measurements should be performed
at the exit visit and recorded on the appropriate eCRF. The eCRF for patient treatment
discontinuation should be completed to document patient withdrawal of consent.
If a patient discontinues topiramate treatment, the eCRF for patient treatment discontinuation
should be completed to document the reason for discontinuation.  The patient should not be


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exited from the study, but should be administered BOTOX at the next scheduled office visit
(ie, week 12, 24, or 36).
If a patient discontinues BOTOX treatment, the eCRF for patient treatment discontinuation
should be completed to document the reason for discontinuation.  The patient should then be
exited from the study and all of the final measurements should be performed at the exit visit
and recorded on the appropriate eCRFs.
If a patient is determined as a loss to follow-up, the eCRF for patient treatment
discontinuation should be completed to document the reason for discontinuation.
If a patient must exit the study due to pregnancy or the C-SSRS (ie, the patient answers “yes”
to questions 4 or 5 in the suicidal ideation section or “yes” to any question in the suicidal
behavior section), the eCRF for patient treatment discontinuation should be completed to
document the reason for discontinuation. The patient should then be exited from the study
and all of the final measurements should be performed at the exit visit and recorded on the
appropriate eCRF.
Notification of early patient discontinuation from the study and the reason for discontinuation
will be made to Allergan or Allergan designee and will be clearly documented on the
appropriate eCRF.
8.9
Withdrawal Criteria
Female patients must be withdrawn from the study if they become pregnant
(see Section 4.5.1.1). Patients who have replied with “yes” to questions 4 or 5 in the suicidal
ideation section or “yes” to any question in the suicidal behavior section of the C-SSRS
should not receive any further study treatments, must be withdrawn from the study and
should receive appropriate follow-up as in routine clinical practice.
8.10
Study Termination
The study may be stopped at his/her study site at any time by the site investigator.  Allergan
may stop the study (and/or the study site) for any reason with appropriate notification.
9.
Adverse Events
Adverse events occurring during the study will be recorded on an adverse event case report
form. If adverse events occur, the first concern will be the safety of the study participants.


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9.1
Definitions
9.1.1
Adverse Event
An adverse event is any untoward medical occurrence in a patient or clinical investigation
subject administered a pharmaceutical product and that does not necessarily have a causal
relationship with this treatment. An adverse event 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 related to the
medicinal (investigational) product. In addition, during the screening period, adverse events
will be assessed regardless of the administration of a pharmaceutical product.
Note:  Adverse events must be collected once informed consent has been obtained, regardless
of whether or not the patient has been administered study drug.
Progression of treatment indication including new or worsening of anticipated clinical signs
or symptoms, which are collected as clinical efficacy variables and assessed as unequivocally
associated with the disease progression and /or lack of efficacy, should NOT be reported as
adverse events unless the disease progression is greater than anticipated in the natural course
of the disease.
Adverse events will be assessed, documented, and recorded in the eCRF throughout the study
(ie, after informed consent has been obtained). All adverse events prior to study treatment
from the time of informed consent are collected and defined as Pre-Treatment Adverse Event
(PTAE). At each visit, the investigator should begin by querying for adverse events by
asking each patient a general, non-directed question such as “How have you been feeling
since the last visit?” Directed questioning and examination will then be done as appropriate.
All reported adverse events will be documented on the appropriate eCRF.
If the patient reports an AE of cognitive impairment, in addition to completing the detailed
questions on the AE eCRF, the clinician should indicate the patient’s response on the GCIA
eCRF. This assessment aims to provide context for the complex symptoms associated with
cognitive impairment.
9.1.2
Serious Adverse Event
A serious adverse event is any adverse event occurring at any dose that results in any of the
following outcomes: death, a life-threatening adverse event, inpatient hospitalization or
prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a
congenital anomaly/birth defect. Important medical events that may not result in death, be


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life-threatening, or require hospitalization may be considered a serious adverse event when,
based upon appropriate medical judgment, they may jeopardize the patient and may require
medical or surgical intervention to prevent one of the outcomes listed in this definition.
(See Section 9.3 for procedures for reporting a serious adverse event.)
Allergan considers all cancer adverse events as serious adverse events. In addition, Allergan
considers any abortion (spontaneous or nonspontaneous) as a serious adverse event.
Pre-planned surgeries or procedures for pre-existing, known medical conditions for which a
patient requires hospitalization is not reportable as a serious adverse event.
Any pre-planned surgery or procedure should be clearly documented in the site source
documents by the medically qualified investigator at the time of the patient’s entry into the
study.  If it has not been documented at the time of the patient’s entry into the study, then it
should be documented as a serious adverse event and reported to Allergan.
9.1.3
Severity
A clinical determination will be made of the intensity of an adverse event.  The severity
assessment for a clinical adverse event must be completed using the following definitions as
guidelines:
Mild
Awareness of sign or symptom, but easily tolerated.
Moderate
Discomfort enough to cause interference with usual activity.
Severe
Incapacitating with inability to work or do usual activity.
Not applicable
In some cases, an adverse event may be an ‘all or nothing’ finding
which cannot be graded.
9.1.4
Relationship to Study Drug or Study Procedure
A determination will be made of the relationship (if any) between an adverse event and the
study drug or study procedure, as applicable.  A causal relationship is present if a
determination is made that there is a reasonable possibility that the adverse event may have
been caused by the drug or study procedure.
9.2
Procedures for Reporting Adverse Events
Any adverse event must be recorded on the appropriate eCRF.


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All adverse events that are drug-related and unexpected (not listed as treatment-related in the
current Investigator's Brochure) must be reported to the governing Institutional Review
Board (IRB) as required by the IRB, local regulations, and the governing health authorities.
Any adverse event that is marked ‘ongoing’ at the exit visit must be followed-up as
appropriate.
9.3
Procedures for Reporting a Serious Adverse Event
Any serious adverse event occurring during the study period (beginning with informed
consent) and for at least 12 weeks after the last dose of study drug must be immediately
reported but no later than 24 hours after learning of a serious adverse event. Serious adverse
events must be reported to Allergan recorded on the Serious Adverse Event Form (GSE-
SIMR-F-011).  All patients with a serious adverse event must be followed up and the
outcomes reported.  The investigator must supply Allergan and the IRB with any additional
requested information (eg, autopsy reports and discharge summaries).
In the event of a serious adverse event, the investigator must:
1. Notify Allergan immediately by fax or email using the Serious Adverse Event Form
(GSE-SIMR-F-011) (contact details can be found on page 1 of the Serious Adverse
Event Form); phone numbers and relevant Allergan personnel contacts are also on the
front page of protocol.
2. Obtain and maintain in his/her files all pertinent medical records, information, and
medical judgments from colleagues who assisted in the treatment and follow-up of
the patient.
3. Provide Allergan with a complete, written description of the adverse event(s) on the
serious adverse event form describing the event chronologically, including any
treatment given (eg, medications administered, procedures performed) for the adverse
event(s).  Summarize relevant clinical information about the event:
signs, symptoms,
diagnosis, clinical course and relevant clinical laboratory tests, etc.  Include any
additional or alternative explanation(s) for the causality which includes a statement as
to whether the event was or was not related to the use of the investigational drug.
4. Promptly inform the governing IRB of the serious adverse event as required by the
IRB, local regulations, and the governing health authorities.


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10.
Administrative Items
This protocol is to be conducted in accordance with the applicable Good Clinical Practice
(GCP) regulations and guidelines, eg, the International Conference on Harmonisation (ICH)
Guideline on GCP.
10.1
Protection of Human Patients
10.1.1
Compliance with Informed Consent Regulations (US 21 CFR
Part 50) and Relevant Country Regulations
Written informed consent is to be obtained from each patient prior to any study-related
activities or procedures in the study, and/or from the patient's legally authorized
representative.  If the patient is under the legal age of consent, the consent form must be
signed by the legally authorized representative in accordance with the relevant country and
local regulatory requirements.
10.1.2
Compliance With IRB Regulations
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103).
The investigator must obtain approval from a properly constituted IRB prior to initiating the
study and re-approval or review at least annually.  Allergan or Allergan designee is to be
notified immediately if the responsible IRB has been disqualified or if proceedings leading to
disqualification have begun.  Copies of all IRB correspondence with the investigator should
be provided to Allergan or Allergan designee.
10.1.3
Compliance With Good Clinical Practice
This protocol is to be conducted in accordance with the applicable GCP regulations and
guidelines.
10.1.4
Compliance With Electronic Records; Electronic Signatures
Regulations (US 21CFR Part 11)
This study is to be conducted in compliance with the regulations on electronic records and
electronic signature.
10.2
Changes to the Protocol
The investigator must not implement any deviation from or changes of the protocol without
approval by Allergan and prior review and documented approval/favorable opinion from the
IRB of a protocol amendment, except where necessary to eliminate immediate hazards to


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study patients, or when the changes involve only logistical or administrative aspects of the
study (eg, change in monitors, change of telephone numbers).
10.3
Patient Confidentiality
A report of the results of this study may be published, but the patient’s name will not be
disclosed in these documents.  The patient's name may be disclosed to the Sponsor of the
study, Allergan or Allergan designee, or the governing health authorities or the FDA if they
inspect the study records.  Appropriate precautions will be taken to maintain confidentiality
of medical records and personal information.
10.3.1
Patient Privacy
Written authorization and other documentation in accordance with the relevant country and
local privacy requirements (where applicable) is to be obtained from each patient prior to
enrollment into the study, and/or from the patient's legally authorized representative in
accordance with the applicable privacy requirements (eg, the Health Insurance Portability
and Accountability Act Standards for Privacy of Individually Identifiable Health Information
[“HIPAA”]).
In accordance with HIPAA requirements, additional purposes of this study may include
publishing of anonymous patient data from the study.
10.4
Documentation
10.4.1
Source Documents
Source documents may include a patient's medical records, hospital charts, clinic charts, the
investigator's patient study files, as well as the results of diagnostic tests such as X-rays,
laboratory tests, and electrocardiograms. The investigator's copy of the case report forms
serves as part of the investigator's record of a patient's study-related data.
The following information should be entered into the patient's medical record:

Patient’s name

Patient’s contact information

The date that the patient entered the study and patient number

The study title and/or the protocol number of the study and the name of Allergan


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
A statement that informed consent and/or assent was obtained (including the date).
A statement that written authorization and local patient privacy required
documentation for this study has been obtained (including the date).

