A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Parallel Group Study to Evaluate the Efficacy and Safety of SPN-538 as a Therapy for the Prevention of Migraine in Subjects Ages 6-11 Years
Phase: PHASE4
Conditions: Migraine Disorders, Headache Disorders
Sponsor: Supernus Pharmaceuticals, Inc.

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TITLE PAGE 
 
Protocol Number: 
538P401 
Title: 
A Randomized, Double-Blind, Placebo-Controlled, 
Multicenter, Parallel Group Study to Evaluate the Efficacy 
and Safety of SPN-538 as a Therapy for the Prevention of 
Migraine in Subjects Ages 6-11 Years 
Sponsor: 
Supernus Pharmaceuticals, Inc. 
9715 Key West Ave. 
Rockville, MD 20850 
United States 
Phone: (301) 838-2500 
Fax: (240) 403-0065 
IND number: 
138,790 
Investigational 
Medicinal Product: 
SPN-538 (Topiramate XR capsule) 
Indication: 
Prophylaxis of episodic migraine  
Phase: 
4 
Protocol Version: 
Version 4.0 
Date: 
14 December 2022 
Good Clinical Practice 
(GCP) Statement: 
This study is to be performed in full compliance with ICH 
GCP and all applicable local regulations. All required study 
documentation will be archived as required by regulatory 
authorities. 
 
 
 
 
 
 
 
 
 

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INVESTIGATOR’S SIGNATURE PAGE 
 
I, the undersigned, have read this protocol and agree to conduct this trial in accordance 
with all stipulations of the protocol and in accordance with ICH GCP and all applicable 
local guidelines, including the Declaration of Helsinki and all its accepted amendments to 
date. 
 
 
 
 
 
 
 
Principal Investigator’s Signature 
 
 
 
 
Date 
Print Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

This document is confidential. It contains proprietary information of Supernus® Pharmaceuticals, Inc. Any 
viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. 
Such information may be used solely for the purpose of reviewing or performing this study. 

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Such information may be used solely for the purpose of reviewing or performing this study. 
Summary of Changes  
This summary table (Appendix 10.11) lists all clarifications, administrative changes or 
amendments to Supernus protocol 538P401. Additions are denoted by bold text and deletions by 
strikethrough. 

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CLINICAL PROTOCOL SYNOPSIS 
Name of Company: 
Supernus Pharmaceuticals, Inc.  
IND Number:  
138,790 
Name of Product:  
SPN-538 (Topiramate XR capsule) 
Name of Active Ingredient: 
Topiramate (TPM) 
Protocol Number:  
538P401          
Phase of Development:  
Phase 4 
Full Title of the Study: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, 
Parallel Group Study to Evaluate the Efficacy and Safety of SPN-538 as a Therapy for 
the Prevention of Migraine in Subjects Ages 6-11 Years 
Investigator(s)/Center(s):  Approximately 35 US centers 
Number of Subjects:  Approximately 276 subjects aged 6 to 11 years (inclusive) will be 
randomized to achieve 234 completed subjects. 
Objectives:  
Primary:  
• 
To evaluate the treatment effect of SPN-538 compared to placebo in reducing 
MMDs1 in children 6 to 11 years old with migraine. 
Secondary:  
• 
To assess the efficacy of SPN-538 treatment on the following: 
1. Responder rate with a responder defined as a subject with at least a 50% 
reduction in monthly migraine days (MMDs). 
2. Number of days per month requiring acute rescue medication. 
3. Monthly rate of total headache days (migraine and non-migraine), duration 
and severity. 
4. Onset of action, defined as the time to first statistically significant treatment 
effect observed and maintained until the end of study (EOS). 
5. Headache Disability Score as measured by the Pediatric Migraine Disability 
Assessment (PedMIDAS).  
6. Health-related quality of life (HRQoL) as measured by the Pediatric Quality of 
Life Inventory, Version 4.0 (PedsQL 4.0), for the self-report and parent-
report.  
Primary Estimand 
According to the ICH E9 Addendum, the attributes of the primary estimand (target of 
estimation) are provided below. 
1. Treatment: To compare the treatment effect of SPN-538 vs Placebo. 
2. Population: The population targeted for the scientific question is defined via the 
inclusion and exclusion criteria in children 6 to 11 years old (inclusive) with a 
history of migraine.  
3. Variable: The primary efficacy endpoint is the change from baseline in the 
monthly (28-day) rate of migraine days during the last 4 weeks of the 20-week 
double-blind Treatment Phase relative to the Prospective Baseline Period based 

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on the Full Analysis Set (FAS).  
4. Intercurrent Events: For subjects discontinued due to adverse event (AE) or lack 
of efficacy, missing data will be imputed using multiple imputation (MI) under the 
missing not at random (MNAR) assumption. For all other missing data due to 
intercurrent event (ICE), missing data will not be imputed following the treatment 
policy strategy, which assumes that ICE did not occur.  
5. Population level summary: The difference in the mean change from baseline in 
the monthly (28-day) rate of migraine days during the last 4 weeks of the 
Treatment Phase between the SPN-538 and placebo groups will be analyzed 
using a Mixed Model for Repeated Measures (MMRM). 
Safety: 
• 
To evaluate the safety and tolerability of SPN-538 in children 6 to 11 years old 
as assessed by: 
1. Incidence of AEs. 
2. Clinical laboratory tests (blood chemistry and hematology, urinalysis).  
3. Vital signs, physical and neurological examinations, and electrocardiograms 
(ECGs). 
4. Columbia Suicide Severity Rating Scale (C-SSRS) assessment. 
5. Cognitive Assessment. 
 
1A migraine day is defined as a calendar day (12:00am to 11:59pm) in which the subject 
experiences a migraine attack that starts, ends or recurs within 24 hours and lasts for ≥1 
hour (if untreated) or ≥30 minutes (if interrupted with rescue medication). Pain persisting 
for more than 1 calendar day (≥24 hours) after initial onset will be considered as a new, 
distinct headache day. MMDs are defined as the number of migraine days within 28 
days or 4 weeks. 
Study Design:  
This is a multicenter, randomized, double-blind, placebo-controlled, 2-arm, parallel 
group Phase 4 study in children 6 to 11 years of age to evaluate the efficacy and safety 
of SPN-538 for the prevention of migraine. SPN-538 (or matching placebo) will be 
administered as a single oral dose once a day (QD), starting at 25 mg/day and 
increasing every 2 weeks in 25 mg increments to a target dose of 2 to 3 mg/kg/day or 
the maximum tolerated dose (MTD), whichever is less. The total study duration is a 
maximum of 34 weeks including a Screening Period, Prospective Baseline Period of up 
to 8 weeks, a Treatment Phase of 20 weeks (8 weeks titration followed by 12 weeks of 
maintenance dosing), a Dose Tapering Period of 1 to 3 weeks, and a Safety Follow-up 
Period of 1 to 3 weeks. 
 
 

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Treatment Schedule:  
Throughout the duration of the study, rescue medications will be allowed for 
symptomatic relief of headaches (migraine and non-migraine) if the pattern of use 
remains stable and does not meet the criteria for medication overuse (i.e., > 10 
treatment days/month for ergot-containing medication or triptans; >15 treatment 
days/month for simple analgesics/nonsteroidal anti-inflammatory drugs (NSAIDs). 
Simple analgesics are allowed, but use of narcotics is not permitted (Section 4.7).   
Pre-Treatment Phase (Visits 1 and 2) 
Screening Period (Visit 1, up to 8 weeks before Visit 3)  
At Visit 1, initial screening evaluation will be performed (Section 5.1.1). The evaluation 
also includes the visual neurological examination.  
Prophylactic migraine treatments including daily NSAIDs, antihistamines, 
corticosteroids, antiemetics, high-dose magnesium supplements (≥600 mg/day), high-
dose riboflavin (≥100 mg/day), coenzyme Q10, omega-3, melatonin, muscle relaxants, 
and β-blockers will be allowed if on a stable dose for at least 12 weeks prior to the 
Screening visit.  The dose must remain stable (7 days/week) throughout the duration 
of the study (Appendix 10.9). 
Prospective subjects who meet eligibility criteria at Visit 1 will be instructed to 
discontinue the following preventive medications 14 days prior to Visit 2 (see Exclusion 
Criterion #8): antipsychotics, antimanics, barbiturates, benzodiazepines, sedatives, 
serotonin selective reuptake inhibitors (SSRIs), non-selective reuptake inhibitor 
(NSRIs), amitriptyline, tricyclic antidepressants, lithium, valproic acid, AEDs, calcium 
channel blockers, cannabidiol (CBD) oil, calcitonin gene-related peptide (CGRP) 
receptor antagonists, herbal preparations/supplements such as feverfew or St John’s 
Wort and/or any medications that could impair or decrease thinking and concentration. 
It is recommended to taper off antipsychotics, barbiturates, benzodiazepine, tricyclic 
antidepressants, lithium, amitriptyline, valproic acid, SSRIs and NSRIs as applicable 
(Appendix 10.10). 
Re-screening is not permitted, however subjects who screen failed due to a 
PedMIDAS Total score > 50 under any prior version of the protocol, may be 
rescreened if they still meet the study eligibility criteria under this version of the 
protocol (Version 4.0, 14 Dec 2022). 
Prospective Baseline Period (Visit 2, 4 weeks before Visit 3) 
At Visit 2, in addition to routine safety assessments (Section 5.1.2), the subject’s 
parent or guardian will be asked to maintain a daily electronic Headache Diary 
(completed by the parent with the subject’s assistance) in which they will record daily 
headache-associated symptoms and the duration and severity of all headaches. 
Rescue medication usage during this period will also be recorded in the diary.  
Treatment Phase (Visits 3 through 8) 
Randomization (Visit 3, Day 1) 
Upon completion of the Prospective Baseline Period, eligibility for randomization will 
be determined based on 1) the number of migraine episodes2 (must be 3-12 inclusive) 
during Prospective Baseline Period, and 2) the number of total headache days 
(migraine and non-migraine; no more than 14 headache days) during the Prospective 

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Safety Follow-up Telephone Call (Weeks 24 through 26) 
Safety follow-up over the telephone will take place 1 to 3 weeks after the EOS visit 
(Section 5.1.7).  
2Migraine episode is defined as any occurrence of a migraine that starts, ends or 
recurs within a 24-hour period. 
Duration of Treatment and Study:   
The total study duration is up to 34 weeks.  
Pre-Treatment Phase: 8 weeks 
• 
Screening Period: up to 4 weeks  
• 
Prospective Baseline Period: 4 weeks 
Treatment Phase: 20 weeks  
• 
Titration Period: 8 weeks 
• 
Maintenance Period:12 weeks 
Post-Treatment Phase: Up to 3 weeks  
• 
Tapering Period: 1 to 3 weeks 
Safety Follow-up (via telephone): 1 to 3 weeks 
Investigational Medicinal Products, Reference Therapy, Dose and Mode of 
Administration: 
Test Treatment: SPN-538, as 25 mg capsules.     
Reference Treatment: Placebo in matching capsules.   
All SM bottles will be labeled by the Sponsor in a double-blind configuration. 
Dose: The dose will be based on body weight and optimized based on individual 
tolerability. Treatment will be initiated at 25 mg/day (or 1 capsule/day) and increased 
bi-weekly in 25 mg increments to a target dose in the range of 2 to 3 mg/kg/day. The 
total daily dose will not exceed 100 mg/day (or 4 x 25 mg capsules/day). 
Mode of Administration: Placebo or SPN-538 will be administered as a single oral 
dose QD, with or without food, at bedtime. The capsules must be swallowed whole and 
intact and must not be sprinkled on food, crushed, chewed, cut, or dissolved before 
swallowing. 
• 
Treatment A: Placebo  
• 
Treatment B: SPN-538 

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Efficacy Endpoints: 
Primary Endpoint  
The primary efficacy outcome measure is the change in the monthly (28-day) rate of 
MMDs during the last 4 weeks of the 20-week double-blind Treatment Phase relative to 
the Prospective Baseline Period.  
Secondary Endpoints  
1. Responder, defined as a subject with ≥ 50% reduction in the MMDs during the 
last 4 weeks of the Treatment Phase relative to Prospective Baseline Period.  
2. Change from baseline in the mean of monthly migraine-specific acute rescue 
medication use in the last 4 weeks of the Treatment Phase.  
3. Change in the monthly rate of total headache days (migraine and non-migraine), 
duration and severity. 
4. Change in the time to onset of action, defined as the time to first statistically 
significant treatment difference observed and maintained until the EOS.  
5. Change from baseline in the Headache Disability Score as measured by 
PedMIDAS during the last 4 weeks of the Treatment Phase.   
6. Change from baseline in the HRQoL as measured by the PedsQL 4.0 Total 
Scale Score during the last 4 weeks of the Treatment Phase for the self-report 
and the parent-report. 
Safety Endpoints: 
1. Incidence of AEs. 
2. Clinical laboratory test results (blood chemistry and hematology, urinalysis). 
3. Vital signs, physical and neurological examinations, and ECGs. 
4. C-SSRS assessment. 
5. Cognitive Assessment. 
Safety Assessments:  
Safety evaluations will be performed at each clinic visit. Routine safety monitoring will 
include monitoring, evaluation, and recording of all concomitant medications, and the 
evaluation of AEs, clinical laboratory test results, vital signs, 12-lead ECGs, suicidality 
monitoring/C-SSRS results, physical and neurological examinations. Subjects will also 
be monitored for visual/ocular disturbances, nephrolithiasis, oligohydrosis, 
hyperthermia, metabolic acidosis (serum bicarbonate), hyperammonemia, hepatic 
injury, and cognitive assessments.   

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Statistical Methodology: 
Sample Size  
Based on data from previous studies conducted in adolescents and adults (MIGR-001, 
MIGR-002 and MIG-003), a common standard deviation (SD) of 3 is assumed for both 
the treatment and control groups. Assuming a treatment difference of 1.1, a sample size 
of 117 subjects per arm (a total of 234 subjects) will yield 80% power to detect a 
non-zero difference between the mean change from baseline in MMDs between the 
active treatment and the placebo groups using a two-sample t-test at a two-sided 
significance level of alpha=0.05. 
It is assumed that approximately 15% of subjects will drop-out before completing the 
study, hence an adjusted total sample size of 276 subjects (138 subjects per arm) will 
be randomized in a 1:1 ratio to obtain 234 subjects at the completion of the study. 
Analysis Populations: 
The Randomized Population consists of all subjects who are randomized via the IWRS.  
The Full Analysis Set (FAS) is defined as subjects who received at least one dose of 
study drug, have a baseline and at least one valid post-randomization assessment of 
monthly migraine based on diary days. The FAS will be used to assess the primary 
endpoint and secondary efficacy endpoints, and subjects will be included in the 
analyses based on randomized treatment.  
The Per Protocol Set (PPS) includes all subjects in the FAS who have completed Visits 
1-8 with no missing MMDs and no important protocol deviations. The PPS will be used 
as supplementary analysis of the primary and secondary efficacy endpoints based on 
the treatment received.  
The Safety Analysis Set includes all subjects randomized into the study and who 
receive at least 1 dose of SM. Data will be analyzed according to the treatment 
received. 
Efficacy Analyses: Based on the FAS, the observed value and change from baseline 
will be summarized using descriptive statistics and presented for all efficacy endpoints 
by study visit and treatment group. Subject listing of the observed value and change 
from baseline will be provided for all efficacy endpoints. The mean 28-day MMDs will be 
presented by treatment group and study visit. 
Primary Endpoint Analysis: 
The primary efficacy endpoint, change from the Prospective Baseline Period in the 
28-day rate MMDs, will be analyzed using a MMRM, which assumes that missing data 
are missing at random (MAR). All post-baseline study visits will be included in the 
model; however, the primary comparison will be between SPN-538 and Placebo groups 
at Month 5 (last 4 weeks of the Maintenance Period). The model will include fixed effect 
terms for 28-day rate of MMDs for the Prospective Baseline Period, treatment group, 
Prospective Baseline monthly migraine-specific acute rescue medication (28-day rate) 
use, visit, and treatment-by-visit interaction as independent variables. The model 
parameters will be estimated using the restricted maximum likelihood method with an 
unstructured variance-covariance matrix and Kenward-Roger approximation to estimate 
denominator degrees of freedom.  