Dates of all patient visits

Medical history

All current concomitant medication use, including prescription, OTC, herbal, and
illicit drug use

Past and current headache prophylaxis medication use history, including prescription,
OTC, and herbal drug use

Documentation of all procedures conducted during the course of the study

Occurrence and status of any adverse events

The date the patient exited the study, and a notation as to whether the patient
completed the study or reason for discontinuation, withdrawal, or loss to follow-up

The results of laboratory tests performed by the site (eg, urine pregnancy tests)

Key study variables
10.4.2
Case Report Form Completion
The investigator is responsible for ensuring that data are properly recorded on each patient's
eCRF and related documents.  An investigator who has signed the protocol signature page
should personally sign for the eCRF to ensure that the observations and findings are recorded
on the eCRF correctly and completely.  The eCRFs are to be submitted to Allergan or
Allergan designee in a timely manner at the completion of the study, or as otherwise
specified by Allergan or Allergan designee.
10.4.3
Study Summary
An investigator's summary will be provided to Allergan within a short time after the
completion of the study, or as designated by Allergan.  A summary is also to be provided to
the responsible IRB.


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10.4.4
Retention of Documentation
All study related correspondence, patient records, consent forms, patient privacy
documentation, records of the distribution and use of all investigational products, and copies
of case report forms should be maintained on file.
Allergan requires that it be notified in writing if the investigator wishes to relinquish
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of
ownership to a suitably qualified, responsible person.
10.5
Labeling, Packaging, and Return or Disposal of Study
Medications/Treatments
10.5.1
Labeling/Packaging
Investigators will be provided 1 vial of BOTOX 200 Units per participant for each treatment
session and the appropriate number of bottles of topiramate 25 mg tablets for each participant
dispensed according to the schedule of visits and procedures.
10.5.2
Clinical Supply Inventory
The investigator must keep an accurate accounting of the number of investigational units of
BOTOX or topiramate bottles received from Allergan or Allergan designee, dispensed
(administered) to the patients, and the number of units or bottles returned to Allergan or
Allergan designee during and at the completion of the study.  A detailed inventory must be
completed for the study medication. BOTOX must be reconstituted and administered only
by an appropriately qualified person to patients in the study. All study medication is to be
used in accordance with the protocol and package insert by patients who are under the direct
supervision of an investigator.
10.5.3
Return or Disposal of Study Medications/Treatments and/or
Supplies
All clinical study medications/treatments and/or supplies will be returned to Allergan or
Allergan designee for destruction.
10.6
Monitoring by the Sponsor
A representative of Allergan or Allergan designee will monitor the study on a periodic basis.
The determination of the extent and nature of monitoring will be based on considerations
such as the objective, purpose, design, complexity, blinding, size, and endpoints of the study.


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Authorized representatives of Allergan or Allergan designee or regulatory authority
representatives will conduct on-site visits to review, audit and copy study-related documents.
These representatives will meet with the investigator(s) and appropriate staff at mutually
convenient times to discuss study-related data and questions.
10.7
Handling of Biological Specimens
All urine pregnancy testing will be performed on site. Refer to your local laboratory manual
for handling procedures.
Samples of blood for evaluation of chemistry will be analyzed at a centralized clinical
laboratory with certification from a recognized accreditation agency (eg, College of
American Pathology or Clinical Laboratory Improvement Amendments certification). See
the Study Procedure Manual for details regarding specimen sample collection, processing,
and shipment procedures.
All blood samples will be stored at the centralized clinical laboratory until they are analyzed
at the direction of Allergan or Allergan designee.  All samples will be returned to Allergan or
Allergan designee for destruction.  Allergan shall have full ownership rights to any biological
specimens/samples derived from the study.
10.8
Publications
Allergan, as the sponsor, has proprietary interest in this study. Authorship and manuscript
composition will reflect joint cooperation between multiple investigators and sites and
Allergan personnel.  Authorship will be established prior to the writing of the manuscript.
As this study involves multiple centers, no individual publications will be allowed prior to
completion of the final report of the multicenter study except as agreed with Allergan.
11.
References
Aurora SK, Dodick DW, Turkel CT, DeGryse RE, Silberstein SD, Lipton RB, Diener HC and
Brin MF on behalf of PREEMPT 1 Chronic Migraine Study Group. OnabotulinumtoxinA for
treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled
phase of the PREEMPT 1 trial. Cephalalgia. 2010;30:793-803.
Benton AL, Hamsher K, Sivan AB. Multilingual aphasia examination. 3rd ed. Iowa City,
Iowa: AJA Associates; 1983.
Berger A, Bloudek LM, Varon SF, Oster G. Adherence with migraine prophylaxis in clinical
practice. Pain Practice. 2012;12(7):541-549.


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Bigal, ME, Serrano D, Reed M, Lipton RB. Chronic migraine in the population: burden,
diagnosis, and satisfaction with treatment. Neurology. 2008;71:559-566.
Blumenfeld AM, Varon SF, Wilcox TK, Buse DC, Kawata AK, Manack A, et al. Disability,
HRQOL, and Resource Use amongst Chronic and Episodic Migraineurs: Results from the
International Burden of Migraine Study (IBMS). Cephalalgia. 2011;31(3):301-315.
BOTOX® [US package insert]. Irvine, CA: Allergan, Inc.; Revised: 01/2013.
Brandes JL, Saper JR, Diamond M, et al. Topiramate for migraine prevention: A randomized
controlled trial. JAMA. 2004;291:965–973.
Buse DC1, Rupnow MF, Lipton RB. Assessing and managing all aspects of migraine:
migraine attacks, migraine-related functional impairment, common comorbidities, and
quality of life. Mayo Clin Proc. 2009;84(5):422-435.
Cady RK, Schreiber CP, Porter JAH, Blumenfeld AM, Farmer KU. A multi-center double-
blind pilot comparison of onabotulinumtoxinA and topiramate for the prophylactic treatment
of chronic migraine.  Headache. 2011;51:21-32.
Castillo J, Munoz P, Guitera V, Pascual J. Epidemiology of chronic daily headache in the
general population. Headache. 1999;39:190-196.
Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ. Topiramate
reduces headache days in chronic migraine: A randomized, double-blind, placebo-controlled
study. Cephalalgia. 2007;27(7):814-823.
Diener HC, Dodick DW, Aurora SK, Turkel CT, DeGryse RE, Lipton RB, et al.
OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind,
randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. 2010;30:804-
814.
Elashoff JD. nQuery Advisor Version 6.01 User’s Guide. Los Angeles, CA: 2005.
Headache Classification Committee of the International Headache Society (IHS); The
international classification of headache disorders: 3rd ed (beta version). Cephalalgia.
2013;33(9):629-808.
International Conference on Harmonisation (ICH). Statistical Principles for Clinical Trials:
E9: Step 4 version. 05 February 1998.


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Kroenke K, Spitzer RL, Williams JBW.  The PHQ-9: Validity of a brief depression severity
measure.  J Gen Intern Med. 2001;16:606-613.
Kroenke K, Spitzer RL. The PHQ-9: a new depression diagnostic and severity measure.
Psychiatr Ann. 2002;32:509-521.
Lanteri-Minet M, Auray JP, El Hasnaoui A, et al. Prevalence and description of chronic daily
headache in the general population in France. Pain. 2003;102:143-9.
Mathew NT, Jaffri SFA. A double-blind comparison of onabotulinumtoxinA (BOTOX) and
topiramate (TOPAMAX) for the prophylactic treatment of chronic migraine:  a pilot study.
Headache. 2009;49(10):1466-1478.
Munakata J, Hazard E, Serrano D, et al. Economic burden of transformed migraine: results
from the American Migraine Prevalence and Prevention (AMPP) study. Headache.
2009;49(4);498-508.
Natoli JL, Manack A, Dean B, et al.  Global prevalence of chronic migraine:  a systematic
review. Cephalalgia. 2010;30(5):599-609.
Olesen J, Bousser MG, Diener HC, Dodick D, First M, Goadsby PJ, et al. Headache
Classification Committee: New appendix criteria open for a broader concept of chronic
migraine. Cephalalgia. 2006;26:742-746.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al.  The
Columbia-Suicide Severity Rating Scale (C-SSRS):  Initial validity and internal consistency
findings from three multi-site studies with adolescents and adults.  Am J Psychiatry.
2011;168:1266-1277.
Reilly Associates. Work Productivity and Activity Impairment Questionnaire: Specific
Health Problem V2.0 (WPAI:SHP). http://www.reillyassociates.net/WPAI_SHP.html.
Accessed on 08 April 2014.
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity
and activity impairment instrument. Pharmacoeconomics. 1993;4(5):353-365.
Rothrock JF, Parada VA, Drinkard R, Zweifler RM, Key KF. Predictors of a negative
response to topiramate therapy in patients with chronic migraine. Headache.
2005;45:932–935.


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Scher AI, Stewart WF, Liberman J, Lipton RB. Prevalence of frequent headache in a
population sample. Headache. 1998;38(7):497-506.
Silberstein SD, Dodick DW, Lindblad AS, Holroyd K, Harrington M, Mathew NT, Hirtz D.
Randomized, placebo-controlled trial of propranolol added to topiramate in chronic
migraine. Neurology. 2012;78:976–984.
Silberstein SD, Lipton RB, Dodick DW, et al. Efficacy and safety of topiramate for the
treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial.
Headache. 2007;47(2):170-180.
Stokes ME, Davis CS, Koch GG. Categorical data analysis using the SAS system.  2nd ed.
Cary, North Carolina: SAS Institute Inc.; 2000.
Strauss E, Sherman EMS, Spreen O. A compendium of neuropsychological tests:
administration, norms, and commentary. 3rd ed. New York, New York: Oxford University
Press; 2006:501-526.
Topamax® [US package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; Revised:
10/2012.
Yang M, Rendas-Baum R, Varon SF, Kosinski M. Validation of the Headache Impact Test
(HIT-6TM) across episodic and chronic migraine. Cephalalgia. 2011;31(3): 357-367.


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12.
Attachments
12.1
BOTOX Treatment Administration
Standard Injection Methods Regardless of Muscle Location
Prior to injection, the injecting clinician should double-check that 30-gauge, 0.5 inch
injection needles have been securely fastened to the injection syringes. The skin at the
injection sites should be wiped with alcohol prior to the injection.  Each injection (ie, each
time the needle is inserted into the muscle) the injection volume will be 0.1 mL.  Note that
each muscle has a fixed total dose, a fixed number of injection sites, and a fixed location of
the injection sites.  Prior to injecting, palpate the muscle to verify muscle delineation.  For
bilateral muscles, it is suggested that you inject on the LEFT side first at the specified
injection sites, then proceed to the RIGHT side.  Always insert the needle into the muscle
with the bevel side up, at approximately a 45 degree angle.  In the corrugators, procerus and
frontalis muscles, keep the needle superficial to avoid hitting the periosteum.  After the
needle is inserted into the muscle hold the hub of the needle with one hand to ensure that the
needle does not twist in the skin, pull the plunger back slightly to ensure no blood return, and
then push the plunger with the other hand to administer the study treatment.  To reduce pain,
do not inject too deep into the cervical paraspinal and trapezius muscles.  As a general rule,
the hub of a 0.5 inch needle serves as a relatively accurate maximum “depth” guide.  Do not
rub the area after injection.
Patients should be positioned supine for the injection of the corrugators, procerus, frontalis
and temporalis muscles and sitting up for injection of the occipitalis, cervical paraspinal
muscle group and trapezius muscles.  Further, to ensure that all injections are administered, it
is suggested that all patients be injected in a standardized fashion, whereby the “order” of the
injection of the muscles should be corrugators, procerus, frontalis, temporalis, occipitalis,
cervical paraspinal muscle group and trapezius.  In the following sections, specific
instructions for injecting each of these muscles are provided.  After the injection, the patient
should be observed for any immediate post-injection adverse events.


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Corrugator
The patient should be supine for injection into the corrugators muscle.  This muscle will be
injected with 0.1 mL per site, bilaterally for a total of 2 injection sites (Figure 3). The
corrugators muscle injection site is located approximately 1 finger’s breadth (~1.5 cm) above
the medial superior edge of the orbital ridge (bony landmark).  Inject with the bevel of the
needle pointing upward at a 45-degree angle away from the medial aspect of the muscle to
avoid ptosis of the eyelid.  Pinching the muscle may help adjust the depth of the needle
insertion and reduce pain.  Inject the needle halfway to the hub – stay superficial.
Figure 3
Corrugator Muscle FSFD Injection Sites


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Procerus
The patient should be supine for injection into the procerus muscle.  This muscle will be
injected with 0.1 mL for a total of 1 injection site located midline to the forehead (Figure 4).
The insertion site for the procerus muscle injection is midline on the forehead, approximately
1 finger’s breadth (~1.5 cm) above and midline to the medial superior aspect of the orbital
ridge (bony landmark) of each eye. The injection site for this muscle should be
approximately midway between the 2 corrugator injections (visualize a single straight line
connecting all 3 of these injections). Inject with the bevel of the needle pointing directly
upward.  Inject the needle halfway to the hub – stay superficial.
Figure 4
Procerus Muscle FSFD Injection Sites


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Frontalis
The patient should be supine for injection into the frontalis muscle.  This muscle will be
injected both medially and laterally with 0.1 mL per site, bilaterally for a total of 4 injection
sites (Figure 5). For the medial injection sites, visually draw a line up from the medial edge
of the orbital ridge. The injection site is approximately 1 finger’s breadth (~1.5 cm) above
the corrugators injection site.  The lateral injection is parallel and approximately 1 finger’s
breadth (~1.5 cm) lateral to the first 2 injections.  Make sure with these injections that the
needle stays superficial to avoid the periosteum.  A good rule of thumb is to inject
superficially enough to raise a bleb.  A common mistake is to inject the frontalis muscle too
low, which can result in eyebrow ptosis. Go higher on the muscle than you may be first
inclined to inject.  The bevel of the needle should point upward for these injections.
Figure 5
Frontalis Muscle FSFD Injection Sites


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Temporalis
The patient should be supine for injection into the temporalis muscle.  This muscle will be
injected in 4 sites with 0.1 mL per site, bilaterally for a total of 8 injection sites (Figure 6).
Begin with the LEFT temporalis, then repeat the procedure symmetrically on the RIGHT
side.  Ask the patient to clench his or her teeth.  Locate and palpate the anterior aspect of the
temporalis muscle.  Make the first injection approximately 2 finger’s breadth (~3 cm) behind
this point.  Try to stay behind the hairline.  Make the second injection ~0.5 cm superior and
approximately 1 finger’s breadth (~1.5 cm) posterior to the first injection in the medial aspect
of the muscle.  The third injection site will be parallel and ~1.5 cm posterior to the second
injection.  The fourth injection site should be ~1.5 cm below and perpendicular to the second
injection into the medial aspect of the muscle.
Figure 6
Temporalis Muscle FSFD Injection Sites


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Occipitalis
The patient should be sitting for injection into the occipitalis muscle.  This muscle will be
injected in 3 sites with 0.1 mL per site, bilaterally for a total of 6 injection sites (Figure 7).
To locate the occipitalis injection sites, palpate for the external occipital protuberance. Stay
superior to the supranuchal ridge on either side of the occipital protuberance.  Begin with the
LEFT occipitalis muscle, then repeat the procedure symmetrically on the RIGHT side.  Make
the first injection just above the occipital protuberance along the supranuchal ridge and ~1cm
left of the external occipital protuberance.  The second injection site is ~1 cm lateral to the
first injection site and ~1 cm above it.  The third injection site should be ~1 cm medial to the
first injection site and ~1 cm above it.
Figure 7
Occipitalis Muscle FSFD Injection Sites


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Cervical Paraspinal Muscle Group
The patient should be sitting for injection into the cervical paraspinal muscle group.  These
muscles will be injected in 2 sites with 0.1 mL per site, bilaterally for a total of 4 injection
sites (Figure 8).  To locate the cervical paraspinal muscle group injection sites, palpate the
cervical spine.  Begin with the LEFT cervical paraspinal muscle group muscle, then repeat
the procedure symmetrically on the RIGHT side.  Make the first injection ~1 cm left of the
midline of the cervical spine muscle and ~3 to 5 cm inferior to the occipital protuberance.
The second injection site is ~1 cm superior diagonally toward the ear from the first injection.
Figure 8
Cervical Paraspinal Muscle Group FSFD Injection Sites


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Trapezius
The patient should be sitting for injection into the trapezius muscle.  This muscle will be
injected in 3 sites with 0.1 mL per site, bilaterally for a total of 6 injection sites (Figure 9).
The trapezius muscle is a triangular-shaped, superficial muscle that fans from the neck into
the shoulder.  Visually divide the upper portion of the muscle (from the neck to the shoulder)
into 3 sections per side.  Injections will be in the middle of each of these sections.  Begin
with the LEFT trapezius muscle, then repeat the procedure symmetrically on the RIGHT
side.  Make the first injection to the lateral, inferior section of the muscle (closest to the
shoulder).  Move medially to the middle section of the trapezius muscle for the second
injection.  Then, move sideways and upward to the superior section of the muscle for the
third injection.
Figure 9
Trapezius Muscle FSFD Injection Sites


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12.2
Glossary of Abbreviations
Term/Abbreviation
Definition
ACM-I
Assessment of Chronic Migraine – Impact
AE
adverse event
ANCOVA
analysis of covariance
BOTOX®
Botulinum Toxin Type A Purified Neurotoxin Complex
(US Adopted Name is onabotulinumtoxinA)
C
Celsius
CM
chronic migraine
COWAT
Controlled Oral Word Association Test
C-SSRS
Columbia-Suicide Severity Rating Scale
CTS
Clinician Treatment Satisfaction
eCOA
electronic clinical outcomes assessment
eCRF
electronic case report form
FDA
Food and Drug Administration
GCIA
Global Cognitive Impairment Assessment
GCP
Good Clinical Practices
HIPAA
Health Insurance Portability and Accountability Act
HIT-6 TM
Headache Impact Test
ICH
International Conference on Harmonisation
ICHD-3
International Classification of Headache Disorders, 3nd edition
IM
intramuscular
IRB
Institutional Review Board
ITT
intent-to-treat
IWRS
interactive web response system
MedDRA
Medical Dictionary for Regulatory Activities
MIBS-4
Migraine Interictal Burden Scale
OTC
over-the-counter
PHQ-9
Patient Health Questionnaire
PP
per protocol
PRO
patient-reported outcomes
PTS
Patient Treatment Satisfaction
SAP
statistical analysis plan
SOC
system organ class
ssITT
subset of the ITT population


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TENS
transcutaneous electrical stimulation
triptans
serotonin receptor agonists
U
unit
WCI
worst case imputation
WPAI-SHP
Work Productivity and Activity Impairment Questionnaire -
Specific Health Problem

SAP_000.pdf: 
NCT02191579 
 
 
GMA-US-NEU-0206 
 
Title: A Multicenter, Prospective, Randomized, Open-label Study to Compare the Efficacy, 
Safety, and Tolerability of BOTOX® and Topiramate for Headache Prophylaxis in 
Adults with Chronic Migraine 
 
 
Protocol Date: May 27, 2014 
 
 
Statistical Analysis Plan (SAP) Date: July 17, 2017 


 
Confidential 
 
 
 
 
 
 
 
 
 
ALLERGAN 
 
GMA-US-NEU-0206 
 
A Multicenter, Prospective, Randomized, Open-label Study to 
Compare the Efficacy, Safety, and Tolerability of BOTOX® and 
Topiramate for Headache Prophylaxis in Adults with Chronic 
Migraine 
 
FORWARD Study 
 
17JUL2017 
 
Statistical Analysis Plan 
 
Version 2.0 
 
Prepared by: 
 
 
 


ALLERGAN 
 
Statistical Analysis Plan, Version 2.0 
 
GMA-US-NEU-0206 
 
Date Issued: 17JUL2017 
 
  
 
 
 
II
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ....................................................................................................... I 
1. 
INTRODUCTION ............................................................................................................ 2 
2. 
OBJECTIVES ................................................................................................................... 2 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 2 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 2 
3.2. STUDY ENDPOINTS ............................................................................................................. 4 
3.3. TREATMENTS ...................................................................................................................... 5 
3.4. DOSE ADJUSTMENT/MODIFICATIONS ................................................................................. 6 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 6 
4.1. SAMPLE SIZE ...................................................................................................................... 8 
4.2. RANDOMIZATION, STRATIFICATION, AND BLINDING .......................................................... 9 
4.3. ANALYSIS SETS .................................................................................................................. 9 
4.3.1. 
Intent-to-Treat ............................................................................................................. 9 
4.3.2. 
Subset of ITT ............................................................................................................... 9 
4.3.3. 
Per Protocol .............................................................................................................. 10 
4.3.4. 
Safety ......................................................................................................................... 10 
5. 
PATIENT DISPOSITION ............................................................................................. 10 
5.1. PROTOCOL DEVIATIONS ................................................................................................... 11 
5.2. DEMOGRAPHICS AND BASELINE CHARACTERISTICS ......................................................... 11 
5.3. GENERAL MEDICAL HISTORY ........................................................................................... 11 
5.4. INCLUSION AND EXCLUSION CRITERIA ............................................................................. 12 
6. 
PRIOR AND CONCOMITANT TREATMENTS ....................................................... 12 
7. 
STUDY TREATMENT .................................................................................................. 12 
7.1. Duration of Exposure ................................................................................................... 12 
7.2. Treatment Compliance and Modifications ................................................................... 13 
8. 
EFFICACY ANALYSES ............................................................................................... 14 
8.1. PRIMARY EFFICACY ENDPOINT ......................................................................................... 15 
8.1.1. 
Primary Analysis ....................................................................................................... 15 
8.1.2. 
Sensitivity Analysis.................................................................................................... 16 
8.2. SECONDARY EFFICACY ENDPOINTS .................................................................................. 17 
8.3. EXPLORATORY ENDPOINTS ............................................................................................... 18 
9. 
SAFETY ANALYSES .................................................................................................... 22 
9.1. ADVERSE EVENTS ............................................................................................................. 23 
9.1.1. 
Incidence of Adverse Events ..................................................................................... 24 
9.1.2. 
Relationship of Adverse Events to Study Drug ......................................................... 24 
9.1.3. 
Severity of Adverse Event.......................................................................................... 25 
9.1.4. 
Serious Adverse Events ............................................................................................. 25 
9.1.5. 
Adverse Events Leading to Treatment Discontinuation............................................ 26 