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If the MMRM model with the unstructured variance-covariance matrix does not converge 
using the default Newton-Raphson fitting algorithm by PROC MIXED in SAS, the Fisher 
scoring algorithm or the no-diagonal factor analytic structure will be used (Lu & 
Mehrotra, 2010). If the model still fails to converge, then the first (co)variance structure 
which does not have convergence problem will be used for the analysis from the 
following ordered list:  
 
1. Heterogeneous Toeplitz,  
2. Heterogeneous Autoregressive of order 1  
3. Toeplitz,  
4. Autoregressive of order 1  
5. Compound Symmetry 
 
The denominator degrees of freedom will be estimated using the BETWITHIN option in 
SAS when any of the covariance structures is used with the sandwich variance 
estimator. 
The least square mean (LS Mean) of each treatment group (placebo and SPN-538) 
along with the corresponding standard error, p-values, difference in the LS Mean 
between SPN-538 and placebo (SPN-538 minus placebo), and 95% CIs will be 
computed at each visit.  
Sensitivity analyses will be performed based on MI, assuming that missing data are 
MNAR. 
Secondary Endpoint Analyses: 
Secondary endpoints will be analyzed based on the FAS using appropriate statistical 
models. 
Safety Analyses: 
Safety analyses will be performed by treatment group using the Safety Analysis Set. 
The incidence rate, severity, and relationship to the SM for all AEs will be summarized 
by treatment group, system organ class (SOC), and preferred term (PT).  
Descriptive statistics will be presented for demographics, data from the clinical 
laboratory test results, vital signs, weight, ECGs, physical, neurological and eye 
examinations, suicidal ideation, and cognitive assessment. 
Inclusion Criteria:  
1. Healthy male or female subjects, 6 to 11 years of age (inclusive) at Screening. 
2. History of migraine with or without aura conforming to the International 
Headache Society (IHS) criteria for pediatric subjects (International Classification 
of Headache Disorders, 3rd edition [ICHD-3]) for at least 6 months prior to 
Screening.  

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3. Subjects who experience 3-12 migraine episodes and no more than 
14 headache days (migraine and non-migraine) per month during the 3 months 
prior to Screening and during the 28-day Prospective Baseline Period (based on 
the Headache Diary). 
4. At Screening, a PedMIDAS Disability score of ≥20 (indicating at least mild 
disruption of daily activities) and ≤139 (indicating severe disability that may 
require more comprehensive therapy). 
5. Weight of at least 20 kg and no more than 60 kg (inclusive) at the 
Randomization visit (Visit 3). 
6. Considered medically healthy by the Investigator via assessment of physical, 
neurological and eye examinations, medical history, clinical laboratory tests, vital 
signs, and ECGs. 
7. Able and willing to swallow capsules whole and intact without sprinkling on food, 
crushing, chewing, cutting, or dissolving before swallowing.  
8. Caregiver must be able to read and comprehend written instructions and be 
willing to supervise the completion of all headache records and questionnaires 
by the subject as required in the protocol. 
9. Written Informed Consent obtained from the subject’s parent or legal 
representative, and written Informed Assent obtained from the subject if 
required. 
10. Female subjects must be premenarchal or otherwise incapable of pregnancy, or 
have practiced one of the following methods of contraception for at least 1 month 
prior to study entry: 
a. Simultaneous use of male condom, spermicide and barrier, and 
placement of intrauterine contraceptive device  
b. Surgically sterile male partner 
c. Simultaneous use of male condom and diaphragm with spermicide. 
d. Established hormonal contraceptive, sterility; or 
e. Be practicing abstinence and agree to continue abstinence or to use an 
acceptable method of contraception (as listed above) should sexual 
activity commence during the study. 
Exclusion Criteria: 
1. Subjects with chronic migraine (>14 headache days per month), cluster 
headaches, or migraine aura without headache, and who are unable to 
distinguish migraines from other headache types.  
2. Subjects with more than 14 headache days during the 28-day Prospective 
Baseline Period (based on the Headache Diary). 
3. Have taken any disallowed migraine preventive medication including TPM 
within 14 days prior to the start of the Prospective Baseline Period; or used 
onabotulinumtoxinA (Botox®) within 3 months prior to entering the Screening 
period. 
4. Previously failed to respond to TPM prophylaxis therapy using an adequate 
dose (2 to 3 mg/kg/day) for an adequate period of time (minimum of 3 months), 
or those who have previously discontinued TPM due to AEs within 6 months 
prior to Screening.  

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5. Previously failed more than 2 adequate clinical trials (defined as non-response 
to treatment at a full therapeutic dose for at least 1 month) of an established 
prophylactic antimigraine regimen within 6 months prior to Screening. 
6. Known history of allergic reaction or anaphylaxis to TPM. 
7. Overuse of analgesic or migraine-specific agents for acute treatment of 
migraine defined as:  
a. >10 treatment days/month of ergot-containing medications or triptans 
b. >15 treatment days/month with simple analgesics (including NSAIDs) 
c. Use of narcotics  
8. Subjects treated with the following prophylactic medications should discontinue 
the treatment 14 days prior to the Prospective Baseline Period: antipsychotics, 
antimanics, barbiturates, benzodiazepines amitriptyline, lithium, valproic acid, 
tricyclic antidepressants, AEDs, calcium channel blockers, sedatives, SSRIs, 
NSRIs, CGRP receptor antagonists, CBD oil, herbal preparations/supplements 
such as feverfew or St John’s wort and/or any medications that could impair or 
decrease thinking and concentration. It is recommended to taper off 
antipsychotics, barbiturates, benzodiazepine, tricyclic antidepressants, lithium, 
amitriptyline, valproic acid, SSRIs and NSRIs as applicable.  
Note: Subjects must refrain from using these medications throughout the 
duration of the study.  
9. Subjects using non-pharmacologic complementary and alternative prophylactic 
approaches for migraine prevention, such as neuromodulation, acupuncture, 
behavioral interventions, spinal manipulation, occipital nerve block and 
neurofeedback. 
Note: Non-pharmacologic approaches involving lifestyle modifications (e.g., 
trigger factor avoidance, stress reduction techniques, regular exercise, and 
good sleep hygiene) will be allowed if they were started at least 1 month prior 
to Screening and are continued throughout the study. 
10. Currently on a ketogenic diet, or on a ketogenic diet within 6 months prior to 
Screening. 
11. Significant major psychiatric disorder (e.g., psychosis, bipolar disorder, major 
depression and generalized anxiety disorders), or documented developmental 
delays or impairments (e.g., autism, cerebral palsy, or mental retardation) that, 
in the opinion of the Investigator, would interfere with adherence to study 
requirements or safe participation in the trial. 
Note: Subjects with an established diagnosis of Attention Deficit Hyperactivity 
Disorder (ADHD), will be allowed if they are taking a stable dose (7 days/week) 
of ADHD stimulant medication (extended or controlled release) for at least 12 
weeks prior to the Screening visit and refrain from changing the dose or the 
ADHD medication during the study duration.  
12. Subjects with seizures or a history of seizure-like events within 6 months prior 
to Screening, or a history of seizure disorder within the immediate family 
(siblings, parents). 
13. Known history of visual field defects regardless of etiology. 
14. Presence of active liver disease (including baseline serum ammonia levels 
>2 times the upper limit of normal).  

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15. Abnormal kidney function, subjects undergoing hemodialysis, or subjects with 
a history of nephrolithiasis. 
16. Known neurological disorder or a structural disorder of the brain from birth; 
head trauma or infectious disease resulting in migraine or worsening of 
migraine symptoms; or previous central nervous system (CNS) surgery.   
17. Known history of uncontrolled asthma, uncontrolled diabetes, arrhythmias or 
congenital heart disease. 
18. Evidence of suicidal ideation and/or suicidal behaviors within 6 months prior to 
Screening or during the Pre-treatment Phase.  
19. Pregnancy, breastfeeding, or refusal to practice abstinence or acceptable birth 
control during the study for females of childbearing potential (FOCPs). 
20. Known history of substance-use disorder according to the Diagnostic and 
Statistical Manual of Mental Disorders 5th Edition (DSM-5) or used alcohol or 
illicit drugs in the 3 months prior Screening. 
21. Any other reason that could interfere with the subject’s participation in the 
study as determined by the Investigator. 
 
Note: Abnormal results on screening laboratory tests and/or ECG may be repeated 
once per test at the discretion of the Investigator. 

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TABLE OF CONTENTS 
 
TITLE PAGE .................................................................................................................. 1 
INVESTIGATOR’S SIGNATURE PAGE ........................................................................ 2 
SUPERNUS PHARMACEUTICALS, INC. PROTOCOL APPROVAL PAGE ................. 3 
Summary of Changes ................................................................................................... 4 
CLINICAL PROTOCOL SYNOPSIS .............................................................................. 5 
Primary Estimand ...................................................................................................... 5 
TABLE OF CONTENTS ................................................................................................16 
LIST OF ABBREVIATIONS ..........................................................................................21 
1 
INTRODUCTION .......................................................................................23 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................25 
2.1 
Primary Objective .......................................................................................... 25 
2.2 
Secondary Objectives ................................................................................... 25 
2.3 
Safety Objective ............................................................................................ 26 
2.4 
Optional Objective ......................................................................................... 26 
2.5 
Primary Endpoint .......................................................................................... 26 
2.6 
Secondary Endpoints .................................................................................... 26 
2.7 
Optional Endpoint ......................................................................................... 27 
3 
INVESTIGATIONAL STUDY PLAN ..........................................................27 
3.1 
Overall Study Design and Plan ..................................................................... 27 
3.2 
Rationale for Study and Study Design ......................................................... 34 
3.2.1 
Study Population .......................................................................................34 
3.2.2 
Topiramate Dose Selection .......................................................................34 
3.2.3 
Selection of Assessment Instruments ........................................................35 
3.3 
Study Population Selection .......................................................................... 36 
3.3.1 
Number of Subjects ...................................................................................36 
3.3.2 
Inclusion Criteria .......................................................................................36 
3.3.3 
Exclusion Criteria ......................................................................................37 
3.4 
Completion of Study ..................................................................................... 39 
3.4.1 
Discontinuation of Subjects .......................................................................39 
3.4.2 
Early Termination Procedures ...................................................................40 
4 
STUDY TREATMENT ...............................................................................40 
4.1 
Study Medication Identity, Packaging and Labeling ................................... 40 
4.2 
Study Medication Administration ................................................................. 41 
4.3 
Study Medication Dosing .............................................................................. 41 

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4.4 
Method of Assigning Subjects to Treatment Group ................................... 42 
4.5 
Blinding .......................................................................................................... 42 
4.6 
Study Medication Handling and Accountability .......................................... 43 
4.7 
Concomitant Medications ............................................................................. 44 
4.8 
Non-pharmacologic Adjunctive Treatments ................................................ 44 
4.8.1 
Prohibited Medications ..............................................................................45 
5 
STUDY METHODS ...................................................................................45 
5.1 
Study Visits and Procedures ........................................................................ 45 
5.1.1 
Visit 1 – Screening (Day -56) .....................................................................50 
5.1.2 
Visit 2 – Prospective Baseline Period (Day -28, Weeks -4 to -1)................50 
5.1.3 
Visit 3 (+2 days) – Randomization (Day 1) ................................................51 
5.1.4 
Titration Period (Days 1 to 56, Week 1 to end of Week 8) .........................51 
5.1.5 
Maintenance Period (Days 57 to 140, Week 9 to the end of Week 20) ......52 
5.1.6 
Taper Period (Days 141 to 161, Week 21 to the end of Week 23) .............53 
5 1 7
Safety Follow-up Telephone Call (Weeks 24 through 26) 
54
6 
STUDY VARIABLES AND ASSESSMENTS ............................................56 
6.1 
Headache Diary– Preventive Therapies (Version 2.0) ................................. 56 
6.2 
Pediatric Migraine Disability Assessment Questionnaire .......................... 56 
6.3 
Pediatric Quality of Life Inventory, Version 4.0 ........................................... 57 
............................................. 58 
6.5 
Safety Variables and Assessments .............................................................. 58 
6.6 
Adverse Events ............................................................................................. 58 
6.6.1 
Causality ...................................................................................................58 
6.6.2 
Recording and Evaluation of Adverse Events ............................................59 
6.6.3 
Criteria for Assessing Severity ..................................................................59 
6.6.4 
Criteria for Assessing Causality .................................................................60 
6.6.5 
Serious Adverse Events ............................................................................60 
6.6.6 
Investigator Responsibilities for Reporting SAEs .......................................61 
6.6.7 
Other Events Requiring Immediate Reporting ...........................................61 
6.6.8 
Sponsor Responsibilities for Reporting SAEs ............................................62 
6.6.9 
Adverse Events of Special Interest ............................................................62 
6.7 
Treatment-Emergent Suicidal Ideation ........................................................ 63 
6.7.1 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................63 
6.7.2 
Suicide Risk Management Plan .................................................................63 
6.7.3 
Assessment of Suicide Risk ......................................................................64 
6.7.4 
Acute Suicidal Crisis ..................................................................................64 
6.7.5 
Non-acute Suicidal Risk ............................................................................64 
6.8 
Clinical Measurements .................................................................................. 64 

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6.8.1 
Laboratory .................................................................................................64 
6.8.2 
Vital Signs .................................................................................................65 
6.8.3 
Medical and Psychiatric History .................................................................65 
6.8.4 
Retrospective 3-months Headache History ...............................................65 
6.8.5 
Physical and Neurological Examinations ...................................................65 
6.8.6 
Eye Exam ..................................................................................................66 
6.8.7 
Cognitive Assessment ...............................................................................67 
6.8.8 
Electrocardiograms (ECGs) .......................................................................68 
7 
STATISTICAL METHODS ........................................................................69 
7.1 
General Considerations ................................................................................ 69 
7.2 
Handling of Missing Data .............................................................................. 69 
7.3 
Analysis Populations .................................................................................... 70 
7.4 
Demographics and Baseline Analysis ......................................................... 70 
7.5 
Subject Disposition ....................................................................................... 70 
7.6 
Study Medication Exposure and Compliance ............................................. 71 
7.7 
Concomitant Medications ............................................................................. 71 
7.8 
Efficacy Analysis ........................................................................................... 72 
7.8.1 
Primary Efficacy Analysis ..........................................................................72 
7.8.2 
Multiple Comparisons ................................................................................73 
7.8.3 
Secondary Efficacy Analyses ....................................................................73 
7.9 
Sample Size and Power Considerations ...................................................... 74 
...................................................................... 74 
7.11 Safety Analysis .............................................................................................. 74 
8 
DOCUMENTATION ..................................................................................76 
8.1 
Adherence to the Protocol ............................................................................ 76 
8.2 
Changes to the Protocol ............................................................................... 76 
8.3 
Data Quality Assurance ................................................................................ 76 
8.3.1 
Data Collection ..........................................................................................76 
8.3.2 
Clinical Data Management ........................................................................77 
8.3.3 
Database Quality Assurance .....................................................................77 
8.3.4 
Bioanalytical Sample Handling ..................................................................77 
8.4 
Retention of Records .................................................................................... 77 
8.5 
Auditing Procedures ..................................................................................... 78 
8.6 
Publication of Results ................................................................................... 78 
8.7 
Financing and Insurance .............................................................................. 78 
8.8 
Disclosure and Confidentiality ..................................................................... 78 
8.9 
Discontinuation of Study .............................................................................. 79 
9 
ETHICS .....................................................................................................79 
9.1 
Institutional Review Boards.......................................................................... 79 

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9.2 
Ethical Conduct of the Study ........................................................................ 79 
9.3 
Investigators and Study Personnel .............................................................. 79 
9.4 
Subject Information and Consent ................................................................ 80 
10 
APPENDICES ...........................................................................................81 
10.1 Study Definitions and ICHD-3 Diagnostic Criteria ...................................... 81 
10.2 Headache Diary – Preventive Therapies (Version 2.0) ................................ 84 
10.3 Pediatric Migraine Disability Assessment Questionnaire (PedMIDAS) ..... 87 
10.4 Pediatric Quality of Life Inventory, Version 4.0 (PedsQL, 4.0) ................... 88 
10.5 Cognitive Assessment .................................................................................. 97 
10.6 Columbia-Suicide Severity Rating Scale ..................................................... 98 
10.6.1 C-SSRS - Children’s Baseline ...................................................................98 
10.6.2 C-SSRS - Children’s Since Last Visit....................................................... 101 
10.7 Visual Neurological Exam Checklist .......................................................... 104 
10.8 Eye Exam Checklist .................................................................................... 105 
10.8.1 Wall Snellen Chart................................................................................... 106 
10.8.2 Amsler Grid Test ..................................................................................... 107 
10.9 Concomitant Medications ........................................................................... 108 
10.10 Prohibited Medications ............................................................................... 109 
10.11 Summary of Changes .................................................................................. 110 
11 
REFERENCES ........................................................................................ 140 
  