ALLERGAN 
 
Statistical Analysis Plan, Version 2.0 
 
GMA-US-NEU-0206 
 
Date Issued: 17JUL2017 
 
  
 
 
 
III
9.1.6. 
Death ......................................................................................................................... 26 
9.2. SERUM CHEMISTRY .......................................................................................................... 26 
9.3. VITAL SIGN MEASUREMENTS ........................................................................................... 26 
9.4. PHYSICAL EXAMINATION ................................................................................................. 27 
9.5. PREGNANCY TEST............................................................................................................. 27 
9.6. URINE DRUGS OF ABUSE .................................................................................................. 28 
9.7. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS)................................................ 28 
10. 
INTERIM ANALYSIS ................................................................................................... 28 
11. 
DEVIATION FROM PROTOCOL-SPECIFIED ANALYSES ................................. 29 
12. 
REFERENCES ................................................................................................................ 29 
APPENDIX A: SCHEDULE OF VISITS AND PROCEDURES ........................................... 30 


 
Confidential 
List of Abbreviations 
ACM-I  
Assessment of Chronic Migraine – Impact 
AE  
adverse event 
ANCOVA 
analysis of covariance 
BLOCF 
baseline observation carried forward  
BOTOX®  
botulinum toxin Type A purified neurotoxin complex 
CM  
chronic migraine 
COWAT  
Controlled Oral Word Association Test 
C-SSRS  
Columbia-Suicide Severity Rating Scale 
CTS  
Clinician Treatment Satisfaction 
eCOA  
electronic clinical outcomes assessment 
eCRF  
electronic case report form 
FDA  
Food And Drug Administration 
HIT-6  
Headache Impact Test 
IM  
Intramuscular 
ITT  
intent-to-treat 
IWRS 
interactive web response system 
MedDRA  
Medical Dictionary For Regulatory Activities 
MIBS-4  
Migraine Interictal Burden Scale 
PHQ-9  
Patient Health Questionnaire 
PP  
per protocol 
PRO  
Patient-Reported Outcomes 
PT 
preferred term 
PTS  
Patient Treatment Satisfaction 
SAE 
Serious Adverse Event 
SOC 
system organ class 
ssITT  
subset of the ITT Set 
TEAE 
treatment-emergent adverse event 
U  
Unit 
WHO 
World Health Organization 
WOCF 
worst observation carried forward 
WPAI-SHP  
Work Productivity and Activity Impairment Questionnaire 
 
 
 
 
 
 


ALLERGAN 
 
Statistical Analysis Plan, Version 2.0 
 
GMA-US-NEU-0206 
 
Date Issued: 17JUL2017 
  
 
 
 
2
1. Introduction 
 
This document details the planned analyses for the FORWARD study, GMA-US-NEU-0206. 
This study was designed to evaluate the efficacy, safety, and tolerability of BOTOX® versus 
topiramate in adult patients with chronic migraine (CM) and consists of a 28-day run-in period 
within a 6-week screening window, followed by up to 36 weeks of study treatment, followed by 
up to 12 weeks of post-treatment follow-up. 
 
A clinical study report will be prepared for the primary analysis when all patients have 
completed a Week 36 office visit (or exited the study prior to reaching the primary endpoint). 
There will be a database lock for the primary analysis after Week 36. A final clinical study report 
will be prepared after the final database lock and completion of the planned statistical analyses. 
This analysis plan will address both the primary analysis and the final analysis. 
2. Objectives 
 
The overall objective of this study is to compare the efficacy, safety, and tolerability of 
prophylactic treatment with BOTOX and topiramate in adults with CM. 
 
3. Investigational Plan 
3.1. Overall Study Design and Plan 
 
This is a prospective, multicenter, randomized, open-label, parallel-group, post-authorization 
study to evaluate the efficacy, safety, and tolerability of BOTOX versus topiramate in adult 
patients with CM. The study consists of a pretreatment period lasting 4 weeks, a treatment period 
with BOTOX or topiramate treatment lasting up to 36 weeks, and a post-treatment follow-up 
period lasting 12 weeks (for patients receiving BOTOX) (Figure 1). All randomized patients are 
to remain in the study until Week 36; however, patients who discontinue topiramate treatment on 
or before Week 36 will switch over to treatment with BOTOX and remain in the study until 
Week 48. Therefore, a patient could remain in the study for a maximum of 54 weeks. Patients are 
required to maintain a daily electronic headache diary (eDiary) during the entire study period 
(i.e., screening visit to exit visit). 
 
The pretreatment period consists of a screening visit that occurs within 6 weeks prior to Day 1 
and a prospective 28-day run-in period. The prospective run-in period should begin as soon as 
the patient completes the screening procedures. Patients who complete the run-in period and 
meet the prespecified entry criteria will be randomized on Day 1 in a 1:1 ratio to receive 
BOTOX or topiramate. Approximately 400 patients (200 patients per arm) will be enrolled at 
approximately 40 US sites. For data analysis purposes, the number of headache days during the 
first 28 calendar days of the screening period starting on the day of eDiary Touch device setup 
will serve as the “baseline” for calculating change from baseline for 28-day periods subsequent 
to each office visit. 


ALLERGAN 
 
Statistical Analysis Plan, Version 2.0 
 
GMA-US-NEU-0206 
 
Date Issued: 17JUL2017 
  
 
 
 
3
 
The treatment period consists of patients receiving intramuscular (IM) injections of either 
BOTOX 155 U approximately every 12 weeks or up to 100 mg/day of oral topiramate 
administered daily up to Week 36. Patients randomized to BOTOX will receive 3 treatment 
sessions of BOTOX155 U (Day 1, Week 12 ± 7 days, and Week 24 ± 7 days) according to the 
fixed-site, fixed-dose injection paradigm. The final/exit visit for these patients will be at 
Week 36 (or approximately 12 weeks after the last injection). 
 
Patients randomized to receive topiramate treatment will receive up to 36 weeks of daily 
topiramate treatment. A stable topiramate dose of at least 50 mg/day is required (maximum 
100 mg/day). The final/exit visit for patients who complete topiramate treatment will be at 
Week 36. Patients who discontinue topiramate treatment on or before the Week 36 visit will 
return to the office approximately every 12 weeks (up to and including the Week 36 visit) to 
receive BOTOX 155 U, for a maximum of 3 BOTOX treatment sessions in the study. The 
final/exit visit for patients who discontinue topiramate and subsequently receive BOTOX will be 
at Week 48 (or approximately 12 weeks after the last injection). 
Figure 1 Study Design 
 
 
 


ALLERGAN 
 
Statistical Analysis Plan, Version 2.0 
 
GMA-US-NEU-0206 
 
Date Issued: 17JUL2017 
  
 
 
 
4
3.2. Study Endpoints  
 
Baseline for all eDiary efficacy endpoints is defined as the first 28 calendar days of the screening 
period starting on the day of eDiary Touch device setup and will be referred to as the baseline 
period. Baseline assessments for non-daily eDiary data (e.g., Headache Impact Test [HIT-6], 
Assessment of Chronic Migraine – Impact [ACM-I], and Controlled Oral Word Association Test 
[COWAT]) will be collected on the day of randomization and will be referred to as Day 1.  
  
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of patients with a ≥50% decrease from 
the baseline period in the frequency of headache days per 28-day period, at the primary 
timepoint of Week 32 (defined as the 28-day period ending with Week 32). 
 
Secondary Efficacy Endpoints   
The secondary efficacy endpoints are as follows: 
1. Change from the baseline period in the frequency of headache days per 28-day period 
ending with Week 32. This endpoint will be derived from the daily eDiary reports. It will 
be based on the count of headache days, defined as a calendar day (00:00 to 23:59), with 
at least 4 continuous hours in total duration of headaches, and/or headache of any 
duration with the use of migraine-specific acute headache medication(s) (ie, ergot 
alkaloids, ergot combinations, opioids, serotonin receptor agonists [“triptans”], or 
combination analgesics [simple analgesics combined with opioids or barbituates with or 
without caffeine]).  
2. Change from baseline Day 1 (randomization) in total HIT-6 score per 28-day period 
collected at Week 30. 
3. Proportion of patients with a ≥70% decrease from the baseline period in the frequency of 
headache days per 28-day period, at the primary timepoint of Week 32 (defined as the 28-
day period ending with Week 32). This responder endpoint will be derived from the 
underlying primary variable of headache days. 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.3. Treatments   
Patients randomized to receive BOTOX will receive 3 treatment sessions of BOTOX over the 
course of the treatment period, ie, at Day 1, Week 12 ± 7 days, and Week 24 ± 7 days. During 
each of the treatment sessions, each patient will receive a dose of 155 U BOTOX administered as 
31 fixed-site, fixed-dose IM injections across 7 specific head/neck muscle areas (ie, the US 
labeled injection paradigm; BOTOX® US package insert, 2015). 
 
Topiramate will be provided for oral administration as 25-mg tablets in 60 tablet count bottles. A 
sufficient supply will be provided to ensure a 13-week supply. 
 


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3.4. Dose Adjustment/Modifications 
 
Patients randomized to receive topiramate will receive up to 36 weeks of daily treatment. 
There will be a 4-week titration phase starting on Day 1 (randomization), followed by a dose 
maintenance phase for the remainder of topiramate treatment. At the Day 1 office visit, patients 
will receive an initial dose of topiramate 25 mg/day and will be instructed to continue this dose 
for 1 week. Patients will be instructed that, during the next 3 weeks of the titration phase, the 
topiramate dose should be increased in weekly increments of 25 mg/day until a dose of 100 
mg/day (or a lower maximum tolerated dose) is reached. Upon discussion with the investigator, 
the patient may also decrease the dose until the topiramate dose is optimized. Starting at Week 2, 
topiramate will be administered in 2 divided doses (morning and evening dose). Starting at 
Week 4 (ie, the maintenance phase), a stable topiramate dose of at least 50 mg/day is required. 
As per the recommended topiramate dose for migraine prophylaxis, the topiramate dose must not 
exceed 100 mg/day (Topamax® US package insert, 2012). At the next scheduled office visit (ie, 
Week 12), the investigator, at his/her discretion, may adjust the topiramate dose (upward or 
downward) to be within the range of 50 to 100 mg/day; the patient should remain on this dose for 
the remainder of topiramate treatment in the study. For all patients who complete or discontinue 
from treatment, a dose taper period of up to 2 weeks is recommended. 
 
Patients who discontinue topiramate at any time on or before Week 36 will receive treatment 
with BOTOX 155 U for the remainder of the study. The first BOTOX treatment will be 
administered during the office visit, and the patient will return every 12 weeks up to and 
including the Week 36 visit to receive BOTOX treatments, with a final exit visit at Week 48. 
BOTOX treatment can be initiated during the topiramate dose tapering period. A patient who 
discontinues topiramate early will be considered a nonresponder even if they receive BOTOX 
treatment.  
 
BOTOX treatment is administered by the physician per protocol and according to the BOTOX® 
US package insert, 2015, thus dose adjustment/modification will not be made. As with a 
topiramate patient who discontinues treatment, a patient who discontinues BOTOX early will be 
considered a nonresponder. 
 
4. General Statistical Considerations 
 
 
 
Continuous data will be summarized using descriptive statistics (ie, n, mean, standard deviation 
[SD], median, minimum, and maximum). Categorical data will be summarized using the patient 
count and percentage in each category. Confidence intervals (CIs) will be 95% and 2-sided, 
unless otherwise stated. Data will be displayed in all listings sorted by treatment group and 
patient number. P-values will be rounded to three decimal places. If a p-value is less than 0.001 it 
will be reported as “<0.001.” If a p-value is greater than 0.999 it will be reported as “>0.999.” 
Data will be displayed in all listings sorted by treatment group.  


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Patients will be identified in the listings by the patient identification number concatenated with 
the investigator number. 
 
When count data are presented, the percentage will be suppressed when the count is zero in order 
to draw attention to the nonzero counts. A row denoted “Missing” will be included in count 
tabulations specified on the shells to account for dropouts and missing values. The denominator 
for all percentages will be the number of patients in that treatment group within the analysis set 
of interest, unless otherwise specified. Nonzero percentages will be rounded to one decimal 
place, except 100%, which will be displayed without any decimal places. Additional rounding 
rules are as follows: 
 If the original value has 0 decimal places: mean, median, and CIs will have one decimal 
place and SD will have 2 decimal places 
 If the original value has 1 decimal place: mean, median, and CIs will have 2 decimal 
places and SD will have 3 decimal places 
 If the original value has 2 or more decimal places: mean, median, CIs, and SD will all 
have 3 decimal places 
 
Minimum and maximum will always have the same decimal places as the original value, up to a 
maximum of 3 decimal places. 
 
Visit labels will be assigned to each post-baseline record based on the windows or intervals for 
study day relative to the date of first dose (Table 1). A record with a study day closest to the 
target visit day will be chosen when multiple records fall in the same visit window. In case of a 
tie, the record with the earlier date will be chosen. Records that are not chosen will be treated as 
unscheduled assessments and will still be included in all analyses except ‘by visit’ analyses. If 
Day 1 is missing, the closest visit on or before the date of first dose will be used as baseline. 
Only nominal/scheduled visit data will be reported in the tables. All visits, including 
unscheduled visits, will be presented in the listings.   
 
Table 1: Visit Windows 
Visit 
Range 
Target Day 
Screening 
<Day 1 
 
Day 1 
Day 1 to Day 7 
Day 1 
Week 6 
Day 8 to Day 71 
Day 43 
Week 12 
Day 72 to Day 99 
Day 85 
Week 18 
Day 100 to Day 141 
Day 127 
Week 30 
Day 142 to Day 255 
Day 211 
Week 24 
Day 256 to Day 183 
Day 169 
Week 36 
Day 184 to Day 267 
Day 253 
Week 42 
Day 268 to Day 309 
Day 295 
Week 48 
>Day 310  
Day 337 
 


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For the e-diary data used to produce the headache endpoints, the intervals specified in Table 2 
will be used. Baseline for the eDiary data is defined as the number of headache days during the 
28 day run-in period. This run-in period will be the first 28 calendar days of the screening period 
starting on the day of eDiary Touch device setup.  
 
Table 2: eDiary Analysis Endpoints 
eDiary Week Ending 
Trial Time 
Baseline 
The 28 days starting from the first eDiary entry  
Weeks 1- 4 
Days: 1-28 
Weeks 5- 8 
Days: 29-56 
Weeks 9- 12 
Days: 57-84 
Weeks 13-16 
Days: 85-112 
Weeks 17-20 
Days: 113-140 
Weeks 21-24 
Days: 141-168 
Weeks 25-28 
Days: 169-196 
Weeks 29-32 
Days: 197-224 
Weeks 33-36 
Days: 225-252 
Weeks 37-40 
Days:253-280 
Weeks 41-44 
Days: 281-308 
Weeks 45-48 
Days: 309-336 
 
4.1. Sample Size 
 
Approximately 400 patients (200 per arm) are required to provide 90% statistical power to detect 
an expected treatment difference of 16%. This calculation assumes a topiramate responder rate of 
28% and a BOTOX responder rate of 44% at the primary timepoint of Week 32. A responder is 
defined as having a ≥50% decrease from baseline in the frequency of headache days per 28-day 
period. The above calculations were based on a 2-sided test at alpha = 0.05, using the 
commercial software nQuery Advisor version 6.01, procedure PTT1 for a two-group continuity 
corrected Chi-squared test of equal proportions, with equal sample sizes. 
 
The assumed responder rate for BOTOX was estimated from 2 Allergan Phase 3 double-blind, 
placebo-controlled studies which reported observed rates of 43.5% (113/260), 50.5% (141/279), 
and 47.1% (254/539) for Study 191622-079, Study 191622-080, and their pooled/combined data, 
respectively, at the primary timepoint of Week 24 (Aurora et al, 2010; Diener et al, 2010). At 
Week 32, the observed rates were 55.7% (141/253), 61.7% (161/261), and 58.8% (302/514), 
respectively. The corresponding rates for the Intent-To-Treat (ITT) analysis where patients who 
terminated from the study were treated as failures were reported as 41.3% (141/341), 46.4% 
(161/347), and 43.9% (302/688), respectively. Based on these 2 studies, the BOTOX responder 
rate for an ITT analysis at Week 32 ranged from 41.3% to 46.4%, and the value of 44% was 
chosen as reasonable for the purposes of sample size calculation for the current study. 
 


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The topiramate responder rate was estimated from 2 published articles. A double-blind, placebo-
controlled study with combination therapies, topiramate + placebo (n = 95) and topiramate + 
propranonol (n = 96) is described in Silberstein et al, 2012. The observed responder rates for 
≥50% decrease in headache days from baseline reported at Week 24 were 28% (23/82) and 31% 
(26/84), respectively, for the 2 treatment groups. These rates correspond to 24% and 27%, 
respectively, for an ITT analysis where patients who terminate from the study are treated as 
failures. Rothrock et al, 2005 also describes an open-label study involving topiramate (n = 170), 
where a responder rate (≥50% reduction from baseline) of 38.8% (45/116) was reported. This 
rate corresponds to 29.4% for an ITT analysis where patients who terminate from the study are 
treated as failures. Thus, the ITT responder rate for topiramate ranged from 24% to 29.4%, and 
the value of 28% was deemed reasonable for sample size calculation purposes. 
 
4.2. Randomization, Stratification, and Blinding 
 
On Day 1, qualified patients will be randomly assigned at a 1:1 treatment allocation ratio to 1 of 
2 treatment arms: 155 U BOTOX given IM or up to 100 mg/day of oral topiramate. 
 
Randomization is not stratified for this study. 
 
At the screening visit, once informed consent is obtained, the site staff will log onto the 
interactive web response system (IWRS) to obtain a unique patient number, which will be used 
as identification for the electronic patient eDiary, electronic case report form (eCRF), electronic 
clinical outcomes assessments (eCOA), and all source documentation throughout the study. 
 
The IWRS system will provide the site with the treatment assignment to which the patient is 
assigned. Sites will dispense study medication according to the IWRS instructions. Sites will log 
onto the IWRS at subsequent visits to log dispending of additional study medication as needed. 
Sites will receive the IWRS confirmation notifications for each transaction. All notifications are 
to be maintained with the study source documents. 
 
4.3. Analysis Sets 
4.3.1. Intent-to-Treat 
 
The ITT Set will include all randomized patients.  
 
4.3.2. Subset of ITT 
 
A subset of the ITT Set (ssITT) will exclude patients who discontinue treatment for any reason 
other than the following: AE, lost to follow-up, lack of efficacy, C-SSRS response of “yes” to 
questions 4 or 5 in the suicidal ideation section or “yes” to any question in the suicidal behavior 
section, or noncompliance with the study treatment regimen.  


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ssITT set analyses will be performed only as needed which will be determined when number of 
subjects in this population will be known. 
4.3.3. Per Protocol 
 
The Per Protocol (PP) Set will be a subset of patients in the ssITT Set who complete the study 
without major protocol deviations. Major protocol deviations include one or more of the 
following categories: major inclusion/exclusion criteria violations, poor study drug compliance, 
and other. The prespecified criteria for exclusion from the per protocol set are detailed in Section 
115.1, and will be finalized prior to the database lock following the completion of the final post-
treatment follow-up visit. 
 
PP set analyses will be performed only as needed which will be determined when number of 
subjects in this population will be known. 
 
4.3.4. Safety 
 
The Safety Set will include all patients who received at least one dose of study drug.  
 
5. Patient Disposition 
 
Patient disposition will be summarized for all enrolled patients and will include the number and 
percentage of patients for the following categories: patients randomized, patients treated (Safety 
Set), patients in the ITT Set, patients in the ssITT Set, patients in the PP Set, patients completed 
(study treatment and study), patients who discontinued study treatment (including patients who 
discontinued from topiramate and switched to BOTOX), and patients who discontinued from the 
study. Denominators for percentages will be the total number of patients randomized into each 
treatment arm, and overall.  
 
The reasons for study treatment discontinuation and study discontinuation will also be 
summarized in this table. The reasons for treatment discontinuation may include any of the 
following: AE, death, lost to follow-up, withdrawal of consent, patient became pregnant, 
includes non-compliant with study treatment regiment, treatment was ineffective, treatment was 
no longer needed, existed study due to C-SSRS or other. The reasons for discontinuation will be 
counted in the treatment arm for which the patient was receiving treatment at the time of 
discontinuation. These treatment arms will include BOTOX, topiramate, and 
topiramate + BOTOX. 
 
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5.1. Protocol Deviations 
 
Protocol deviations will be documented by the clinical trial manager and reviewed monthly. 
They will be categorized as major and minor, and major deviations that would exclude patients 
from the PP analysis set will be identified and finalized prior to database lock in accordance with 
International Council for Harmonisation guideline -E9 (Statistical Principles for Clinical Trials). 
Major protocol deviations include but are not limited to: 
 
 Violation of any inclusion/exclusion criteria 
 Poor study drug compliance 
 Other protocol deviations as defined by clinical review 
 
Major protocol deviations will be summarized for the ITT Set. Patients will be counted in the 
treatment arm to which they were randomized. Counts and percentage of patients with each type 
of deviation will be provided. Denominators for percentages will be the total number of patients 
randomized into each treatment arm or overall. 
 