 
 

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LIST OF TABLES 
Table 1 
Weight-based Determination for the Maximum and Minimum Daily Dose of 
Study Medication ......................................................................................41 
Table 2 
Schedule of Events and Assessments ......................................................47 
Table 3 
Clinical Laboratory Tests ..........................................................................64 
 
LIST OF FIGURES 
Figure 1 
Study Schematic .......................................................................................33 
 
 
 

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LIST OF ABBREVIATIONS 
ADR 
adverse drug reaction 
ADHD 
attention-deficit/hyperactivity disorder 
AE 
adverse event 
AED 
AESI 
ATC 
antiepileptic drug 
adverse event of special interest 
Anatomical-Therapeutic-Chemical (code) 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CBD 
CDE 
CGRP 
cannabidiol 
Common Data Elements 
calcitonin gene-related peptide 
CNS 
central nervous system 
CRA 
Clinical Research Associate 
CRF 
case report form 
C-SSRS 
DSM-5 
Columbia Suicide Severity Rating Scale 
Diagnostic and Statistical Manual of Mental Disorders 5th Edition 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
ePRO 
end of study 
electronic patient reported outcome 
ET 
early termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FOCP 
females of childbearing potential 
GCP 
Good Clinical Practice 
HR  
heart rate 
HRQoL 
health-related quality of life 
IAF 
informed assent form 
ICE 
Intercurrent events 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICHD-3 
International Classification of Headache Disorders, 3rd edition 
IHS 
IND 
IR 
IRB 
International Headache Society 
Investigational New Drug 
immediate release 
Institutional Review Board 
IWRS 
interactive web response system 

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MAR 
Missing at Random 
MedDRA 
MI 
MIDAS 
MMD 
Medical Dictionary for Regulatory Activities 
multiple imputation 
Migraine Disability Assessment 
monthly migraine day 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing not at random 
MTD 
NINDS 
NSAID 
NSRI 
maximal tolerated dose 
National Institute of Neurological Disorders and Stroke 
nonsteroidal anti-inflammatory drug 
non-selective reuptake inhibitor 
OD 
overdose 
PedMIDAS 
Pediatric Migraine Disability Assessment  
PedsQL 4.0 
Pediatric Quality of Life Inventory, Version 4.0 
PPS 
Per Protocol Analysis Set 
PK 
PREA 
pharmacokinetic 
Pediatric Research Equity Act 
PT 
preferred term 
QD 
QTcF 
once a day 
QT interval corrected using Fridericia’s method 
RR 
respiratory rate 
SADR 
suspected adverse drug reaction 
SAE 
serious adverse event 
SAP 
SD 
statistical analysis plan 
standard deviation 
SM 
study medication 
SOC 
system organ class 
SOP 
standard operating procedure 
SSRI 
serotonin selective reuptake inhibitors 
TEAE 
treatment-emergent adverse event 
TPM 
topiramate 
TPM XR 
US 
WBC 
topiramate extended release 
United States 
white blood cell 
WHO DD 
World Health Organization Drug Dictionary 
XR 
extended release 

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1 
INTRODUCTION 
Migraine is a disabling primary headache disorder characterized by recurrent attacks of 
predominantly unilateral headache that is pulsatile in nature, moderate to severe in 
intensity, and often aggravated by routine physical activity. Migraine affects up to 15% of 
the world population (Stovner et al., 2007). Recurrent headache is one of the most 
common complaints among children and adolescents, with an estimated 75% of children 
reporting significant headache by the age of 15 years (Antonaci et al., 2014). Moreover, 
approximately 4% to 11% of children between the ages of 7 and 11 years are affected 
by migraine, with one-third of pediatric patients meeting the criteria for pharmacologic 
prophylaxis (Lewis et al., 2004). The International Classification of Headache Disorders, 
3rd edition (ICHD-3) summarizes definitions and diagnostic criteria for migraine with and 
without aura, as well as special features that are characteristic of migraine headaches in 
children and adolescents (Appendix 10.1). 
Symptomatic manifestations of migraine are often different between adults and children. 
Pediatric migraine attacks are more often bilateral, of shorter duration than in adults, and 
have a higher prevalence of gastrointestinal complaints such as nausea, vomiting and 
pain (Kacperski, Kabbouche, O'Brien, & Weberding, 2016). Recurrent migraine attacks 
are associated with significant functional impairment, resulting in poor long-term 
educational, occupational, and social outlook and reduced life satisfaction (Powers, 
Patton, Hommel, & Hershey, 2003). The long-term outcome of childhood headaches and 
their progression to chronic conditions is unknown.  
Treatment and management of migraine require a multilevel approach, including 
medication management of acute episodes, prophylactic treatment for frequent and 
disabling headaches, and non-pharmacologic approaches, such as cognitive and 
behavioral therapies, lifestyle modifications, and trigger avoidance strategies, to facilitate 
better therapeutic outcomes. In general, pharmacologic preventive therapies are 
indicated when other approaches have been ineffective (Bonfert et al., 2013).  
Topiramate (TPM), an antiepileptic drug (AED), is the only drug indicated for migraine 
prophylaxis in the pediatric patient population, specifically for children and adolescents 
≥12 years of age. The efficacy and safety of TPM in migraine prophylaxis have been 
clearly demonstrated in several randomized, double-blind, placebo-controlled trials in 
thousands of patients (Jackson et al., 2015). These studies have provided consistent 
evidence that TPM reduces migraine frequency and acute medication use, improves 
quality of life, and reduces disability in patients with episodic and in those with chronic 
migraine, with or without medication overuse headache. As a result, TPM has become 
the most commonly prescribed migraine preventative in adults and is frequently 
recommended for migraine prophylaxis in children and adolescents (Kacperski et al., 
2016; Silberstein, 2017).  

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Trokendi XR® (SPN-538) was developed by Supernus Pharmaceuticals as an 
extended release (XR) formulation of topiramate (TPM XR), a once a day (QD) 
product designed to be equivalent to TPM immediate release (IR) (Topamax®, 
Janssen Pharmaceuticals, Inc.) administered twice daily. Currently, Trokendi XR is 
marketed as an AED (monotherapy and adjunctive therapy) for patients 6 years of age 
and older and as a preventive for migraine headaches in adults and adolescents 
12 years of age and older ("National Institutes of Health-DailyMed- Trokendi XR- 
Prescribing Information.," 2022). United States (US) Food and Drug Administration 
(FDA) approval of Trokendi XR was based on the product’s demonstrated 
bioequivalence to Topamax. 
The safety and tolerability of TPM has been studied extensively in adult and pediatric 
patients with epilepsy but has not been definitively established for prophylaxis of 
migraine headache in patients younger than 12 years of age. In a meta-analysis of 
randomized clinical trials of TPM in children with migraine <18 years of age, the most 
frequently reported adverse events (AEs) included paresthesia, upper respiratory tract 
infections, fatigue, weight decrease, anorexia, and cognitive impairments (Le, Yu, 
Wang, Ali, & Guo, 2017). Most AEs, including those leading to discontinuation of TPM, 
occurred during the titration period and did not worsen during maintenance (Lainez et 
al., 2007). In pediatric patients, slow dose titration is recommended to alleviate AEs, 
and dose reductions may improve treatment compliance.   
In previous migraine studies MIGR-001 (Silberstein, Neto, Schmitt, Jacobs, & Group, 
2004), MIGR-002 (Brandes et al., 2004), MIGR-003 (Diener et al., 2004), and 
MIG-3006 (Lewis et al., 2009), most AEs reported with the use of TPM were mild to 
moderate in severity, and no unusual or unexpected safety risks were identified. 
However, long-term TPM treatment requires continuous assessment for AEs that are 
specifically attributable to this drug. These include ophthalmologic side effects (acute 
myopia, secondary angle closure glaucoma, and visual field defects), oligohydrosis 
and hyperthermia, treatment-related laboratory abnormalities (e.g., metabolic acidosis, 
hyperammonemia, and changes in complete blood count values), nephrolithiasis, 
negative effects on growth, and suicidal behavior and ideation.  
Monitoring for neuropsychiatric effects and cognitive impairment is of crucial 
importance because of the effect of TPM on cognitive function, specifically on 
concentration/attention, memory, and speech/language abilities. This risk for cognitive 
adverse reactions is dose dependent and is greater in younger pediatric patients (6 to 
11 years) than in older children (12 to 17 years)("National Institutes of Health-
DailyMed- Trokendi XR- Prescribing Information.," 2022; "National Institutes of Health 
-DailyMed- Topamax- Prescribing Information," 2022).  

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Trokendi XR is an approved agent for the prophylaxis of migraine in adults and 
adolescents 12 years of age and older; however, its efficacy as a migraine preventative 
has not been established in the 6-to-11 year age range. In this study (538P401), the 
efficacy and safety of Trokendi XR as a preventative therapy for migraines in this 
younger pediatric population will be explored. The XR formulation of SPN-538 is 
expected to be beneficial in this patient population where, compared to the IR TPM 
products, it offers more constant plasma drug concentrations, less frequent dosing, and 
an improved AE profile (Silberstein, 2017).  
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
To evaluate the treatment effect of SPN-538 compared to placebo in reducing MMDs in 
children 6 to 11 years old with migraine. 
2.2 
Secondary Objectives 
To assess the efficacy of SPN-538 treatment on the following: 
1. Responder rate with a responder defined as a subject with at least a 50% 
reduction in monthly migraine days (MMDs).  
2. Number of days per month requiring acute rescue medication. 
3. Monthly rate of total headache days (migraine and non-migraine), duration and 
severity. 
4. Onset of action, defined as the time to first statistically significant treatment effect 
observed and maintained until the end of study (EOS). 
5. Headache Disability Score as measured by the Pediatric Migraine Disability 
Assessment (PedMIDAS).  
6. Health-related quality of life (HRQoL) as measured by the Pediatric Quality of 
Life Inventory, Version 4.0 (PedsQL 4.0), for the self-report and parent-report.  
Primary Estimand 
According to the International Conference on Harmonisation (ICH) E9 Addendum, 
the attributes of the primary estimand (target of estimation) are provided below. 
1. Treatment: To compare the treatment effect of SPN-538 vs placebo. 
2. Population: The population targeted for the scientific question is defined via the 
inclusion and exclusion criteria in children 6 to 11 years old (inclusive) with a 
history of migraine.  
3. Variable: The primary efficacy endpoint is the change from baseline in the 
monthly (28-day) rate of migraine days during the last 4 weeks of the 20-week 
double-blind Treatment Phase relative to the Prospective Baseline Period based 
on the Full Analysis Set (FAS) as defined in Section 7.3. 
4. Intercurrent event (ICE): For subjects discontinued due to AE or lack of efficacy, 
missing data will be imputed using MI under the MNAR assumption. For all other 
missing data due to ICE, missing data will not be imputed following the treatment 

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policy strategy, which assumes that ICE did not occur. Methods of handling 
missing data are described in Section 7.2. 
5. Population level summary: The difference in the mean change from baseline in 
the monthly (28-day) rate of migraine days during the last 4 weeks of the 
Treatment Phase between the SPN-538 and placebo groups will be analyzed 
using a MMRM as discussed in Section 7.8.1. 
2.3 
Safety Objective 
To evaluate the safety and tolerability of SPN-538 in children 6 to 11 years old as 
assessed by: 
1. Incidence of AEs. 
2. Clinical laboratory tests (blood chemistry and hematology, urinalysis). 
3. Vital signs, physical and neurological examinations, and electrocardiograms 
(ECGs). 
4. Columbia Suicide Severity Rating Scale (C-SSRS) assessment. 
5. Cognitive Assessment. 
2.5 
Primary Endpoint   
The primary efficacy outcome measure is the change in the monthly (28-day) rate of 
MMDs during the last 4 weeks of the 20-week double-blind Treatment Phase relative to 
the Prospective Baseline Period. 
• 
28-day rate of Migraine Days = (total number of migraine days during the last 4 
weeks of the double-blind treatment phase/total number of days during the last 4 
weeks of the double-blind treatment phase) *28. 
• 
Prospective Baseline = total number of migraine days in the last 28 days prior to 
randomization. 
A migraine day is defined as a calendar day (12:00 am to 11:59 pm) in which the subject 
experiences a migraine attack that starts, ends, or recurs within 24 hours and lasts for 
≥1 hour (if untreated) or ≥30 minutes (if interrupted with rescue medication). Pain 
persisting for more than 1 calendar day (≥24 hours) after initial onset will be considered 
as a new, distinct headache day. MMDs is defined as the number of migraine days 
within 28 days or 4 weeks. 
2.6 
Secondary Endpoints 
The secondary efficacy endpoints are: 
1. Responder, defined as a subject with ≥ 50% reduction in the MMDs during the 
last 4 weeks of the Treatment Phase relative to Prospective Baseline Period.  

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2. Change from baseline in the monthly migraine-specific acute rescue medication 
use in the last 4 weeks of the Treatment Phase. 
3. Change in the monthly rate of total headache days (migraine and non-migraine), 
duration and severity. 
4. Change in the time to onset of action, defined as the time to first statistically 
significant treatment effect observed and maintained until the EOS.  
5. Change from baseline in the Headache Disability Score as measured by 
PedMIDAS during the last 4 weeks of the Treatment Phase.   
6. Change from baseline in the HRQoL as measured by the PedsQL 4.0 Total 
Scale Score during the last 4 weeks of the Treatment Phase for the self-report 
and the parent-report. 
The safety endpoints are: 
1. Incidence of AEs. 
2. Clinical laboratory test results (blood chemistry and hematology, urinalysis).  
3. Vital signs, physical and neurological examinations, and ECGs. 
4. C-SSRS assessment. 
5. Cognitive Assessment. 
3 
INVESTIGATIONAL STUDY PLAN 
3.1 
Overall Study Design and Plan 
This is a multicenter, randomized, double-blind, placebo-controlled, 2-arm, parallel group 
Phase 4 study in children 6 to 11 years of age to evaluate the efficacy and safety of 
SPN-538 for the prevention of migraine. SPN-538 (or matching placebo) will be 
administered as a single oral dose QD, starting at 25 mg/day and increasing every 
2 weeks in 25 mg increments to a target dose of 2 to 3 mg/kg/day or the maximum 
tolerated dose (MTD), whichever is less. The total study duration is a maximum of 
34 weeks, including a Screening Period and a Prospective Baseline Period of up to 
8 weeks; a Treatment Phase of 20 weeks (8 weeks titration followed by 12 weeks of 
maintenance dosing); a Dose Tapering Period of 1 to 3 weeks; and a Safety Follow up 
period of 1 to 3 weeks. Approximately 35 sites in the United States (US) are planned. 
The study schematic is shown in Figure 1 and described below. 
Pre-treatment Phase 
Screening Period (Visit 1, up to 8 weeks before Visit 3)  
At Visit 1, informed consent and informed assent (if applicable) will be obtained. Initial 
screening evaluation includes headache history, medical, family and psychiatric 
histories, ECG and vital sign assessments, physical and neurological examinations, 

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concomitant medications, headache disability, and laboratory tests including 
hematology, chemistry, urinalysis, drug screen, and serum pregnancy test (females of 
childbearing potential [FOCPs] only). Suicidality will be evaluated using the C-SSRS, 
Children’s version. A visual neurological examination will also be required prior to Visit 2 
(Section 6.8.5).   
Subjects treated with the following prophylactic medications should discontinue the 
treatment 14 days prior to the Prospective Baseline Period: antipsychotics, antimanics, 
barbiturates, benzodiazepines amitriptyline, lithium, valproic acid, tricyclic 
antidepressants, AEDs, calcium channel blockers, sedatives, serotonin selective 
reuptake inhibitors (SSRIs), non-selective reuptake inhibitor (NSRIs), calcitonin gene-
related peptide (CGRP) receptor antagonists, cannabidiol (CBD) oil, herbal 
preparations/supplements such as feverfew or St John’s wort and/or any medications 
that could impair or decrease thinking and concentration. It is recommended to taper off 
antipsychotics, barbiturates, benzodiazepine, tricyclic antidepressants, lithium, 
amitriptyline, valproic acid, SSRIs and NSRIs as applicable (Appendix 10.10). 
Note: Subjects must refrain from using these medications throughout the duration of the 
study.  
Non-pharmacologic approaches involving life-style modifications are allowed if initiated 
more than 1 month prior to Screening.  
For subjects who met the eligibility criteria, prophylactic migraine treatments will be 
allowed if on a stable dose for at least 12 weeks prior to the Screening Visit including 
daily nonsteroidal anti-inflammatory drugs (NSAIDs), antiemetics, antihistamines, 
corticosteroids (i.e., systemic inhaled, or topical), high-dose magnesium supplements 
(≥600 mg/day), high-dose riboflavin (≥100 mg/day), coenzyme Q10, omega-3, 
melatonin, muscle relaxants and β-blockers (Appendix 10.9). 
Note: The dose and the medication must remain stable (7 days/week) during the 
duration of the study. 
During Screening, acute rescue medications (e.g., ibuprofen, acetaminophen, ergot 
derivates and triptans) will be allowed for symptomatic relief of headaches (migraine and 
non-migraine) as long as the pattern of use remains stable and does not meet the 
criteria for medication overuse (i.e., > 10 treatment days/month for ergot-containing 
medication or triptans; >15 treatment days/month for simple analgesics/NSAIDs). The 
use of narcotics is not permitted. 
Re-screening is not permitted, however subjects who screen failed due to a PedMIDAS 
Total score > 50 under any prior version of the protocol, may be rescreened if they still 
meet the study eligibility criteria under this version of the protocol (Version 4.0, 
14 Dec 2022). 