All protocol deviations will be presented in a data listing. 
 
5.2. Demographics and Baseline Characteristics 
The demographic characteristics consist of age (years), age categories, sex, race, and ethnicity. 
The patient’s age in years is recorded at screening. Age will be categorized as follows: 18 to <25, 
25 to <35 years, 35 to <45 years, 45 to <55 years, and ≥55, and <40 years and, 40 years. Race 
categories will be reported as White, Black, Asian, Hispanic and Other. The baseline 
characteristics consist of baseline height, baseline weight, and baseline body mass index (BMI) 
(kg/m2). Body mass index is calculated as body weight in kilograms/(height in meters)2. 
 
A summary of demographics and baseline information will be presented for the ITT, ssITT, and 
PP Sets. Patients will be counted in the treatment arm to which they were randomized. All 
continuous data will be summarized using descriptive statistics. Counts and percentage of 
patients for will be provided for all categorical data. Denominators for percentages will be the 
total number of patients randomized into each treatment arm or who received topiramate + 
BOTOX. 
 
All patient demographics and baseline characteristics will be presented in a data listing. 
 
5.3. General Medical History 
 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The Safety Set will be used to summarize medical history overall (patients with any 
medical history) and for each system organ class (SOC) and preferred term (PT). Patients will be 
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with each type of SOC and PT will be provided. Denominators for percentages will be the total 
number of patients randomized into each treatment arm, overall. 
 
All patient medical history data including specific details will be presented in a listing. 
 
5.4. Inclusion and Exclusion Criteria 
 
The inclusion/exclusion criteria can be found in Section 4.3 and Section 4.4 of the protocol. A 
listing of patients not satisfying all inclusion/exclusion criteria will be presented in a listing. 
Inclusion/exclusion exemption along with the reason for the exception will also be presented in 
this listing. 
 
6. Prior and Concomitant Treatments  
 
A prior treatment is defined as any treatment that is started prior to the first dose of study drug. A 
concomitant treatment is defined as any treatment that has a start date and a stop date that is on 
or after the date of first dose of study drug. Treatments with start and stop dates that bracket the 
first dose date will be summarized as both a prior and concomitant treatment. 
 
All treatments being taken by the patients upon entry into the study or at any time during the 
study (in addition to the investigational product) are regarded as concomitant treatments and 
must be documented on the appropriate section of the eCRF. Prior and concomitant medications 
will be coded using the World Health Organization (WHO) drug dictionary. The total number of 
concomitant medications and procedures and the number and percentages of patients with at 
least one concomitant medication will be summarized by treatment arm. The number and 
percentages of all concomitant medications will be summarized by treatment arm and listed by 
drug class and preferred term and will be flagged as prophylactic or acute headache medications, 
if applicable. All summaries will be performed using the Safety Set. Patients will be counted in 
the arm in which they received treatment. Denominators for percentages will be the total number 
of patients treated in each treatment arm and overall. 
 
All prior and concomitant medications as well as concomitant non-drug therapies, surgeries, and 
procedures will be presented in listings. 
 
7. Study Treatment 
7.1. Duration of Exposure 
 
Duration of exposure is defined as the total number of days a patient is exposed to any study 
drug. For topiramate it will be presented as the total number of days from the first dose date 
(Day 1) to the last dose date (date of last dose minus the date of first dose + 1) as recorded on the 
End of Study/Early Withdrawal page on the eCRF. If the last dose date on the End of 


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Study/Early Withdrawal page is missing, or if a patient is lost to follow-up, but the eDiary 
confirms that the patient has taken study drug, the visit date following the last completed eDiary 
entry will be used. For BOTOX the duration of exposure will be defined as the total number of 
days from the first injection date (Day 1) to the last injection date plus 84 days (date of last dose 
+ 84 days minus the date of first dose + 1) as recorded in the eCRF. 
 
The duration of study drug exposure will be summarized for the Safety Set. Patients will be 
counted in the treatment arm for which they received treatment. Denominators for percentages 
will be the total number of patients treated in each arm. 
 
 
7.2. Treatment Compliance and Modifications 
 
Over the course of active treatment, each patient receiving topiramate will record the total daily 
dose taken in the eDiary system. If a patient skips a dose(s) or fails to take the specific 
maintenance dosing regimen, the patient will still be able to continue in the study.  
 
Topiramate treatment compliance will be calculated based on the e-dairy data and if necessary, 
corresponding pill counts (number of pills actually taken, number of pills retrieved/returned, and 
the number of pills expected to have been taken by the patient while in the topiramate arm of the 
study). The overall topiramate compliance rate will be calculated by dividing the total mg of 
topiramate taken after Week 12 visit by the total mg of topiramate prescribed for all visits after 
Week 12 visit based upon the duration in the study and then multiplying by 100. The total mg of 
topiramate prescribed will be based on the maintenance dose set during the Week 12 visit.  
 
The BOTOX compliance rate per visit will be calculated by choosing the minimum of the total 
units of BOTOX received at a visit divided by 155 U, the total number of injections sites divided 
by 31, 0.90 if a patient is +/- 8 to 10 days from the visit schedule or 0.80 if a patient is +/- 11 to 
14 days from the visit schedule. This minimum value will then be multiplied by 100%. A patient 
that is 15 or more days from the visit schedule will result in a 0% for compliance (Table 3). The 
visit schedule is Day 1, Day 84 and Day 168. Overall BOTOX compliance will be the average of 
the total compliance from each visit. 
 
Table 3: BOTOX Compliance Formula 
Time to Next BOTOX Injection 
BOTOX Compliance Formula 
+/- 7 days from the visit schedule 
Min (Units Injected
155 U
,    Sites Injected
31 Sites
) ∗100% 
+/- 8 to 10 days from the visit schedule 
Min (Units Injected
155 U
,
Sites Injected
31 Sites
,
0.90 ) ∗100% 
+/- 11 to 14 days from the visit schedule 
Min (Units Injected
155 U
,
Sites Injected
31 Sites
,
0.80) ∗100% 


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+/- 15 or more days from the visit schedule 
0% 
 
For both the BOTOX and topiramate treatment arms, the number and percentage of patients in 
each compliance rate category (<80%, 80% – 100%, 100% – 120% and >120% as well as <80% 
and ≥80%) will be reported. If the treatment compliance is less than 80% or greater than 120% 
and treatment discontinuation is reported at the subsequent office visit, then date of last treatment 
taken/received from either the eCRF or the eDiary will be the reported as date of discontinuation. 
Percentages will be calculated from the number of patients who have received treatment in the 
study period. 
 
If a patient discontinues topiramate treatment, the eCRF for treatment discontinuation must be 
completed to document the reason for discontinuation. The patient should not be exited from the 
study, because BOTOX must be administered at the next scheduled office visit (ie, Week 12, 24, 
or 36). 
 
If a patient discontinues BOTOX treatment, the eCRF for treatment discontinuation must be 
completed to document the reason for discontinuation and the patient will be exited from the 
study. 
 
Treatment compliance will be summarized for the Safety Set. Patients will be counted in the 
treatment arm in which treatment was received. The study drug compliance rate will be 
summarized using descriptive statistics. Counts and percentage of patients in each compliance 
rate category will be provided. Denominators for percentages will be the total number of patients 
who received treatment in each treatment arm and overall. 
 
BOTOX treatment administration by visit, topiramate drug accountability, and topiramate drug 
accountability per eDiary will be presented in data listings. 
 
8. Efficacy Analyses 
 
All efficacy analyses will be conducted by grouping patients according to the treatment they 
were randomized to receive. The primary and secondary efficacy endpoints will be analyzed on 
the ITT Set. These analyses will be repeated for the ssITT and PP analysis sets. The primary 
indicator of efficacy for this study is the analyses on the ITT Set. The analyses for the ssITT and 
PP Sets will be considered supportive.   
 
Family-wise error rate will be controlled using a hierarchical testing gatekeeping procedure. The 
testing will begin with the primary efficacy endpoint and continue with the first secondary 
endpoint in the ranking order, followed by the next, and so on, in a sequential fashion. If the test 
of the primary endpoint shows statistical significance at the 0.05 level (2-sided), then there is 
justification to proceed to test the next endpoint in the ranking order; this stepwise process 
continues for all the endpoints listed in the hierarchical order. However, if no statistical 


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significance is shown at the 0.05 level (2-sided) for the test of any specified endpoint in the 
hierarchical order, then that endpoint and all subsequent endpoints below this in the ranking 
order should be not be considered as an indicator of efficacy, but rather should be considered 
supportive, regardless of their nominal p-value. 
 
For efficacy analyses, patients who discontinue topiramate and then receive BOTOX will be 
considered nonresponders and baseline data will be used for the remaining study days for the 
primary and secondary efficacy endpoints.  
 
All efficacy data will be provided in data listings. 
 
8.1. Primary Efficacy Endpoint 
 
The primary efficacy measure is the proportion of patients with a ≥50% decrease from baseline 
in the frequency of headache days. 
 
A headache day will be defined as a calendar day (00:00 to 23:59) with 4 or more hours of 
headache and/or headache of any duration with the use of migraine-specific acute headache 
medication(s) (ie, ergot alkaloids, ergot combinations, opioids, triptans, or combination 
analgesics [simple analgesics combined with opioids or barbiturate with or without caffeine]). 
This variable is derived from the eDiary reports of total duration of all headaches for a given day. 
It is based on the count of days with at least 4 hours total duration of headaches and/or headache 
of any duration with the use of migraine-specific acute headache medication(s). The primary 
timepoint is Week 32, encompassing the last 28-day period ending with Week 32 
(ie, Day 198 to Day 225, inclusive, following the Day 1 office visit). 
 
8.1.1. Primary Analysis 
 
Missing data 
 
If there are at least 20 days for which the patient has reported headache data (for either headache 
days or headache-free days), but less than 28 days in a diary period, the data for counts will be 
prorated accordingly and rounded to the nearest whole number. The prorating will be based on 
the number of days with reported data in that period. 
 
For example, if there are 24 days with reported data in a 28-day diary window, the headache day 
count will be multiplied by 28/24 and rounded to a whole number. If the patient reported total 
daily headache durations that indicated 16 headache days and 8 headache-free days, the patient’s 
standardized counts after prorating by 28/24 would be 19 headache days and 9 headache-free 
days. 
 
If a patient reports eDiary data for less than 20 days in a 28-day period, the patient’s entries for 
this time period will be set to missing. 


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A baseline observation carried forward (BLOCF) method will be utilized to impute missing 
values for the primary analysis. This type of imputation replaces the missing value with the 
baseline value; thus, if a patient has a missing entry for any reason (eg, discontinuation due to 
AE, lost to follow-up, lack of efficacy), the baseline value data will be utilized and the patient 
will be considered a nonresponder. Patients who discontinue BOTOX and patient randomized to 
topiramate who discontinue treatment and subsequently receive BOTOX will be considered 
nonresponders for the primary and secondary analyses and thus baseline value data will be 
utilized. 
 
BLOCF will also be used to impute missing values for the PRO analyses. 
 
Analysis method 
 
The primary null hypothesis is that BOTOX and topiramate are equally effective, as measured by 
the proportion of patients with a ≥50% decrease from baseline in the frequency of headache days 
per 28-day period at Week 32. The alternative hypothesis is that BOTOX has a different effect 
than topiramate. 
 
The primary comparison between treatment arms will be performed using a logistic regression 
model, adjusted by the baseline number of headache days as a covariate. The treatment effect 
will be summarized using an adjusted odds ratio and 95% Wald confidence limits. The p-value 
from the Wald Chi-square test will also be reported. A 2-sided test with a p-value less than or 
equal to 0.05 will be considered as statistically significant. All centers will be pooled for this 
analysis. 
 
The primary analysis will be repeated for the PP and ssITT Sets, if appropriate.  
 
8.1.2. Sensitivity Analysis 
 
Sensitivity analyses of the primary variable will be performed for the ITT Set in the following 
ways: 
1. Repeating the primary analysis using Fisher’s exact test. 
2. The same logistic regression methods but applying the Worst Observation Carried Forward 
(WOCF) imputation method for missing values when there are less than 20 days of reported 
data in the eDiary. Specifically, this will use a patient’s worst-case observation within the 
28-day period to populate the missing values within that time period.  
3. The same logistic regression methods will be re-calculated on “observed data” (ie, without 
imputation for missing counts when there are less than 20 days of reported data).  
 
A sensitivity analysis will also be performed for the PRO variables to determine if there is a 
difference in the imputed data versus the observed data. Continuous data will be analyzed with a 
t-test and Fisher’s exact test will be used for the categorical data.  


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8.2. Secondary Efficacy Endpoints 
 
The 3 secondary efficacy variables are ranked in a hierarchical order of clinical importance. To 
control for Type I error rate for multiple secondary endpoints, a hierarchical testing gatekeeping 
procedure will be used, starting with the first secondary endpoint in the ranking order, followed 
by the next, and so on, in a sequential fashion. If the test of the first secondary endpoint shows 
statistical significance at the 0.05 level (2-sided), then there is justification to proceed to test the 
next endpoint in the ranking order; this stepwise process continues for all the endpoints listed in 
the hierarchical order. However, if no statistical significance is shown at the 0.05 level (2-sided) 
for the test of any specified endpoint in the hierarchical order, then that endpoint and all 
subsequent endpoints below this in the ranking order should not be considered statistically 
significant, regardless of their nominal p-value.  
 
1. Change from baseline in the frequency of headache days per 28-day period. 
This variable will be derived from the daily eDiary reports. It will be based on the count 
of headache days with at least 4 continuous hours in total duration of headaches, and/or 
headache of any duration with the use of migraine-specific acute headache medication(s) 
(ie, ergot alkaloids, ergot combinations, opioids, serotonin receptor agonists [“triptans”], 
or combination analgesics [simple analgesics combined with opioids or barbituates with 
or without caffeine]) days per 28-day period at Week 32. 
 
The change from baseline in frequency of headache days will be compared between 
BOTOX and topiramate arms via analysis of covariance (ANCOVA) with baseline 
headache day count as the covariate. The estimated mean change from baseline and 95% 
CIs will be summarized for each treatment along with the 2-sided p-value. If the p-value 
is less than or equal to 0.05 then it will be considered as statistically significant and 
testing will continue to the next secondary efficacy analysis. The rules for data handling 
and missing value imputation will be the same as used for the primary endpoint. 
 
2. HIT-6 Score change from baseline 
The HIT-6 comprises 6 items that assess pain, role functioning, social functioning, 
cognitive functioning, vitality, and psychological distress. A total score is created by 
summing across all items, and ranges from 36 (no impact) to 78 (severe impact), 
reflecting a “best to worst” scoring. Score categories are based on the total score and 
include “little to no impact” (total score 36 to 49), “some impact” (total score 50 to 55), 
“substantial impact” (total score 56 to 59) and “severe impact” (total score 60 to 78). The 
continuous total score will be used in this analysis. The categorical HIT-6 scores will be 
summarized in a separate table.  
 
The total HIT-6 score from the 28-day period collected at Week 30 will be compared 
between treatment arms using a nonparametric rank analysis of covariance (rank 
ANCOVA) (Stokes et al, 2000), with treatment as a factor and adjusting for the baseline 
value. If the p-value is less than or equal to 0.05, then it will be considered statistically 
significant and testing will continue to the final secondary efficacy analysis. The BLOCF 
method will be used for missing values for this endpoint. 


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3. The proportion of patients with a ≥70% decrease from baseline in the frequency of 
headache days. 
The ≥70% responder rate will be analyzed using the same methods used to analyze the 
primary endpoint; a logistic regression model adjusted by the baseline frequency of 
headache days. Exact conditional logistic regression analysis will be performed if there 
are convergence issues with the default unconditional analysis. The rules for data 
handling and missing value imputation will be the same as used for the primary endpoint. 
 
All secondary analyses will be repeated for the PP and ssITT Sets, if appropriate.  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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eDiary. The sum of the total scores will be divided by the number of MIBS-4 questionnaires 
taken over each 28-day period. The average continuous score will be used for this analysis. 
 
The 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9. Safety Analyses 
 
All analyses of safety will be conducted using the Safety Set. All patients will be summarized 
according to the treatment they actually received, but the subgroup of topiramate patients who 
initially received topiramate and then switched to BOTOX will be summarized as follows: 
 All safety assessments occurring prior to the date of the first dose of BOTOX will be 
summarized for the topiramate treatment arm. 
 All safety assessments except AEs occurring on or after the date of the first dose of 
BOTOX will be summarized separately for the topiramate + BOTOX subgroup. 
For all AEs, the total number of patients (N) in each treatment arm will represent the 
number of patients that received that treatment. A patient may be counted in both 
treatment arms. The overall total will be the number of patients that received any 
treatment. The topiramate + BOTOX treatment arm will be a subset of the BOTOX 
treatment arm and will include patients that received both treatments. Denominators for 
percentages will be the total number of patients in each treatment arm or overall. 
Treatment-emergent AEs (TEAEs) include all AEs that start on or after the first dose of 
study medication up to the final visit, or are present prior to the first dose but increase in 
severity after the first dose of study medication up to the final visit. For patients who 
switch from topiramate to BOTOX, TEAEs starting on or after the date of the first 
BOTOX injection will be counted in the treatment arm that they are related to, as 
determined by a physician. If the TEAE is related to both treatments or if the relationship 
is unknown, it will be counted in both treatment arms but only once in the total. The 
topiramate + BOTOX subset will summarize all TEAEs that occurred after a patient has 
switched from topiramate to BOTOX.  
 
Statistical hypothesis testing will not be performed on any safety results 
 


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9.1. Adverse Events 
 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. In addition, during the screening period, AEs will be assessed 
regardless of the administration of a pharmaceutical product. 
 
Adverse events will be assessed, documented, and recorded in the eCRF and will be classified by 
SOC and PT according to MedDRA version 16.0 or higher throughout the study (ie, after 
informed consent has been obtained). All AEs collected from the time of informed consent that 
are prior to study treatment will be defined as pretreatment AEs and will be presented in the 
listings.  
 
A TEAE is defined as an AE that meets any of the following conditions: 
 Begins on or after the first dose of study drug and before the final scheduled office visit 
at Week 36; 
 Begins before the first dose of study drug and worsens in severity on or after the first 
dose of study drug and before the final scheduled office visit at Week 36; 
 Is completely missing an onset date and the end date is on or after the first dose of study 
drug 
 
If a patient receives BOTOX after receiving topiramate, the physician will be asked to determine 
if the AE is due to BOTOX or topiramate or unknown.  
 
For the purpose of inclusion in TEAE tables, incomplete AE onset and end dates will be imputed 
as follows: 
Missing onset dates (where “UK” and “UKN” indicate unknown or missing day and month 
respectively): 
 
UK-MMM-YYYY: If the month and year are different from the month and year of the 
first dose of study drug, assume the onset date is 01-MMM-YYYY. If the month and year 
are the same as the first dose of study drug month and year, and the end date (after any 
imputation) is on or after the first dose of study drug, then assume the onset date is the 
date of the first dose of study drug. If the month and year are the same as the first dose of 
study drug month and year and the end date (after any imputation) is prior to the first 
dose of study drug, then assume the end date for the onset date.  
 
DD-UKN-YYYY/UK-UKN-YYYY: If the year is different from the year of first dose of 
study drug, assume 01-JAN-YYYY of the collected year. If the year is the same as the 
first dose of study drug year, and the end date (after any imputation) is on or after the first 
dose of study drug, then assume the onset date is the date of the first dose of study drug. 
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imputation) is prior to the first dose of study drug, then assume the end date for the onset 
date.  
 
Missing end dates (where “UK” and “UKN” indicate unknown or missing day and month 
respectively):  
 UK-MMM-YYYY: Assume the end date is the last day of the month; 
 DD-UKN-YYYY/UK-UKN-YYYY: Assume the end date is 31-DEC-YYYY. 
 
9.1.1. Incidence of Adverse Events 
 
All AEs will be summarized for the Safety Set in the manner described in Section 9. Counts and 
percentage of patients with each type of AE will be provided. Denominators for percentages will 
be the total number of patients treated in each arm or overall. At each level of patient 
summarization, a patient is counted once if the patient reported one or more events. 
 
An overview summary of the number and percentage of patients with any TEAE, serious TEAE, 
study drug-related TEAE, study drug-related serious TEAE, TEAE leading to treatment 
discontinuation, TEAE leading to study discontinuation, and AE leading to death will be 
provided by treatment arm.  
 
Treatment-emergent AEs will also be summarized separately for each injection cycle for 
BOTOX treated patients. 
 
The following summary tables will be repeated for any TEAE, serious TEAE, study drug-related 
TEAE, study drug-related serious TEAE, TEAE leading to treatment discontinuation, TEAE 
leading to study termination, and AE leading to death. 
 
Summaries of the total number of TEAEs and the number and percentage of patients with at least 
one TEAE will be provided by treatment group. The number and percentage of patients and the 
number of events will also be presented by SOC and PT in descending order from the SOC with 
the highest total incidence (that is, summed across all treatment groups) to the SOC with the 
lowest total incidence. If the total incidence for any 2 or more SOCs is equal, the SOCs will be 
presented in alphabetical order. Within each SOC, the PTs will be presented in alphabetical 
order. At each level of patient summarization, a patient is counted once if the patient reported 
one or more events. 
 