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Placebo Training 
During Visit 2, caregivers will be asked to complete a training on the placebo effect. The 
training consists of three parts to be completed using the iPad: Part 1 (10 questions) 
illustrates what is the placebo effect (e.g., ‘What is a placebo?,’ ‘Who knows whether 
your child is getting the study drug or the placebo?’); while Part 2 (6 questions) 
describes the importance of understanding how to use the study application/diary (e.g., 
‘What is the study application used for?’, ‘Who is collecting the data in the study 
application?’) and Part 3 (8 questions) highlights the importance of providing accurate 
information about the study (e.g., ‘What is a pediatric migraine?’, ‘What’s the purpose of 
the trial?’). 
For any incorrect answer during the training, the next page will provide an explanation 
and the correct answer. 
Refresher placebo training will be administered at Visits 4 and 6.  
Prospective Baseline Period (Visit 2, 4 weeks before Visit 3) 
At Visit 2, the subject’s parent or guardian will be asked to maintain a daily electronic 
Headache Diary (completed by the parent with the subject’s assistance) in which they 
will record daily headache-associated symptoms and the duration and severity of all 
headaches. Rescue medication usage during the 28-day Prospective Baseline Period 
will also be recorded in the diary. Vital signs, concomitant medications, clinical laboratory 
tests, urine pregnancy test (FOCP only) and suicidality evaluation using the C-SSRS will 
be obtained at the visit.  
Treatment Phase 
Randomization (Visit 3, Day 1) 
Upon completion of the Prospective Baseline Period, eligibility for randomization will be 
determined based on 1) the number of migraine episodes (must be 3-12 inclusive) 
during the Prospective Baseline Period, and 2) the number of total headache days 
(migraine and non-migraine; no more than 14 headache days) during the Prospective 
Baseline Period as observed and recorded using the Headache Diary. 
All eligible subjects will be randomized in a blinded fashion by the interactive web 
response system (IWRS) in a 1:1 ratio of placebo or SPN-538. Subjects will receive a 
4-week supply of their assigned study medication (SM). Safety evaluations including 
AEs, vital signs and suicidality evaluation (using the C-SSRS), eye examinations, 
concomitant medications, urine pregnancy test (FOCP only), headache disability, 
HRQoL, and cognitive assessments will be obtained at the visit. SM accountability and 
resupply will occur at each subsequent study visit.  

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Maintenance Period (Visits 6 to 8, Weeks 9 to 20)  
Once the target dose or MTD is reached, treatment at that dose will continue for the 
12 weeks of the maintenance period; up to one dose reduction will be allowed for safety 

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and tolerability during this period. Additional dose titration related to body weight 
changes will be reviewed and approved by the Medical Monitor and the Sponsor on a 
case by case basis. The number, severity, and symptoms of all headaches, as well as 
the type and dose of rescue medication and SM compliance will be recorded daily in the 
Headache Diary. During the Maintenance Period, clinic visits will be scheduled every 4 
weeks. During each clinic visit, a 4-week supply of SM will be provided, and SM 
compliance and the Headache Diary will be reviewed. Safety evaluations, including vital 
signs, concomitant medications, cognitive assessment, C-SSRS, clinical laboratory tests 
(only at Visit 8), urine pregnancy test (FOCP only), urine drug screen, physical and 
neurological evaluations will also be performed. 
 
 
 
During Visit 6, the eye exam will be performed, and another refresher placebo training 
will be administered. 
Telephone contacts will occur at the intervening 2-week periods [Days 71, 99 and 127 
(±2 days)] between clinic visits for safety assessment and to provide guidance on dose 
reduction (as needed). 
Post-Treatment Phase 
Tapering Period (Weeks 21 to 23):  
During the following 3 weeks the dose of SM will be gradually reduced until the subject is 
no longer taking the SM, so that by the end of Week 23 the subject is out of SM. Dose 
tapering will also be required for subjects who discontinue early during the titration 
period (Week 3 through Week 8) or maintenance period (Week 9 through Week 20). 
Subjects who discontinue early at an MTD of 25 mg/day will not undergo a dose tapering 
period but will return to the clinic to complete the EOS procedures (all procedures 
scheduled to be performed at Visit 9) within 1 week after discontinuation of SM. 
End of Study (Visit 9): 
All subjects who complete the study (Week 20) will return to the clinic for a final safety 
evaluation at the end of the Tapering Period (Visit 9). During this visit, subjects will 
complete the EOS procedures: clinical laboratory tests, AE assessments, vital signs, 
concomitant medications review, ECG, physical and neurological evaluations, eye exam, 
urine pregnancy test (FOCP only) and urine drug screen, headache disability, HRQoL, 
C-SSRS and cognitive assessments. The remaining SM and the Headache Diary 
device, if applicable, will be collected, and safety follow-up instructions will be provided 
to caregivers.  

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Safety Follow-up Telephone Call (Weeks 24 to 26):  
Safety follow-up over the telephone will take place 1 to 3 weeks after the EOS/early 
termination (ET) visit. During the telephone call, all concomitant medications, cognitive 
assessment and AEs will be evaluated and recorded. Any subject who experiences an 
AE (whether serious or non-serious) or has a clinically significant abnormal laboratory 
test value will be followed by the Investigator for up to 30 days after the EOS/ET visit. 
These subjects will be treated and/or followed up until the symptoms or laboratory 
values return to normal/baseline or acceptable levels, as determined by the Investigator.  
 

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3.2 
Rationale for Study and Study Design 
Preventive treatments are typically considered for patients whose migraine has a 
substantial impact on their lives, or whose headaches occur with sufficient frequency 
and severity to warrant daily medication. According to the general principles of migraine 
management, the goals of preventive treatment should be focused on 1) reducing the 
frequency, severity, and duration of attacks; 2) reducing the progression to chronic daily 
headache and avoiding acute headache medication escalation, and 3) decreasing the 
associated disability and improving the quality of life (Lewis et al., 2004). Study 538P401 
aims to explore if these goals are achieved in pediatric migraine patients 6 to 11 years of 
age who are treated with SPN-538. The objectives of the study will address the changes 
in MMDs resulting from TPM therapy, as well as the effects of prophylactic SPN-538 
treatment on acute rescue medication use, migraine-related disability and HRQoL, and 
the total number of all headaches (migraine and non-migraine). From the clinical 
perspective, a preventive migraine treatment is considered successful if ≥ 50% reduction 
in number of migraine days (as compared to baseline values) is achieved; therefore, the 
responder rate (a responder is a subject with ≥ 50% reduction in MMDs) is also a 
secondary efficacy outcome in this study.  
3.2.1 Study Population  
This study is a part of the Supernus PREA commitment for Trokendi XR (SPN-538), 
which requires that pediatric assessments are conducted for drugs that have been 
approved for use in adults but are also likely to be used in a substantial number of 
pediatric patients. Pediatric studies under PREA typically involve “assessments of safety 
and effectiveness of the drug or the biological product for the claimed indications in all 
relevant pediatric populations” ("Center for Drug Evaluation and Research. How to 
comply with the Pediatric Research Equity Act.," 2005). Trokendi XR is already approved 
for use in adolescents ≥12 years of age, and Supernus was granted a waiver for the 
study of migraine prophylaxis in the age group of birth to less than 6 years of age. The 6 
to 11 years age group is an important population of migraine sufferers with an unmet 
need for an effective and safe medication for migraine prevention. 
3.2.2 Topiramate Dose Selection  
The recommended total daily dose of Trokendi XR for prophylaxis of migraine headache 
in adults and adolescents 12 years of age and older is 100 mg once daily. 
 
and then gradually increased over the course of 8 weeks to the 
target dose of 100 mg/day
 In adults 20 years of 
age and older, the 100 mg/day dose corresponds to approximately 0.8 to 1.8 mg/kg/day, 
depending on body weight (Fryar, Gu, Ogden, & Flegal, 2016).  

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Dosing of TPM in patients from 6 to 10 years of age is typically based on body weight. 
The dosage is usually increased slowly at 1 to 2 week intervals in increments of 1 to 
3 mg/kg until a therapeutic target dose is reached. 
For migraine prophylaxis in the pediatric age group, a dose of 2 to 4 mg/kg/day appears 
to be effective (Kacperski et al., 2016). In most recent randomized, controlled trials in 
children and adolescents 6 to 17 years of age, the target dose of TPM was 2 mg/kg/day 
(Powers et al., 2017) or 2 to 3 mg/kg/day (Winner et al., 2005). Other studies examined 
the effective dose of TPM in pediatric migraine prophylaxis and observed improvement 
in migraine symptoms at doses as low as 0.5 mg/kg/day (Abbaskhanian, Sadeghi, 
Erfani, & Rezai, 2012; Cruz et al., 2009). Daily TPM doses of > 3 mg/kg/day were also 
shown to be effective but were associated with a higher incidence of AEs. Based on this 
information, a flexible treatment dose of SPN-538 in the range of 2 to 3 mg/kg/day was 
selected for this study. The maximum allowed daily dose will not exceed that 
recommended for Trokendi XR in the treatment of adults and adolescents, i.e., 
100 mg/day. This TPM dose is well within the range that is considered safe in long-term 
exposure for pediatric patients (i.e., up to 9 mg/kg/day or 400 mg/day for the treatment of 
epilepsy; ("National Institutes of Health-DailyMed- Trokendi XR- Prescribing 
Information.," 2022).  
The AEs associated with TPM treatment are known to be dose dependent and are often 
transient. As the presence and severity of AEs may lessen with dose reduction, subjects 
will be allowed to reduce their daily TPM dose during the Titration Period until a 
maximum tolerated dose is found within a dosing range of 
. A slower 
titration duration of 8 weeks is being implemented to further mitigate the potential for 
AEs. 
3.2.3 Selection of Assessment Instruments 
The assessment instruments selected for this study have been recommended by the 
National Institute of Neurological Disorders and Stroke (NINDS) as part of the Common 
Data Elements (CDEs) for Headache research, Version 2.0 ("U.S. Department of Health 
and Human Services - Headache,"). 
Headache Diary  
The primary tool for collecting daily information about headaches will be the Headache 
Diary - Preventive Therapies. A similar diary was used in the CHAMP study by Powers 
et al (Powers et al., 2017). The Headache Diary will be presented in an electronic format 
that is uploaded on a dedicated electronic patient reported outcome (ePRO) data 
collection application; a device will be provided as needed. The advantages of collecting 
data through electronic modalities include real-time patient data monitoring, more 
efficient data capture within an electronic database, and improved patient compliance. 
Portable electronic devices also allow sending helpful reminders to complete the diary 

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and to enter the dosing information, which ensures more complete and timely collection 
of study data.  
PedMIDAS and PedsQL 4.0 Questionnaires 
HRQoL is emerging as an important element of clinical research in primary headache 
disorders. Quality of life represents the extent to which a particular illness affects a 
patient’s life functioning and can, therefore, be very useful from a clinical perspective. 
Migraine is recognized as one of the most disabling pediatric conditions, as recurring 
headaches often have a profound impact on a child’s life, affecting academic 
performance and interactions with family and peers, and reducing emotional well-being 
(Powers et al., 2003). Restoring patients’ ability to function, as well as improving quality 
of life, is among the main objectives of migraine therapy. Hence, the International 
Headache Society (IHS) recommends including functionality and HRQoL measures as 
secondary endpoints for migraine clinical trials for the purpose of assessing changes in a 
subject’s ability to function and enjoy life (Tfelt-Hansen et al., 2012). Topcu et al used 
the PedMIDAS to evaluate the effectiveness of prophylactic drugs, including TPM, in 
pediatric migraine studies, and saw significantly decreased disability scores 
demonstrating the usefulness of this questionnaire in evaluating patients’ quality of life 
(Topcu, Hiz Kurul, Bayram, Sozmen, & Yis, 2014). The PedsQL 4.0 was an effective 
measure of quality of life in children with migraine demonstrating that the total score was 
the lowest for children with chronic headache compared to top healthy normal children, 
supporting the evidence that headaches in children and adolescents have a great impact 
similar to that found in chronic illness conditions (Powers et al., 2003). The PedMIDAS 
and PedsQL 4.0 questionnaires are NINDS recommended assessments for evaluating 
Activities of Daily Living/Performance and Quality of Life domains in headache clinical 
trials (Connelly & Rapoff, 2006; Hershey et al., 2001; Powers et al., 2017).  
3.3 
Study Population Selection 
3.3.1 Number of Subjects 
Approximately 276 subjects aged 6 to 11 years (inclusive) will be randomized to achieve 
234 completed subjects.  
3.3.2 Inclusion Criteria  
1. Healthy male or female subjects, 6 to 11 years of age (inclusive) at Screening. 
2. History of migraine with or without aura conforming to the IHS criteria for 
pediatric subjects (International Classification of Headache Disorders, 3rd edition 
[ICHD-3]) for at least 6 months prior to Screening.  
3. Subjects who experience 3-12 migraine episodes and no more than 14 headache 
days (migraine and non-migraine) per month during the 3 months prior to 
Screening and during the 28-day Prospective Baseline Period (based on the 
Headache Diary). 

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4. At Screening, a PedMIDAS Disability score of ≥ 20 (indicating at least mild 
disruption of daily activities) and ≤ 139 (indicating severe disability that may 
require more comprehensive therapy). 
5. Weight of at least 20 kg and no more than 60 kg (inclusive) at the Randomization 
visit (Visit 3). 
6. Considered medically healthy by the Investigator via assessment of physical, 
neurological and eye examinations, medical history, clinical laboratory tests, vital 
signs, and ECGs. 
7. Able and willing to swallow capsules whole and intact without sprinkling on food, 
crushing, chewing, cutting, or dissolving before swallowing.  
8. Caregiver must be able to read and comprehend written instructions and be 
willing to supervise the completion of all headache records and questionnaires by 
the subject as required in the protocol. 
9. Written Informed Consent obtained from the subject’s parent or legal 
representative, and written Informed Assent obtained from the subject if required. 
10. Female subjects must be premenarchal or otherwise incapable of pregnancy, or 
have practiced one of the following methods of contraception for at least 1 month 
prior to study entry: 
a. Simultaneous use of male condom, spermicide and barrier, and 
placement of intrauterine contraceptive device  
b. Surgically sterile male partner 
c. Simultaneous use of male condom and diaphragm with spermicide. 
d. Established hormonal contraceptive, sterility; or 
e. Be practicing abstinence and agree to continue abstinence or to use an 
acceptable method of contraception (as listed above) should sexual 
activity commence during the study. 
3.3.3 Exclusion Criteria 
1. Subjects with chronic migraine (>14 headache days per month), cluster 
headaches, or migraine aura without headache, and who are unable to 
distinguish migraines from other headache types.  
2. Subjects with more than 14 headache days during the 28-day Prospective 
Baseline Period (based on the Headache Diary). 
3. Have taken any disallowed migraine preventive medication including TPM within 
14 days prior to the start of the Prospective Baseline Period; or used 
onabotulinumtoxinA (Botox®) within 3 months prior to entering the Screening 
period. 
4. Previously failed to respond to TPM prophylaxis therapy using an adequate dose 
(2 to 3 mg/kg/day) for an adequate period of time (minimum of 3 months), or 
those who have previously discontinued TPM due to AEs within 6 months prior to 
Screening.  
5. Previously failed more than 2 adequate clinical trials (defined as at least 1 month 
of treatment at a full therapeutic dose) of an established prophylactic 
anti-migraine regimen within 6 months prior to Screening. 
6. Known history of allergic reaction or anaphylaxis to TPM. 

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7. Overuse of analgesic or migraine-specific agents for acute treatment of migraine 
defined as:  
a. >10 treatment days/month of ergot-containing medications or triptans; 
b. >15 treatment days/month with simple analgesics (including NSAIDs) 
c. Use of narcotics 
8. Subjects treated with the following prophylactic medications should discontinue 
the treatment 14 days prior to the Prospective Baseline Period: antipsychotics, 
antimanics, barbiturates, benzodiazepines amitriptyline, lithium, valproic acid, 
tricyclic antidepressants, AEDs, calcium channel blockers, sedatives, SSRIs, 
NSRIs, CGRP receptor antagonists, CBD oil, herbal preparations/supplements 
such as feverfew or St John’s wort and/or any medications that could impair or 
decrease thinking and concentration. It is recommended to taper off 
antipsychotics, barbiturates, benzodiazepine, tricyclic antidepressants, lithium, 
amitriptyline, valproic acid, SSRIs and NSRIs as applicable. 
Note: Subjects must refrain from using these medications throughout the duration 
of the study. 
9. Subjects using non-pharmacologic complementary and alternative prophylactic 
approaches for migraine prevention, such as neuromodulation, acupuncture, 
behavioral interventions, spinal manipulation, occipital nerve block and 
neurofeedback. 
Note: Non-pharmacologic approaches involving lifestyle modifications (e.g., 
trigger factor avoidance, stress reduction techniques, regular exercise, and good 
sleep hygiene) will be allowed as long as they were started at least 1 month prior 
to Screening and are continued throughout the study. 
10. Currently on a ketogenic diet, or on a ketogenic diet within 6 months prior to 
Screening. 
11. Significant major psychiatric disorder (e.g., psychosis, bipolar disorder, major 
depression and generalized anxiety disorders), or documented developmental 
delays or impairments (e.g., autism, cerebral palsy, or mental retardation) that, in 
the opinion of the Investigator, would interfere with adherence to study 
requirements or safe participation in the trial.  
Note: Subjects with an established diagnosis of Attention Deficit Hyperactivity 
Disorder (ADHD), will be allowed if they are taking a stable dose (7 days/week) 
of ADHD stimulant medication (extended or controlled release) for at least 12 
weeks prior to the Screening visit and refrain from changing the dose or the 
ADHD medication during the study duration. 
12. Subjects with seizures or a history of seizure-like events within 6 months prior to 
Screening, or a history of seizure disorder within the immediate family (siblings, 
parents). 
13. Known history of visual field defects regardless of etiology. 
14. Presence of active liver disease (including baseline serum ammonia levels 
>2 times the upper limit of normal).  
15. Abnormal kidney function, subjects undergoing hemodialysis, or subjects with a 
history of nephrolithiasis. 
16. Known neurological disorder or a structural disorder of the brain from birth; head 
trauma or infectious disease resulting in migraine or worsening of migraine 
symptoms; or previous central nervous system (CNS) surgery.  

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17. Known history of uncontrolled asthma, uncontrolled diabetes, arrhythmias or 
congenital heart disease. 
18. Evidence of suicidal ideation and/or suicidal behaviors within 6 months prior to 
Screening or during the Pre-treatment phase.  
19. Pregnancy, breastfeeding, or refusal to practice abstinence or acceptable birth 
control during the study for FOCPs. 
20. Known history of substance-use disorder according to the Diagnostic and 
Statistical Manual of Mental Disorders 5th Edition (DSM-5) or used alcohol or 
illicit drugs in the 3 months prior Screening. 
21. Any other reason that could interfere with the subject’s participation in the study 
as determined by the Investigator. 
 
Note: Abnormal results on screening laboratory tests and/or ECG may be repeated once 
per test at the discretion of the Investigator. 
3.4 
Completion of Study  
Subjects will be considered to have completed the study if they complete all visits up to 
and including Visit 9 (EOS).  
3.4.1 Discontinuation of Subjects 
Subjects who discontinue early will complete the procedures listed for Visit 9 
(Section 5.1.6). 
The Investigator(s) or subjects/caregivers may stop SM treatment at any time for safety 
or personal reasons. The subject’s caregiver is free to withdraw their child from the study 
at any time for any reason without prejudice to their future medical care by the physician 
or at the institution. The Sponsor may also withdraw the subject at any time in the 
interest of subject safety. The withdrawal of a subject from the study should be 
discussed where possible with the Medical Monitor and/or clinical research associate 
(CRA) before the subject discontinues taking SM. Subjects removed from the study for 
any reason will not be replaced. 
Reasons for subject discontinuation may include: 
• 
Withdrawal of consent and assent 
• 
Non-compliance with study procedures 
• 
Lack of efficacy 
• 
Investigator decision 
• 
Occurrence of unmanageable AEs 
• 
Lost to follow-up 
• 
Other (study is terminated by the Sponsor, blind is broken, subject has relocated 
or death etc.) 
 
The primary reason for subject discontinuation must be recorded in the electronic case 
report form (eCRF). If a subject is withdrawn for more than one reason, each reason 

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should be documented and the most medically significant reason should be entered on 
the eCRF. 
If a subject misses any doses of SM during this study, the Investigator shall counsel the 
subject’s caregiver on the importance of adherence. If the subject has consistently 
missed doses, he or she may be discontinued from the study at the discretion of the 
Investigator and in consultation with the Medical Monitor and the Sponsor; all 
procedures for discontinuation will be followed. 
Efforts will be made by the study site staff to discuss with the parents/caregivers the 
meaning of adherence on the completion of the daily diary as at least 70% compliance 
with the migraine diary is requested. 
3.4.2 Early Termination Procedures 
Subjects who are randomized and dosed with the SM, but who withdraw or are 
withdrawn from participation in the study by the Investigator prior to study completion 
(Week 20), will be instructed to return to the study site for an ET visit within 1 week after 
discontinuation of SM. Procedures listed for Visit 9 should be completed at the ET visit. 
Subjects who exit the study early will also be required to gradually discontinue their SM 
over a period of up to 3 weeks by reducing their daily dose by one capsule every week 
until subjects are no longer taking the SM. The subject will return to the clinic for the 
EOS assessments within 1 week after discontinuation of SM. The final safety 
assessment will be conducted via telephone contact 1 to 3 weeks after the ET/EOS visit. 
The reason for ET must be recorded in the eCRF. 
4 
STUDY TREATMENT 
4.1 
Study Medication Identity, Packaging and Labeling 
SPN-538 consists of a three-pellet composite formulation containing one enhanced 
immediate release (IR) pellet type contributing 6% of the label claim, and two extended 
release (XR) pellet types contributing 10% and 84% of the label claim, respectively. The 
drug product contains the same active pharmaceutical ingredient, TPM, as the marketed 
IR product Topamax. 
SPN-538 25-mg capsules will be used for the study. Placebo capsules will be identical in 
appearance to the SPN-538 capsules but contain no TPM. SM (active and matching 
placebo capsules) will be supplied in 100-count bottles. All SM bottles will be labeled by 
the Sponsor in a double-blind configuration and numbered according to the randomized 
assignment.  

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changes will be reviewed and approved by the Medical Monitor and the Sponsor on a 
case-by-case basis.   
Overdosage of TPM has been reported. Signs and symptoms include convulsions, 
drowsiness, speech disturbance, blurred vision, diplopia, impaired mentation, lethargy, 
abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and 
depression. Similar signs and symptoms may occur with overdosage of SPN-538. In the 
event of suspected OD with SPN-538, the caregiver should be instructed to call 911 
and/or the local poison control center at 1-800-222-1222. 
Taking 1 or 2 more pills over the dose is considered a PD. Not every OD is a reportable 
event, only reportable if the overdose (OD) is a serious adverse event (SAE). Gastric 
lavage or induction of emesis is recommended. Activated charcoal might be considered 
since it has been shown to absorb TPM. Hemodialysis is also effective to remove TPM 
from the body. 
4.4 
Method of Assigning Subjects to Treatment Group 
Eligible subjects will be randomized in a 1:1 ratio at Randomization Visit (Visit 3) to 
receive either SPN-538 or placebo. Randomization will be stratified by number of 
migraine days (high vs. low) at baseline to ensure treatment balance in each stratum. 
High monthly migraine stratum will be defined as 6 to 14 migraine days observed during 
the 28-day Prospective Baseline Period; and low monthly migraine stratum will be 
defined as 3 to < 6 migraine days during the 28-day Prospective Baseline Period.  
Treatment A: Placebo 
Treatment B: SPN-538 
Allocation of study treatment will occur centrally via an IWRS using a randomization 
schedule to determine the SM assignment for each subject being randomized.  
4.5 
Blinding 
Study subjects/caregivers and all personnel involved with the conduct and interpretation 
of the study, including the Investigators, study site personnel, the Sponsor and clinical 
staff including the Medical Monitor, will be blinded to the treatment codes. Blinding will 
be maintained by providing capsules for placebo that are identical in appearance to the 
active drug. Neither the Sponsor, subjects, caregivers, Investigators, nor other study 
personnel will be aware of a subject’s treatment assignment. In the event that it 
becomes medically necessary to identify which treatment a subject has received, the 
blind can be broken. The Investigator will follow the trial's randomization procedures and 
should ensure that the code is broken only in accordance with the protocol. The 
Investigator will promptly document and explain to the Sponsor any premature 
unblinding (e.g., accidental unblinding, unblinding due to a SAE) of treatment 
assignment.  

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viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. 
Such information may be used solely for the purpose of reviewing or performing this study. 
Randomization schedule data will be kept strictly confidential, filed securely by the IWRS 
vendor, and accessible only to authorized persons until the time of unblinding. The 
IWRS manager is not required to be blinded, and he or she will have access to the SM 
list and the randomization code. 
 
 
 
 
 
  
4.6 
Study Medication Handling and Accountability 
All SM is supplied to the Investigator by the Sponsor. SM supplies must be kept in an 
appropriate secure area (e.g., locked cabinet) and stored according to the conditions 
specified on the SM label. 
Following Sponsor instructions and in compliance with ICH E6 as well as local, state, 
and federal regulations, the Investigator and study staff will be responsible for the 
accountability of all clinical supplies (receiving, shipment, dispensing, inventory, and 
record keeping). Study sites are also responsible for maintaining a SM accountability 
log, a copy of which will be collected by the Sponsor at the end of the study. 
Under no circumstances will the Investigator allow the SM to be used in a manner other 
than as directed by this protocol. Clinical supplies will not be dispensed to any individual 
who is not enrolled into the study. 
An accurate and timely record of the receipt of all clinical supplies; dispensing of SM to 
the subject/caregiver; collection of unused supplies; and subsequent return of unused 
SM to the Sponsor must be maintained with dates. This SM accountability log includes 
but may not be limited to: (a) documentation of receipt of clinical supplies, (b) SM 
inventory log, (c) SM accountability log, and (d) all shipping service receipts. Forms may 
be provided by the Sponsor. Any comparable forms that the study site wishes to use 
must be approved by the Sponsor. 
The supplies and inventory records must be made available, upon request, for 
inspection by the designated representative of the Sponsor, or a representative of the 
FDA. The assigned CRA will review these documents along with all other study conduct 
documents at specified intervals once SM has been received by the study site. All used, 
partly used, and unused clinical supplies, including empty containers, are to be returned 
to the Sponsor designated sites at the conclusion of the study, unless provision is made 
by the Sponsor for destruction of supplies and containers at the study site. Upon 
completion of SM accountability and reconciliation procedures by study site personnel 
and documentation procedures by Sponsor personnel, SM is to be returned to the 
Sponsor with a copy of the completed SM disposition form. 

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4.7 
Concomitant Medications  
Throughout the duration of the study, rescue migraine treatments such as simple 
analgesics are allowed for symptomatic relief of acute headache episodes as long as 
their use does not exceed 3 times per week (or 15 treatment days/month) and the 
pattern of use remains stable. Use of narcotics is not permitted (Appendix 10.9). 
Stimulant medications (extended or controlled release formulation) for the treatment of 
ADHD will be allowed if initiated and maintained on a stable dose (7 days/week) for at 
least 12 weeks prior to the Screening Visit and continued on the same dose during the 
study duration (Appendix 10.9).  
Prophylactic treatment for migraine is permitted if on a stable dose for at least 12 weeks 
prior to the Screening Visit including: daily NSAIDs, antiemetics, antihistamines, 
corticosteroids (i.e., systemic inhaled, or topical), high-dose magnesium supplements 
(≥600 mg/day), high-dose riboflavin (≥100 mg/day), coenzyme Q10, omega-3, 
melatonin, muscle relaxants and β-blockers. The dose and the medication must be 
maintained during the duration of the study (Appendix 10.9). 
Triptans, ketorolac, and ergotamines must be used with caution and with a frequency 
that does not exceed 10 treatment days/month. Subjects will be asked to be consistent 
in the use of their preferred acute migraine medication and encouraged not to initiate 
new therapies during the course of the trial (Appendix 10.9).  
If a subject exceeds rescue treatment more than 3 times per week, concomitant 
medication use will not be considered a protocol deviation.  
Anti-asthma medication: Albuterol sulfate is the only antiasthma medication allowed as 
needed (PRN) to keep any respiratory conditions under control (Appendix 10.9). 
Treatment for AEs other than minor transient ailments is permitted only in consultation 
with the Medical Monitor or his/her designee with the exception of required treatments 
for acute conditions in the emergency room/hospital and/or office visit as indicated.  
Additional concomitant medications allowed during the study include: nutritional 
supplements (e.g., multivitamins), EMLA® or other numbing cream for venipuncture, 
routine childhood vaccinations, Coronavirus Disease 2019 (COVID-19) vaccine and 
mydriatics (as needed per Principal Investigator discretion) (Winner et al.). 
All concomitant medications will be recorded in the eCRF. Use of rescue medication will 
also be recorded in the daily Headache Diary and in between visits to the clinical site. 
4.8 
Non-pharmacologic Adjunctive Treatments 
The following complementary and alternative prophylactic approaches to migraine are 
prohibited during the participation in this study (and as applicable, should be recorded as 
part of the subject’s retrospective headache history):  

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• 
Acupuncture 
• 
Manual therapies (chiropractic spinal manipulation, occipital nerve block, 
massage therapy, physical therapy) 
• 
Herbal and nutritional supplement therapies for migraine prevention (butterbur, 
feverfew and St. John’s Wort) 
• 
Cognitive-behavioral therapy, biofeedback, hypnosis 
• 
Neuromodulation devices  
 
Certain behavioral approaches (e.g., trigger factor avoidance, adequate hydration, 
migraine prevention diet, stress reduction techniques, regular exercise, and sleep 
hygiene) are allowed as long as they have been practiced for at least 1 month prior to 
Screening and will be continued throughout the study. These will be captured in the 
eCRF. 
Prohibited interventions must be discontinued at least 2 weeks prior to Prospective 
Baseline, and no new non-pharmacologic therapies may be initiated within 1 month prior 
to Screening or during the study.  
4.8.1 Prohibited Medications 
Subjects may not be on any prohibited medication as indicated in the Inclusion/Exclusion 
Criteria. 
Subjects treated with the following prophylactic medications should discontinue the 
treatment 14 days prior to the Prospective Baseline Period: antipsychotics, antimanics, 
barbiturates, benzodiazepines amitriptyline, lithium, valproic acid, tricyclic 
antidepressants, AEDs, calcium channel blockers, sedatives, SSRIs, NSRIs, CGRP 
receptor antagonists, CBD oil, herbal preparations/supplements such as feverfew or St 
John’s wort and/or any medications that could impair or decrease thinking and 
concentration. It is recommended to taper off antipsychotics, barbiturates, 
benzodiazepine, tricyclic antidepressants, lithium, amitriptyline, valproic acid, SSRIs and 
NSRIs as applicable. (Appendix 10.10).  
Note: Subjects must refrain from using these medications throughout the duration of the 
study.  
Non-stimulant ADHD medications (e.g., clonidine, atomoxetine, viloxazine and 
guanfacine) must be discontinued 14 days prior the Prospective Baseline Period 
(Appendix 10.10).  
5 
STUDY METHODS 
5.1 
Study Visits and Procedures 
All subjects who are randomized and take at least one dose of SM will be followed 
according to the protocol regardless of the number of doses of SM taken, unless consent 
for follow-up is withdrawn. The Sponsor or the Sponsor’s designee must be notified of all 

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deviations from protocol visits or procedures, and these procedures, if applicable, will be 
rescheduled or performed at the nearest possible time to the original schedule. 
Subjects/caregivers will be instructed to call study personnel to report any abnormalities 
during the intervals in between study visits and to come to the study site if medical 
evaluation is needed and as the urgency of the situation indicates. For emergency and 
other unscheduled visits to a medical facility other than the study site, medical records 
will be obtained by the Investigator or qualified designee as source data for study 
follow-up. 
Table 2 shows the Schedule of Events and Assessments for the study. Deviations from 
study visit windows will be recorded in the eCRF but will not require separate notification 
to the Sponsor. 
Study visits must be scheduled according to the Schedule of Events relative to the 
Randomization Visit (Visit 3). Visits must not be scheduled relative to the previous visit. 
Bi-weekly telephone contacts will occur between study visits at Days 14, 43, 71, 99, 127, 
and 148 (± 2 days).   
 