All AEs, will be presented in a by-patient listing. 
 
9.1.2. Relationship of Adverse Events to Study Drug 
 
A summary of TEAEs by relationship to study drug will be presented in a table by incidence of 
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and will be reported as “Related” or “Not Related”. In the TEAE relationship table, if a patient 
reports multiple occurrences of the same AE, only the most closely related occurrence will be 
presented. Treatment-emergent AEs that are missing a relationship will be presented in the 
summary table as “Related”, but will be presented in the data listing with a missing relationship. 
Percentages will be calculated by the number of patients in the Safety Set. Denominators for 
percentages will be the total number of patients treated in each arm or overall. 
 
The TEAE data will be categorized and presented by SOC, PT, and relationship in a manner 
similar to that described in Section 9.1.1. 
 
9.1.3. Severity of Adverse Event 
 
A summary of TEAEs by severity will be presented in a table. The severity that will be presented 
represents the most extreme severity captured on the eCRF page. In the TEAE severity table, if a 
patient reported multiple occurrences of the same TEAE, only the most severe will be presented. 
Treatment-emergent AEs that are missing severity will be presented in tables as “Severe” but 
will be presented in the data listing with a missing severity. Counts and percentage of patients 
within each category will be provided using the Safety Set. Denominators for percentages will be 
the total number of patients treated in each arm or overall. 
 
A clinical determination will be made of the intensity of an AE. The severity assessment for a 
clinical adverse event must be completed using the following definitions as guidelines: 
 Mild:  
 
Awareness of sign or symptom, but easily tolerated. 
 Moderate: 
 
Discomfort enough to cause interference with usual activity. 
 Severe:  
 
Incapacitating with inability to work or do usual activity. 
 Not applicable: 
In some cases, an adverse event may be an ‘all or nothing’ finding 
which cannot be graded. 
 
The AE data will be categorized and presented by SOC, PT, and severity in a manner similar to 
that described in Section 9.1.1. 
 
9.1.4. Serious Adverse Events 
 
The seriousness of an AE should be assessed by the Investigator independently from the severity 
of the AE. A serious AE (SAE) is defined as any untoward medical occurrence that, at any dose, 
results in death, is life-threatening, is a congenital anomaly/birth defect, requires inpatient 
hospitalization or prolongation of existing hospitalization, or results in a persistent or significant 
disability/incapacity. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
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The serious TEAE data will be categorized and presented by SOC and PT in a manner similar to 
that described in Section 9.1.1. 
 
A by-patient listing of SAEs will be presented. 
 
9.1.5. Adverse Events Leading to Treatment Discontinuation 
 
A summary of TEAEs with a study drug action taken of either “Drug Withdrawn” or “Switched 
to BOTOX” will be presented in a table. At each level of patient summarization, a patient is 
counted once if the patient reported one or more events. Counts and percentage of patients within 
each category will be provided. Denominators for percentages will be the total number of 
patients treated in each arm or overall.  
 
Treatment-emergent AEs leading to treatment discontinuation will be categorized and presented 
by SOC and PT in a manner similar to that described in Section 9.1.1. 
 
9.1.6. Death 
 
All deaths occurring any time from the time of informed consent to study conclusion will be 
summarized by reason and presented in a table. A supportive listing will be generated to provide 
patient-specific details including the reason for death for all patients in the ITT Set.  
 
9.2. Serum Chemistry  
 
Blood samples will be collected for clinical laboratory testing at screening for all patients. Blood 
samples will additionally be collected for patients who discontinue topiramate and switch to 
BOTOX prior to their first administration of BOTOX. 
 
The following serum chemistry laboratory tests will be included: blood urea nitrogen (BUN) 
(mg/dL), calcium (mg/dL), creatinine (mg/dL), sodium (mEq/mL), potassium (mEq/mL), 
chloride (mEq/mL), carbon dioxide (mEq/mL), and alkaline phosphatase (U/L). All chemistry 
data will be presented in a by-patient listing. 
 
Laboratory assessments will be performed by a central laboratory. All summaries will be based 
on the units provided by the central laboratory; no conversion will be done.  
 
 
9.3. Vital Sign Measurements 
 
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Systolic and diastolic blood pressure and pulse rate over 30 seconds should be taken after 
patients have been at rest (seated) for at least 2 minutes. Blood pressure should be recorded in 
mmHg. Pulse rate should be measured in beats per minutes. Oral, axillary, or tympanic body 
temperature should be taken. The same route should be used throughout the study. If oral 
temperature is taken, the patient should not have any oral intake for at least 5 minutes prior to the 
measurement. Temperature as Fahrenheit (°F) or Celsius (°C) should be specified on the source 
document and the eCRF. 
 
Summary tables will be presented for vital sign data by treatment group for patients in the Safety 
Set. Observed results at each visit will be presented. 
 
All vital sign data will be presented in a by-patient listing. 
 
9.4. Physical Examination 
 
At screening and study exit, the investigator will examine the patient for any detectable 
abnormalities of the following body systems: general appearance; neck (including thyroid); head, 
eyes, ears, nose, and throat; lungs; heart/cardiovascular; abdomen; neurologic; extremities; back; 
musculoskeletal; lymphatic; skin; and other. The neurologic examination should be conducted to 
detect the presence of any significant sensory/motor abnormalities.  
 
Height and weight should be measured at screening, Day 1, and each subsequent office visit 
using the same scale and ruler for all patients at a given investigator site when possible. 
 
A table will summarize physical examination results by treatment group and overall for the 
Safety Set. Each visit captures the status of a body system and any finding associated with the 
body system as normal, abnormal, or not done. The summary will include the number and 
percentage of patients with each physical examination outcome for the following body systems: 
skin; head, eyes, ears, nose, and throat (respiratory; cardiovascular; gastrointestinal; 
endocrine/metabolic; genitourinary; neurological; blood/lymphatic; musculoskeletal; and other. 
Patients will be counted in the arm in which they were treated. Denominators for percentages 
will be the total number of patients treated in each arm. 
 
Physical examination results for all patients will be presented in a listing.  
 
9.5. Pregnancy Test 
 
Urine pregnancy testing will be conducted at screening, on day 1, and each subsequent office 
visit to confirm continued non-pregnant status prior to study drug administration or study 
completion.   
 
A listing will be presented for pregnancy test status. 
 


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9.6. Urine Drugs of Abuse  
 
Illicit drug urine testing will be conducted at screening and day 1, prior to study treatment 
administration, and will be performed at the investigator site. 
 
A listing will be presented for urine drugs of abuse at screening. 
9.7. Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
The C-SSRS will be conducted at the screening visit and each subsequent office visit. At 
screening, patients will be asked about the 12 months prior to the screening visit along with a 
separate assessment for lifetime prior to the screening visit. For visits after the screening visit, 
the assessment will be for the time period since the previous visit. The assessments will be 
summarized for each treatment group using the Safety Set.   
 
Among the questions for each assessment time period (lifetime, prior 12 months, since previous 
visit) are a set of 10 questions intended to elicit a yes or no response from the patient (as deduced 
by the investigator site's interview of the patient) and a question (post-screening only) regarding 
completed suicide. Among those questions are 5 regarding suicidal ideation, arranged in order of 
increasing severity (1= wish to be dead, 2= non-specific suicidal thoughts, 3= method without 
intent to act, 4= some intent but without plan and 5= intent and plan). Also included are 
6 questions in the suicidal behavior section of the C-SSRS (non-suicidal self-injurious behavior, 
preparatory behavior, aborted attempt, interrupted attempt, actual attempt, and completed 
suicide). 
 
C-SSRS data will be summarized separately for the following sets of responses: (1) year prior to 
screening, (2) baseline as reported under "since screening" at the randomization visit and (3) by 
visit reported as "since last visit." Overall ideation and behavior responses for the treatment 
period will be done by taking the most severe response (eg, a yes response at any time point for a 
specific ideation or behavior question).  
 
Counts and percentage of patients with each answer on the questionnaire will be provided. 
Summary statistics will include the count and percentage of patients for each of the 11 ideation 
and behavior categories separately and also overall for any ideation, for any behavior and for any 
ideation or behavior. Denominators for percentages will be the total number of patients treated in 
each arm. 
 
10. Interim Analysis 
 
There is no interim analysis planned for this study. 
 


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11. Deviation from Protocol-Specified Analyses 
 
The subset of ITT and Per-protocol population analyses will not be performed since subjects who 
would discontinued due to reasons specified and subjects with major protocol deviations, 
respectively, is expected to be few; hence difference on number of subjects in each of the two 
populations and the ITT population is minimal. 
 
 
12. References 
 
Aurora SK, Dodick DW, Turkel CT, DeGryse RE, Silberstein SD, Lipton RB, Diener HC and 
Brin MF on behalf of PREEMPT 1 Chronic Migraine Study Group. OnabotulinumtoxinA for 
treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled 
phase of the PREEMPT 1 trial. Cephalalgia. 2010;30:793-803. 
 
Diener HC, Dodick DW, Aurora SK, Turkel CT, DeGryse RE, Lipton RB, et al. 
OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, 
randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. 2010;30:804-814.  
 
Rothrock JF, Parada VA, Drinkard R, Zweifler RM, Key KF.  Predictors of a negative 
response to topiramate therapy in patients with chronic migraine. Headache. 2005;45:932–
935.  
Silberstein SD, Dodick DW, Lindblad AS, Holroyd K, Harrington M, Mathew NT, Hirtz D.  
Randomized, placebo-controlled trial of propranolol added to topiramate in chronic 
migraine.  Neurology. 2012;78:976–984. 
 
Stokes ME, Davis CS, Koch GG. Categorical data analysis using the SAS system. 2nd ed. Cary, 
North Carolina: SAS Institute Inc.; 2000. 
 


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ALLERGAN 
 
GMA-US-NEU-0206 
 
A Multicenter, Prospective, Randomized, Open-label Study to Compare the Efficacy, Safety, 
and Tolerability of BOTOX® and Topiramate for Headache Prophylaxis in Adults with 
Chronic Migraine 
 
17JUL2017 
 
Statistical Analysis Plan Version 2.0 
 
 
 
 
 
 
 
Issued by: 
Date:  ___/___/___ 
 
 
 
 
 
 
 
Reviewed by: 
Date:  ___/___/___ 
 
 
 
 
 
 
 
Upon review of this document, including table, listing, and figure shells, the undersigned approves the 
statistical analysis plan. The analysis methods and data presentation are acceptable, and the table, listing, 
and figure production can begin. 
 
 
Reviewed by: 
 
 
 
Reviewed by: 
 
 
Reviewed by: 
 
 
 
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