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h. Subjects will start the first dose on the same day of Visit 3 at the clinical site, instructions for dose titration will be provided.  
i. Provide instructions for dose tapering at Visit 8. 
j. Any subject who experiences an AE (whether serious or non-serious) or has a clinically significant abnormal laboratory test value will be followed by the Investigator for up to 30 days after the EOS visit.  
These subjects will be treated and/or followed up until the symptoms or value(s) return to normal/baseline or acceptable levels, as determined by the Investigator. 
  
l. Safety Follow Up (by Phone) is not a site visit and falls within a range of 1-3 weeks after Visit 9/ET Visit occurs. 
m. Subjects who discontinue from the study earlier than the EOS visit (visit 9) should undergo all EOS procedures included in visit 9 during the ET visit. 
 
Note: Besides the testing specified during the respective visits in the Table 2 above, repeat testing for clinical laboratory parameters, vital signs, and/or ECG may be permitted, at the discretion of the 
Investigator. However, these repeat testing will require justification from the site and agreement with the Medical Monitor and the Sponsor on a case-by-case basis prior to conducting the tests. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5.1.1 Visit 1 – Screening (Day -56) 
All reasons for screening failure will be recorded. If the subject passes screening but 
fails eligibility at Randomization visit (Visit 3), the reason(s) will also be recorded in the 
eCRF. 
For subjects eligible for study participation, a Prospective Baseline Visit will be 
scheduled allowing for at least a 2-week/14-day washout of any disallowed migraine 
preventative medications the subject was receiving at Screening. 
The following assessments will be conducted at this visit (screening assessments may 
be performed over multiple days):  
• 
Obtain written informed consent/assent 
• 
Obtain demographics 
• 
Collect retrospective headache history, including non-pharmacological 
adjunctive treatments (last 3 months) 
• 
Review inclusion/exclusion criteria 
• 
Collect medical, family and psychiatric histories  
• 
Perform physical examination (excluding genitourinary system) including 
height, weight and neurological examination  
• 
Perform visual neurological exam 
• 
Perform 12-lead ECG 
• 
Record vital signs (pulse rate, blood pressure [BP], temperature, and 
respiration rate [RR]) 
• 
Collect blood samples for hematology and serum chemistry 
• 
Collect serum sample for pregnancy testing (FOCP only) 
• 
Collect urine sample for drug screen and urinalysis 
• 
Administer C-SSRS 
• 
Administer PedMIDAS scale 
• 
Record concomitant medications 
5.1.2 Visit 2 – Prospective Baseline Period (Day -28, Weeks -4 to -1) 
The following assessments will be conducted at this visit:  
• 
Complete caregiver placebo training 
• 
Record vital signs (pulse rate, BP, temperature, and RR) 
• 
Collect blood samples for hematology and serum chemistry 
• 
Collect urine sample for urinalysis and for pregnancy testing (FOCP only) 
• 
Administer C-SSRS 
• 
Review and record concomitant medications 
• 
Provide Headache Diary training to record daily headache activity/symptoms 
and rescue medication usage  

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• 
Download Headache Diary app on caregivers’ phone 
5.1.3 Visit 3 (+2 days) – Randomization (Day 1) 
The following assessments will be conducted at this visit:  
• 
Review inclusion/exclusion criteria 
• 
Record vital signs (pulse rate, BP, temperature, and RR) 
• 
Collect urine sample for pregnancy test (FOCP only) 
• 
Administer C-SSRS 
• 
Review and record concomitant medications 
• 
Review Headache Diary for eligibility  
• 
Administer PedMIDAS, PedsQL 4.0 scales 
• 
Perform cognitive assessment 
• 
Perform eye exam 
• 
Record AEs 
• 
Randomization  
• 
Dispense SM (4-week supply) and provide instructions for dose titration  
5.1.4 Titration Period (Days 1 to 56, Week 1 to end of Week 8) 
Intervening Phone Calls 
At Days 14 (± 2 days) and 43 (± 2 days) there will be telephone calls to subjects to 
assess the tolerability of the SM treatment.   
The following assessments will be made during these telephone contacts:  
• 
Review and record concomitant medications 
• 
Record AEs 
• 
Provide guidance (as needed) on dose reduction 
Visit 4 (Day 29 ± 7 days) 
During Treatment Phase (Visits 4 through 9), sample collection and testing have been 
specified for respective visits by the Sponsor. Besides the testing specified during these 
respective visits, repeat testing for clinical laboratory parameters, vital signs, and/or ECG 
may be permitted, at the discretion of the Investigator. However, these repeat testing will 
require justification from the site and agreement with the Medical Monitor and the 
Sponsor on a case-by-case basis prior to conducting the tests.  
The following assessments will be conducted at this visit:  
• 
Perform physical examination (excluding genitourinary system) including height 
and weight, and neurological examination 

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• 
Record vital signs (pulse rate, BP, temperature, and RR) 
• 
Collect urine sample for pregnancy test (FOCP only) 
• 
Administer C-SSRS 
• 
Review and record concomitant medications 
• 
Review Headache Diary 
• 
Record AEs 
• 
Collect SM and assess adherence; retrain as needed  
• 
Dispense SM (4-week supply) and review medication instructions with subject 
and caregiver 
• 
Placebo training refresher  
5.1.5 Maintenance Period (Days 57 to 140, Week 9 to the end of Week 20) 
Visit 5 (Day 57 ± 7 days) 
The following assessments will be conducted at this visit:  
• 
Perform 12-lead ECG 
• 
Record vital signs (pulse rate, BP, temperature, and RR) 
• 
Collect blood samples for hematology and serum chemistry 
• 
Collect urine sample for urinalysis and for pregnancy test (FOCP only) 
• 
Collect urine sample for drug screen 
• 
Administer C-SSRS 
• 
Review and record concomitant medications 
• 
Review Headache Diary 
• 
Administer PedMIDAS, PedsQL 4.0 scales 
• 
Perform cognitive assessment 
• 
Record AEs 
• 
Collect SM and assess adherence; retrain as needed 
• 
Dispense SM (4-week supply) and review medication instructions with subject 
and caregiver 
Visits 6 (Day 85 ± 7 days) and Visit 7 (Day 113 ± 7 days) 
The following assessments will be conducted at these visits:  
• 
Perform physical examination (excluding genitourinary system) including height 
and weight, and neurological examination  
• 
Record vital signs (pulse rate, BP, temperature, and RR) 
• 
Collect urine sample for pregnancy testing (FOCP only) 
• 
Collect urine sample for drug screen 
• 
Perform eye exam (only at Visit 6)  
• 
Administer C-SSRS 
• 
Perform cognitive assessment 

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• 
Review and record concomitant medications 
• 
Review Headache Diary 
• 
Record AEs 
• 
Collect SM and assess adherence; retrain as needed 
• 
Dispense SM (4-week supply) and review medication instructions with subject 
and caregiver 
• 
Placebo training refresher (only at Visit 6) 
Intervening Phone Calls 
At Days 71 (± 2 days), 99 (± 2 days) and 127 (± 2 days), there will be telephone calls to 
subjects to assess the tolerability of SM treatment.   
The following assessments will be made during these telephone contacts:  
• 
Review and record concomitant medications 
• 
Record AEs 
• 
Provide guidance (as needed) on dose reduction, up to one dose reduction will 
be allowed for safety and tolerability during this period. Additional dose titration 
related to body weight changes will be reviewed and approved by the Medical 
Monitor and the Sponsor on a case by case basis. 
5.1.6 Taper Period (Days 141 to 161, Week 21 to the end of Week 23) 
Intervening Phone Call 
At Day 148 (± 2 days) there will be a telephone call to subjects to assess the tolerability 
of the SM treatment.   
The following assessments will be made during these telephone contacts:  
• 
Review and record concomitant medications 
• 
Record AEs 
• 
Provide guidance (as needed) on dose reduction 
Visit 8 (Day 141 ± 7 days) 
The following assessments will be conducted at this visit:  
• 
Perform physical examination (excluding genitourinary system) including height 
and weight, and neurological examination  
• 
Record vital signs (pulse rate, BP, temperature, and RR) 
• 
Collect blood samples for hematology and serum chemistry 
• 
 
• 
Collect urine sample for urinalysis and for pregnancy testing (FOCP only) 
• 
Collect urine sample for drug screen 
• 
Administer C-SSRS 

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• 
Administer PedMIDAS, PedsQL 4.0 
• 
Perform cognitive assessment 
• 
Review and record concomitant medications 
• 
Review Headache Diary 
• 
Record AEs 
• 
Collect SM and assess adherence 
• 
Dispense 3-week supply of SM and provide instructions for dose tapering 
Visit 9 (Day 162 ± 7 days) – End of Study (EOS) Visit 
The following assessments will be conducted at this visit:  
• 
Perform physical examination (excluding genitourinary system) including height 
and weight, and neurological examination  
• 
Perform 12-lead ECG 
• 
Record vital signs (pulse rate, BP, temperature, and RR) 
• 
Collect blood samples for hematology and serum chemistry 
• 
Collect urine sample for urinalysis and for pregnancy testing (FOCP only) 
• 
Collect urine sample for drug screen 
• 
Perform visual neurological exam 
• 
Perform eye exam  
• 
Administer C-SSRS 
• 
Review and record concomitant medications 
• 
Administer PedMIDAS, PedsQL 4.0 scales 
• 
Perform cognitive assessment 
• 
Record AEs 
• 
Collect SM and assess adherence 
5.1.7 Safety Follow-up Telephone Call (Weeks 24 through 26) 
The following assessments will be made during this telephone contact, at 1 to 3 weeks 
following the EOS/ET visit:  
• 
Review concomitant medications 
• 
Record AEs 
• 
Perform cognitive assessment (Appendix 10.5) 

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6 
STUDY VARIABLES AND ASSESSMENTS 
6.1 
Headache Diary– Preventive Therapies (Version 2.0) 
The Headache Diary (Appendix 10.2) is the primary tool for collecting information about 
migraine headaches and will be used in the format recommended by the NINDS. The 
diary will serve as the primary source for the primary outcome measure of MMDs. The 
diary will be provided to caregivers in an electronic format as an application and 
uploaded on the caregivers’ personal mobile device or on a dedicated locked mobile 
device in case the caregiver does not have a personal device. Reminder alarms will be 
programmed for diary completion and SM administration to ensure regular data entry 
and treatment compliance.  
The caregiver will enter data with the subject’s assistance every day during the 
Prospective Baseline Period and throughout the duration of treatment, regardless of 
whether they experienced a headache.  
Subject’s caregivers will be trained to complete a prospective 28-day headache calendar 
to document if a headache occurred. Based on the diagnostic criteria for migraine 
(ICHD-3), if the subject experienced a migraine headache as documented in the 
calendar, the dairy will be completed to record headache specific and detailed 
information. 
For any given headache day, the responder will include information about the timing of 
the attack (when the headache started and ended and whether or not it recurred within a 
24-hour period), the location and severity of the pain, premonitory and aura symptoms 
(nausea, photophobia and phonophobia), rescue medications (if used, selected from a 
list), the impact of the headache on subject’s daily activities, and treatment adherence 
after randomization. Severity of pain will be measured on a scale of 0 to 10, where 0 = 
No pain and 10 = The worst pain. 
6.2 
Pediatric Migraine Disability Assessment Questionnaire   
The PedMIDAS was developed based on the adult migraine disability assessment and 
measures the effect of migraine headaches on school absence, functioning during 
school, and disruption of home and social/recreational activities. It is the only instrument 
designed and validated to assess migraine disability in pediatric and adolescent patients 
(Hershey et al., 2001), and has been validated for the age range of 4 to 18 years.  
The PedMIDAS (Appendix 10.3) is a publicly available tool that evaluates the impact of 
headaches on school, home, play, and social activities. It is comprised of 6 questions 
related to the impact of headache on school performance such as number of days 
missed in various activities over the past 90 days (Questions 1-3). The fourth question 
concerns the disability at home, while the last two questions relate to social and sport 
activities. The Headache Disability Score is a composite of the values for the 
6 questions, where a total disability score of 0 to 10 = Little to no disability; 

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11 to 30 = Mild disability; 31 to 50 = Moderate disability; and >50 = Severe disability. The 
ratings for two additional prompts for Headache Frequency and Headache Severity are 
not included in the Headache Disability Score but are used for clinical reference. 
The questionnaire is self-administered by the subject and may be completed in 
collaboration with the subject’s parent or caregiver, as long as the answers are 
confirmed by the subject. 
The PedMIDAS will be administered at the Screening Visit, Visit 3, Visit 5, Visit 8 and 
Visit 9. 
6.3 
Pediatric Quality of Life Inventory, Version 4.0  
The PedsQL 4.0 is a generic measure of HRQoL that has been developed for use with 
children 2 to 18 years of age (Varni, Seid, & Rode, 1999). The questionnaire allows a 
comparison of QoL effects across acute and chronic health conditions and with healthy 
children and is available as child self-report and parent-proxy report. The measure has 
been validated in patient populations with cancer, rheumatoid disease, diabetes, and 
orthopedic conditions, as well as in children ages 7 to 12 years with a recurrent 
headache symptom.  
The PedsQL 4.0 (Appendix 10.4) has two forms: a child self-report and a parent-report 
form. The child self-report includes 3 age ranges for young children (5-7 years), children 
(8-12 years), and adolescents (13-18 years). The PedsQL scale consists of 23 items 
(questions) comprising four areas of functioning, including physical (8 items), emotional 
(5 items), social (5 items), and school (5 items). The items are assessed based on the 
recall interval of 1 month and are scored on a 5-point Likert scale of 0 to 4, where 0= 
Never; 1 = Almost never; 2 = Sometimes; 3 = Often; and 4 = Almost always. 
The PedsQL 4.0 will yield a total score, 2 summary scores, (the Physical Health 
Summary Score and the Psychosocial Health Summary Score) and 3 sub-scores 
(Emotional, Social and School Functioning). The Psychosocial Health Summary Score is 
a composite of the scores from the Emotional, Social and School Functioning scales; the 
Physical Health Summary Score is the same as the Physical Functioning scale score. 
To obtain the total score, the items are reverse-scored and linearly transformed (0 = 100, 
1 = 75, 2 = 50, 3 = 25, and 4 = 0) to a scale that ranges from 0 (worst HRQoL) to 100 
(best HRQoL). The Total Scale Score is the sum of all the items in all the scales.  
The parent and child should be completing their respective questionnaires independently 
of each other. 
The PedsQL 4.0 will be administered at Visit 3, Visit 5, Visit 8 and Visit 9. 

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6.5 
Safety Variables and Assessments 
Investigators are responsible for monitoring the safety of subjects who have entered this 
study and for alerting Supernus or its designee to any event that seems unusual, even if 
this event may be considered an unanticipated benefit to the subjects. 
Safety assessments include monitoring, evaluation, and recording of all concomitant 
medications, and the evaluation of AEs, clinical laboratory test results, vital signs, 
12-lead ECGs, suicidality monitoring/C-SSRS results, the performance of physical and 
neurological examinations, and cognitive assessment as detailed in the Schedule of 
Events and Assessments (Table 2). Subjects will also be monitored for visual/ocular 
disturbances, nephrolithiasis, oligohydrosis, hyperthermia, metabolic acidosis (serum 
bicarbonate), hyperammonemia, and hepatic injury.  
6.6 
Adverse Events 
As defined by the ICH Guideline for GCP, an AE is any untoward medical occurrence in 
a patient or clinical investigation subject who was administered a pharmaceutical product 
and which does not necessarily have to have a causal relationship with treatment. 
An AE can be: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
• 
Any new disease, intercurrent injuries, or exacerbation of an existing disease. 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG) that 
results in symptoms, a change in treatment, or discontinuation from SM. 
• 
Recurrence of an intermittent medical condition (e.g., muscle pain) not present at 
baseline. 
 
Surgical procedures are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required is an AE, if it occurs or is 
detected during the study period. 
6.6.1 Causality 
AEs may be categorized as either ADRs or SADRs based on their relationship to SM 
and the degree of certainty about causality. 

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SADRs are a subset of AEs for which there is evidence to suggest a causal relationship 
between the drug and the AE, i.e., there is a reasonable possibility that the drug caused 
the AE. 
ADRs are a subset of all SADRs for which there is reason to conclude that the drug 
caused the event. 
6.6.2 Recording and Evaluation of Adverse Events 
All subjects who provided written Informed Consent (Visit 1) and prior to randomization, 
will be questioned regarding the occurrence of AEs which will be captured as medical 
history. TEAEs are AEs that occur after study treatment has started, or an already 
present event that worsens either in intensity or frequency following the study treatment.  
At each subsequent visit or contact with the subject, after the first administration of SM, 
the investigator must seek information on AEs by specific questioning and, as 
appropriate, by examination. Information on all AEs should be recorded immediately in 
the appropriate AE module of the eCRF. All clearly related signs, symptoms, and 
abnormal results for diagnostic procedures should be recorded in the source document, 
though they may be grouped under one diagnosis. For example, fever, elevated WBC 
count, cough, abnormal chest X-ray, etc., may be reported as a single AE of 
“pneumonia”. The clinical course of each AE will be followed for at least 30 days after 
subject’s early discontinuation/EOS, until resolution (AEs in general) or based on the 
medical judgment of the Investigator, the event has stabilized or is assessed as chronic. 
The Investigator is responsible for evaluating AEs and determining the following: 
• 
Serious vs. Non-serious: Is the event an SAE? 
• 
Causality: Was AE related or not related to the SM? 
• 
Severity: How pronounced is the incapacity/discomfort caused by an AE? 
6.6.3 Criteria for Assessing Severity 
The Investigator will evaluate the comments of the subject and the response to 
treatment in order that he or she may judge the true nature and severity of the AE. 
Severity refers to the accumulated intensity of discomfort/impairment of health since the 
last recording of AEs and will be assessed according to the following criteria: 
• 
Mild: Awareness of sign, symptom, or event, but easily tolerated 
• 
Moderate: Discomfort enough to interfere with usual activity and may 
warrant intervention 
• 
Severe:  Incapacitating with inability to do usual activities or significantly 
affects clinical status and warrants intervention 
 
The criteria for assessing severity are different from those used for seriousness. 

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6.6.4 Criteria for Assessing Causality 
The Investigator is responsible for determining the relationship between the 
administration of SM and the occurrence of an AE as not suspected or as a suspected 
reaction to SM. These are defined as follows: 
Not suspected: The temporal relationship of the AE to SM administration makes a 
causal relationship unlikely, or other drugs, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed event.  
• 
Not related: Temporal relationship to SM administration is missing or 
implausible, or there is an evident other cause. 
• 
Unlikely related: Temporal relationship to SM administration makes a causal 
relationship improbable; and other drugs, chemicals, or underlying disease 
provide plausible explanations. 
 
Suspected: The temporal relationship of the AE to SM administration makes a causal 
relationship possible, and other drugs, therapeutic interventions, or underlying 
conditions do not provide a sufficient explanation for the observed event.  
• 
Possibly related: Temporal relationship to SM administration is plausible, but 
concurrent disease or other drugs or chemicals could also explain event. 
Information on drug withdrawal may be lacking or unclear. This will be reported 
as a SADR. 
• 
Definitely related: Temporal relationship to SM administration is plausible, and 
concurrent disease or other drugs or chemicals cannot explain event. The 
response to withdrawal of the medication (dechallenge) should be clinically 
plausible. The event must be definitive pharmacologically or phenomenologically, 
using a satisfactory rechallenge procedure if necessary. This will be reported as 
an ADR. 
6.6.5 Serious Adverse Events 
AEs are classified as serious or non-serious. An AE or ADR is considered “serious” if, in 
the view of either the investigator or Sponsor, it results in one of the following outcomes:  
• 
death 
• 
life-threatening AE (i.e., the subject was at immediate risk of death from the AE as it 
occurred. This does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death.) 
• 
in-patient hospitalization or prolongation of existing hospitalization 
• 
persistent or significant disability or incapacity or substantial disruption of the ability 
to conduct normal life functions 
• 
a congenital anomaly or birth defect 
• 
an important medical event 
 

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Important medical events are those that may not be immediately life threatening or result 
in death or hospitalization but are clearly of major clinical significance. They may 
jeopardize the subject and may require intervention to prevent one of the other serious 
outcomes noted above. For example, drug overdose or abuse, blood dyscrasias, a 
seizure that did not result in in-patient hospitalization or intensive treatment for allergic 
bronchospasm in an emergency department would typically be considered serious. 
6.6.6 Investigator Responsibilities for Reporting SAEs 
AEs will be followed for at least 30 days after subjects’ early discontinuation/EOS or until 
resolution (AEs in general). SAEs will be followed until resolution or until no 
further/additional information can be obtained regarding the event. 
The Investigator must immediately report to the Sponsor all SAEs, regardless of whether 
the Investigator believes they are drug related.  
All SAEs must be reported to the Drug Safety Contact within 24 hours of first becoming 
aware of the SAE. The Investigator must complete an SAE Form and include a detailed 
description of the SAE, as well as other available information pertinent to the case (e.g., 
hospital records, autopsy reports and other relevant documents as applicable). The 
investigator will keep a copy of this SAE Report form on file at the study site. 
The Investigator or study physician, after thorough consideration of all facts that are 
available, must include an assessment of causality of an AE to SM in the report to the 
Sponsor. 
Follow-up information, or new information available after the initial report, should be 
actively sought and reported to the Sponsor, as it becomes available, using the SAE 
Report Form. 
6.6.7 Other Events Requiring Immediate Reporting 
The Investigator must report a pregnancy that occurs in a subject during a clinical study 
to the Drug Safety Contact within 24 hours of first becoming aware of the event. 
Pregnancy should be reported on a Pregnancy Report Form. The Investigator should 
discuss the case with the Medical Monitor; the Investigator must follow any pregnant 
subject for 3 months after the child is born. Any AEs concerning the pregnancy of the 
subject during pregnancy or the child after birth must be documented and reported to the 
Sponsor. 

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Acute suicidal crisis or clinically significant suicidal behavior or ideation should be 
reported to the Drug Safety Contact within 24 hours of first becoming aware of the event. 
6.6.8 Sponsor Responsibilities for Reporting SAEs 
The Sponsor will inform Investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (i.e., within 
specific timeframes). For this reason, it is imperative that study sites submit SAE 
information to the Sponsor in the manner described above. 
Investigators must comply with the applicable regulatory requirements related to the 
reporting of SAEs to the IRB. Investigators must also submit the safety information 
provided by the Sponsor to the IRB unless the country legal regulation requires that the 
Sponsor should be responsible for the safety reporting to the IRB. 
It is the responsibility of the Sponsor to notify all participating investigators, in a written 
IND safety report, of any SADR that is both serious and unexpected. The Sponsor will 
also notify participating investigators if applicable of any findings that suggest a 
significant risk for human subjects. Such findings will typically lead to safety-related 
changes in the study protocol, Informed Consent, and/or Investigator’s Brochure. 
6.6.9 Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the 
sponsor’s product or program, for which ongoing monitoring and rapid communication by 
the investigator to the sponsor can be appropriate. Such an event might warrant further 
investigation in order to characterize and understand it. Depending on the nature of the 
event, rapid communication by the trial sponsor to other parties (e.g., regulatory 
agencies, IRB, etc.) might also be warranted. 
Several AEs are known to be associated with the long-term use of TPM and can be 
expected with treatment with SPN-538 ("National Institutes of Health-DailyMed- Trokendi 
XR- Prescribing Information.," 2022). Consistent monitoring is required for the following 
AESIs: 
• 
Metabolic acidosis (serum bicarbonate) 
• 
Hyperammonemia 
• 
Oligohydrosis and hyperthermia 
• 
Clinically significant increase in alkaline phosphatase, creatinine, or eosinophils 
(specifically, for patients 6 to 11 years, these were noted to be abnormally 
increased more frequently with TPM than with placebo) 
• 
Clinically significant decrease in total white cell count or neutrophils  
• 
Visual changes: subjects presenting with blurry vision, ocular pain, and visual 
field defects must be discontinued early and closely followed to ensure a prompt 
resolution of ocular AEs.   

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• 
Suicidal behavior and ideation 
• 
Serious skin reactions (TPM should be discontinued at the first sign of rash, 
unless rash is not drug-related) 
• 
Negative effect on growth (weight and height) 
• 
Cognitive and memory function impairments 
• 
Nephrolithiasis 
The Site Investigator must report all AESIs to Supernus drug safety team within 24 hours 
of becoming aware of the information using the SAE/AESI Report form. 
6.7 
Treatment-Emergent Suicidal Ideation 
Prospective assessment of suicidal ideation and suicidal behavior is a mandatory part of 
the safety evaluations for any drugs developed for epilepsy and psychiatric indications 
("Center for Drug Evaluation and Research. Suicidal Ideation and Behavior," 2012). In 
this study, the initial evaluation of subjects will be conducted prior to enrollment to 
assess lifetime suicidal ideation and to identify subjects who must not participate in the 
trial due to pre-existing suicidality risk. The assessment will then be repeated at each 
subsequent study visit (except telephone contacts) to monitor the occurrence of new 
suicidal and self-injurious tendencies. 
6.7.1 Columbia Suicide Severity Rating Scale (C-SSRS) 
Assessment of suicidal ideation and behavior will be conducted using the C-SSRS 
(Appendix 10.6). The C-SSRS is an FDA-recommended prospective assessment 
instrument that directly classifies suicidal ideation and behavior events into 11 preferred 
categories, including 5 levels of suicidal ideation, 5 levels of suicidal behavior, and the 
category of self-injurious behaviors with no suicidal intent.  
The instrument has been validated and used successfully in both children and 
adolescent patients with various psychiatric disorders that do not involve cognitive 
impairment. The C-SSRS outcomes that can be used for clinical management and 
safety monitoring are suicidal lethality rating, suicidal ideation score, and suicidal 
ideation intensity rating. In this study, the Children’s Baseline version (Appendix 10.6.1) 
will be used at Screening, and the Children’s Since Last Visit version (Appendix 10.6.2) 
will be used at each subsequent clinic visit.  
6.7.2 Suicide Risk Management Plan 
The protocol procedures related to clinical care of patients with treatment-emergent 
suicidal ideation and behavior must be implemented to ensure proper management of 
the event and protection of subjects’ safety. If a disclosure of suicidal ideation is 
revealed as part of the C-SSRS questionnaire or when a subject spontaneously 
expresses that he/she may be a threat to him/herself, the study team should be 

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prepared to quickly evaluate the event and to determine the appropriate course of 
action. 
6.7.3 Assessment of Suicide Risk 
Any indication of suicidal ideation should be evaluated as soon as possible by 
appropriately trained staff. The Investigator is responsible for making the final judgment 
regarding potential suicide risk and need for subsequent action.  
6.7.4 Acute Suicidal Crisis 
A person evaluated as being at high risk should be transferred to an immediate care 
facility. The Investigator will guide intervention as clinically indicated and follow up with 
the subject within 1 week and/or refer him/her to a qualified mental health professional. 
6.7.5 Non-acute Suicidal Risk 
The Investigator will conduct safety planning with the subject and will follow up within 
1 week. Reference materials for subjects and caregivers should include lists of mental 
health organizations and professionals, outpatient behavioral services, local crisis, and 
peer support groups and Suicide/Crisis Hotlines. 
6.8 
Clinical Measurements 
6.8.1 Laboratory 
All clinical laboratory tests will be performed by a central laboratory as specified in the 
reference binder. 
Details for collecting, handling, and shipping samples (including shipment addresses) 
will be detailed in a separate clinical laboratory manual. The Schedule of Events and 
Assessments (Table 2) shows the time points at which blood and urine samples will be 
collected for clinical laboratory tests. 
Table 3 presents the clinical laboratory tests to be performed. 
Table 3 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
Red blood cell count, hemoglobin, hematocrit, platelets 
count, and white blood cell count with differential 
Serum Chemistry 
Electrolytes: Na+, K+, phosphate, chloride, bicarbonate 
Liver function tests: alkaline phosphatase, aspartate 
aminotransferase, alanine aminotransferase, total bilirubin, 
direct bilirubin, gamma-glutamyl transpeptidase 
Renal function parameters: blood urea nitrogen, 
creatinine 
Other: glucose, Ca2+, albumin, total protein, ammonia 

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Category 
Parameters 
Urinalysis and urine 
pregnancy test (FOCP 
only) 
Complete urinalysis with microscopic examination, 
human chorionic gonadotropin 
Urine Drug Screen 
Cocaine, amphetamines, barbiturates, benzodiazepines, 
cannabinoids, opioids, phencyclidine, propoxyphene, 
methadone and alcohol 
Serum Pregnancy Test 
(FOCP only) 
Human chorionic gonadotropin 
 
6.8.2 Vital Signs  
Vital signs’ measurements (e.g, BP, pulse rate, temperature, and RR) will be obtained at 
each visit. BP and pulse rate will be measured after the subject has been sitting for 5 
minutes. Route of temperature may be oral or temporal, per clinical practice, but should 
remain consistent throughout the subject’s participation. Vital signs may be taken at any 
other time, as deemed necessary by the Investigator. 
6.8.3 Medical and Psychiatric History 
Medical and psychiatric history will be collected at Screening as per the Schedule of 
Events and Assessments (Table 2). 
6.8.4 Retrospective 3-months Headache History  
Retrospective 3-months headache history will be collected at Screening to record the 
first onset of migraine headache diagnosis, including the duration, frequency and 
location of the experienced migraine. Furthermore, if potential triggers such as food, 
medication, and symptoms associated with the migraine attack are known, these will be 
documented. 
6.8.5 Physical and Neurological Examinations  
The physical examination conducted at Screening will include assessments of all body 
systems other than genitourinary and at visits designated on the Schedule of Events and 
Assessments (Table 2). Measurement of height, and weight will be performed to monitor 
for signs of growth retardation. A special assessment will be made regarding the 
occurrence of decreased sweating and an elevation in body temperature above normal. 
Any findings during screening will be recorded as medical history, and any clinically 
significant abnormal findings during treatment will be recorded as an AE. At the EOS 
physical examination, only changes from baseline (Screening visit) will be noted.  
Routine neurological exam at Screening will be aimed at detecting any possible causes 
of headache other than migraine. After the initiation of treatment, a neurological 
evaluation will help to assess for effects of SPN-538 on the nervous system, such as 

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impaired reflexes, balance problems, muscle weakness, paresthesia/numbness and 
tingling, speech difficulties, mental confusion or excessive fatigue. As part of the visual 
neurological examination, the following will be assessed at Visits 1 and 9: extraocular 
movements, pupils and confrontation visual fields for each eye (Appendix 10.7). 
Equipment necessary for this part of the examination listed in the next section under Eye 
Exam. 
6.8.6 Eye Exam 
An eye examination (does not include intraocular pressure) will be performed at Visits 3, 
6 and 9 (EOS). It will measure visual acuity and visualize the optic disc through a 
fundoscopic exam (Appendix 10.8). Subjects will be monitored for visual/ocular 
disturbances and potential signs of angle closure glaucoma during the participation in 
the study. If signs or symptoms of angle closure glaucoma (see below) develop and are 
observed during the clinical visits or reported at the intervening phone calls, subjects will 
be instructed to stop the SM immediately and be referred to an ophthalmologist or 
optometrist for priority exams (see below) as needed. If the subject goes to the ED, an 
exam by an ophthalmologist (preferred) or optometrist should be performed within 24 
hours of the presentation.   
Equipment at the site necessary to perform the visual neurological and eye exam 
consists of the following:  
• 
Near card 
• 
Wall Snellen Chart (optional, at Investigator’s discretion based on outcome from 
routine eye exam) 
• 
Penlight  
• 
Hand help Ophthalmoscope (direct or Panoptic) 
• 
Amsler grid (optional, at Investigator’s discretion based on outcome from routine 
eye exam) 
The Wall Snellen Chart uses a geometric scale to measure visual acuity, with normal 
vision at a distance being set at 20/20. The numerator represents the distance that the 
patient is standing from the chart (in feet), while the denominator represents the distance 
from which a person with perfect eyesight is still able to read the smallest line that the 
patient can clearly visualize.  
The Amsler grid could be used to help detect early signs of retinal disease and monitor 
changes in vision after diagnosis. 
Note: The Sponsor has appended Snellen chart (Appendix 10.8.1) and Amsler grid 
(Appendix 10.8.2) for every participating site as a tool to be used by the investigator if 
further examination is deemed necessary after a routine eye exam outcome.  

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Symptoms and signs of Angle Closure Glaucoma that might develop within the first 2-3 
weeks of starting the medication, consist of the following: 
• 
Rapid onset of pain that is often severe (typically, both eyes are affected) 
• 
Headache (may be different from usual migraine) 
• 
Nausea and/or vomiting 
• 
Blurred vision, worse at distance and better at near 
• 
Cloudy vision 
• 
Halos around lights 
• 
Conjunctival injection (redness) 
• 
Mid-dilated and fixed or poorly reactive pupils 
If symptomatic, the Sponsor recommends an urgent referral to an ophthalmologist or 
optometrist for priority exams (marked with asterisk):  
• 
Best corrected visual acuity at far distance, usual correction at near distance*  
• 
Pupil exam (Equal? Reaction to light? Afferent pupillary defect?) * 
• 
Eye movements (up, down, horizontal) * 
• 
Slit lamp exam (for corneal edema and narrow angle) * 
• 
Intraocular pressure (applanation, air puff or Tonopen) * 
• 
Anterior segment ocular coherence tomography (OCT) to confirm angle closure* 
• 
Gonioscopy if intraocular pressure is elevated  
• 
Dilated fundus exam (if possible) or B-scan ultrasound (for choroidal effusions) 
6.8.7 Cognitive Assessment 
Cognition refers to the mental processes involved in gaining knowledge and 
comprehension such as thinking, knowing, remembering, judging, and problem solving. 
These higher-level functions of the brain encompass language, imagination, perception, 
and the planning and execution of complex behaviors. Monitoring for 
cognitive/neuropsychiatric effects is recommended as part of standard clinical practice in 
TPM use ("National Institutes of Health-DailyMed- Trokendi XR- Prescribing 
Information.," 2022).  The sponsor created a checklist (Appendix 10.5) of questions 
related to the subject’s daily activities; subjects are asked to rate each question on a 
scale from 0 to 3 where 0 means never and 3 very often based on his/her recollection of 
the past weeks since the last visit. It is recommended to conduct the assessment with 
the parent(s) first. If discrepancies are found between different sources of information, 
the study staff will have to use their best clinical judgement. 
Changes in cognitive function will be assessed at Visit 3, Visits 5 through 9 and at the 
safety follow-up phone call after the EOS. 

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6.8.8 Electrocardiograms (ECGs) 
A 12-lead ECG will be obtained as per the Schedule of Events and Assessments  
(Table 2). Additional ECGs may be performed at other times if deemed necessary by the 
Investigator. 
The ECG will be recorded while the subject is resting in a supine position. The ECG will 
electronically measure the PR, QRS, QT, and QTc intervals, and HR. All ECG tracings 
will be reviewed within 24 hours by the Investigator or qualified Sub-Investigator. PR 
intervals will be determined for each of these ECGs from a single reading. Invalid 
measurements will be repeated. QTc will be reported as QTcF. 

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7 
STATISTICAL METHODS 
7.1 
General Considerations 
All data will be analyzed using SAS® (SAS Institute, Inc., Version 9.3 or later).  
In general, continuous variables will be summarized using standard descriptive statistics 
including number of subjects (n), mean (S), median, interquartile range (Q1, Q3) 
minimum, and maximum. Categorical variables will be summarized with frequencies and 
percentages. 
The data summaries will be accompanied by individual subject data listings, as specified 
in Sections 16.2 and 16.4 of ICH Guidance E3, sorted by unique subject identifier. All 
data available from the electronic CRFs will be listed. Unscheduled measurements will 
be excluded from the descriptive statistics and statistical analysis but will be included in 
listings. 
Categorical variables will be analyzed using categorical statistical methods such as 
Pearson’s Chi-square test or Fisher’s exact test as appropriate.  
Treatment comparison for all efficacy variables will be evaluated based on a two-sided 
significance level of 0.05. 
Unless specified otherwise, baseline is defined as the non-missing value collected most 
recent to and before the time of the very first dose of the SM. 
Complete details of the statistical analysis will be provided in a separate SAP.  
7.2 
Handling of Missing Data 
Missing endpoint values in this study may result from subjects discontinuing from the 
study prematurely or missing intermediate assessments while remaining on study. The 
primary efficacy analysis method will be based on a Mixed Model for Repeated 
Measures (MMRM) which utilizes all available data (complete and partial) from subjects 
included in an analysis set. The MMRM-based approach assumes that missing diary 
data are MAR. MAR refers to a missingness mechanism that is independent of missing 
responses, conditionally on observed response history and covariates. That is, given the 
observed data, the reason for the missing data does not depend on the underlying 
unseen data.   
For primary analysis, missing 28-day MMDs for subjects discontinued due to AE or lack 
of efficacy will be explicitly imputed by the mean values obtained from MI under the 
missing not at random (MNAR) assumption before implementing the MMRM. Missing 
28-day MMDs for subjects discontinued due to reasons other than AE or lack of efficacy 
will not be imputed for the primary efficacy analysis. 
Sensitivity analyses of the primary endpoint to investigate robustness to missing primary 
endpoint data will be performed by assuming that missing diary data are MNAR, 

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meaning that the probability that an observation is missing may depend on its underlying 
unobserved value. Missing data handling for safety data will be described in the SAP. 
7.3 
Analysis Populations 
The Randomized Population consists of all subjects who are randomized via the 
IWRS.  
The Full Analysis Set (FAS) is defined as subjects who received at least one dose of 
study drug and have a baseline and at least one valid post-randomization assessment of 
monthly migraine based on diary days. The FAS will be used to assess the primary 
endpoint and secondary efficacy endpoints, and subjects will be included in analyses 
based on randomized treatment.  
The Per Protocol Set (PPS) includes all subjects in the FAS who have completed Visits 
1-8 with no missing MMDs and no important protocol deviations. PPS will be used as 
supplementary analysis of the primary and secondary efficacy endpoints with treatment 
classification based on the treatment received. 
The Safety Analysis Set includes all subjects randomized into the study who received 
at least 1 dose of SM. Data will be analyzed according to the treatment received. 
7.4 
Demographics and Baseline Analysis 
Demographic/baseline variables including age, sex, ethnicity, race, height, and weight at 
screening, and medical and neurological histories will be summarized using descriptive 
statistics for continuous variables and counts and percentages for categorical variables. 
Descriptive summaries will be presented by treatment group for FAS, PPS, and Safety 
Analysis Set. 
7.5 
Subject Disposition 
A disposition of subjects will include the number and percentage of subjects in each of 
the following categories: 
• 
Subjects in the Randomized Population 
• 
Subjects in the FAS  
• 
Subjects in the PP Analysis Set 
• 
Subjects in the Safety Analysis Set 
Within each of the previous categories, the number and percentage of subjects who 
completed and discontinued from the study and primary reason for early discontinuation 

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will be summarized. The reason for early discontinuation may include any of the 
following: 
• 
Withdrawal of consent and assent 
• 
Lack of efficacy 
• 
Investigator decision 
• 
Noncompliance with study procedures 
• 
Occurrence of unmanageable AEs 
• 
Lost to follow-up 
• 
Other (study is terminated by the Sponsor, blind is broken, subject has relocated 
or death etc.) 
7.6 
Study Medication Exposure and Compliance 
Duration of exposure is defined as the total number of days a subject is exposed to any 
study treatment. This will be calculated for each subject by taking the difference between 
the date of last dose minus the date of the first dose, plus 1 (date of last dose minus 
date of first dose +1). 
Duration of treatment exposure will also be summarized using descriptive statistics. 
Percent of SM Compliance is calculated as % compliance=100*(Num/Den), where 
𝑁𝑢𝑚= ∑#  of capsules dispensed at 𝑣𝑖𝑠𝑖𝑡𝑖−# of capsules returned at  𝑣𝑖𝑠𝑖𝑡 𝑖+1 
7
𝑖=3
 
𝐷𝑒𝑛= ∑𝑥𝑖× (#  of days between 𝑣𝑖𝑠𝑖𝑡𝑖 and 𝑣𝑖𝑠𝑖𝑡𝑖+1)
7
𝑖=3
, 𝑤ℎ𝑒𝑟𝑒 
 𝑥𝑖= # of capsules per day assgined to be administered at 𝑣𝑖𝑠𝑖𝑡𝑖 
For each treatment, SM compliance will be summarized by compliance category (< 80%, 
80-120%, and >120%) and number of subjects in each compliance category. SM 
compliance will also be summarized as a continuous variable using descriptive statistics 
(n, mean, SD, median, minimum, and maximum) for each treatment. 
Summaries of treatment compliance and exposure will be presented separately for the 
Titration Period, Maintenance Period, and combined Titration and Maintenance Periods. 
7.7 
Concomitant Medications 
Prior and concomitant medications will be coded according to the World Health 
Organization Drug Dictionary (WHO DD) and summarized descriptively by ATC 
classification level 4 and preferred term for the Safety Population. Medications used 
within 30 days prior to the start of the study and during the course of the study will be 
listed. Medications with a valid stop date prior to first dose date will be considered prior 

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medications. Incidence (number and percent of subjects reporting the medication at 
least once during the study) will be summarized for all concomitant medications.  
7.8 
Efficacy Analysis 
Based on the FAS, the observed value and change from baseline will be summarized 
using descriptive statistics as described in Section 7.1 and presented for all efficacy 
endpoints by study visit and treatment group. Subject listing of the observed value and 
change from baseline will be listed for all efficacy endpoints. The mean profile of 28-day 
MMDs will be presented by treatment group and study visit. 
7.8.1 Primary Efficacy Analysis 
The primary efficacy endpoint, change from the Prospective Baseline Period in 28-day 
rate MMDs, will be analyzed using MMRM, which assumes that missing data are MAR. 
All post-baseline study visits will be included in the model; however, the primary 
comparison will be between SPN-538 and placebo at Month 5 (last 4 weeks of the 
Maintenance Period). The model will include fixed effect terms for 28-day rate of MMDs 
for the Prospective Baseline Period, treatment group, Prospective Baseline monthly 
migraine-specific acute rescue medication (28-day rate) use, visit, and treatment-by-visit 
interaction as independent variables. The model parameters will be estimated using 
restricted maximum likelihood method with an unstructured variance-covariance matrix 
and Kenward-Roger approximation to estimate denominator degrees of freedom.  
If the MMRM model with the unstructured variance-covariance matrix does not converge 
using the default Newton-Raphson fitting algorithm by PROC MIXED in SAS, then the 
Fisher scoring algorithm or the no-diagonal factor analytic structure will be used (Lu & 
Mehrotra, 2010). If the model still fails to converge, then the first (co)variance structure 
which does not have convergence problem will be used for the analysis from the 
following ordered list:  
 
1. Heterogeneous Toeplitz  
2. Heterogeneous Autoregressive of order 1  
3. Toeplitz  
4. Autoregressive of order 1  
5. Compound Symmetry   
 
The denominator degrees of freedom will be estimated using the BETWITHIN option in 
SAS when any of the covariance structures is used with the sandwich variance 
estimator. 
 
The least square mean (LS Mean) of each treatment group (placebo and SPN-538) 
along with the corresponding standard error, p-values, difference in the LS Mean 
between SPN-538 and placebo (SPN-538 minus placebo), and 95% CIs will be 
computed at each visit. 

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To assess the robustness of the primary analysis under the MAR assumption, two 
sensitivity analyses will be performed based on multiply imputed data assuming missing 
data are MNAR.  The first sensitivity analysis will be based on placebo-based MI in 
which missing values for the subjects in the SPN-538 treatment group would adopt the 
outcome model estimated from the placebo arm. The second sensitivity analysis will be 
performed using a ‘tipping point’ methodology to assess the assumption of MAR in the 
primary analysis. The tipping point analysis will progressively impose increasing shift 
parameters to the imputed observations under the MNAR assumption in the active 
treatment arm, not to the placebo arm, to assess how severe departures from MAR must 
be to overturn the conclusion from the primary analysis. 
The details for both approaches will be provided in the SAP. 
7.8.2 Multiple Comparisons 
The overall type I error rate for the study will be preserved at the two-sided 5% 
significance level by using a sequential (hierarchical) testing for the primary and 
secondary endpoints. The details will be provided in the SAP  
7.8.3 Secondary Efficacy Analyses 
Secondary endpoints will be analyzed based on the FAS using appropriate statistical 
models based on the type of endpoints.  
Analyses of Secondary Endpoints 
1. Monthly Migraine Responders: For each subject, a binary response variable for 
change from baseline in the MMDs during the last 4 weeks of the Treatment 
Phase relative to baseline will be set to 'YES' if a subject’s % reduction is ≥ 50% 
or ‘NO’ otherwise. The proportion of responders will be presented for each 
treatment group. The 2-sided 95% CI around the difference in proportions (SPN-
538 dose minus Placebo) and the p-value from Pearson’s Chi-squared Test or 
Fisher’s Exact Test will be presented. 
2. Migraine-Specific Acute Rescue Medication: The change from Prospective 
Baseline in the 28-day rate of migraine-specific acute rescue medication use in 
the last 4 weeks of the Treatment Phase will be analyzed using the same 
analysis method (MMRM) as for the primary efficacy endpoint. The contrast of 
interest will be at Month 5 for the SPN-538 group compared with placebo. 
3. Total Headache Days, Duration, and Severity: The change from Prospective 
Baseline in the 28-day rate of total headache days, duration of headache days 
(migraine and non-migraine) in the last 4 weeks of the Treatment Phase will be 
analyzed using the same analysis method (MMRM) as for the primary efficacy 
endpoint. The contrast of interest will be at Month 5 for the SPN-538 group 
compared with placebo.  

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The change from Prospective Baseline in the 28-day rate for severity in the last 4 
weeks of the Treatment Phase will be summarized using descriptive statistics by 
severity (mild, moderate, severe, very severe). 
4. Onset of action: The time to first significant treatment effect in the MMDs will be 
based on the MMRM analysis of the primary endpoint. The first month at which a 
statistically significant difference in the change from baseline in 28-day MMDs is 
observed and maintained until the EOS between SPN-538 and placebo will be 
claimed as the first month for the onset of treatment effect. 
5. Headache disability: The change from baseline in the Headache Disability Score 
as measured by PedMIDAS during the last 4 weeks of the Treatment Phase will 
be summarized using descriptive statistics by visit.  
6. HRQoL: The change from baseline in the HRQoL as measured by the 
PedsQL4.0 Total Scale Score during the last 4 weeks of the Treatment Phase for 
the self-report and the parent-report will be summarized using descriptive 
statistics by visit.  
7.9 
Sample Size and Power Considerations 
Based on data from previous studies conducted in adolescents and adults (MIGR-001, 
MIGR-002 and MIGR-003), a common SD of 3 is assumed for both the treatment and 
control groups. Assuming a treatment difference of 1.1, a sample size of 117 subjects 
per arm (a total of 234 subjects) will yield 80% power to detect a non-zero difference 
between the mean change from baseline in the MMDs between the active treatment and 
the placebo groups using a two-sample t-test at a 2-sided significance level of 
alpha=0.05. 
It is assumed that approximately 15% of subjects will drop-out before completing the 
study, hence an adjusted total sample size of 276 subjects (138 subjects per arm) will be 
randomized in a 1:1 ratio to obtain 234 subjects at the completion of the study. 
7.11 Safety Analysis 
Safety analysis as described below will be conducted using the Safety Analysis Set. All 
safety analyses will be performed on the Safety Analysis Set. 
The incidence rate of AEs will be calculated by treatment group for each System Organ 
Class (SOC) and Preferred Term (PT). The severity of the AEs and the relationship to 

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SM will be summarized by treatment group for each SOC and PT. AEs will be 
summarized using discrete summaries at the subject and event level by SOC and PT, 
and by severity and relationship separately for each treatment group. Verbatim 
description and MedDRA SOCs and PTs for all AEs will be contained in the subject data 
listings. 
All AEs occurring after randomization and throughout the study period will be recorded. 
For subjects who receive SM, TEAEs will be collected starting after the first dose of SM 
(Visit 3) to the end of the study. These AEs include those that emerge during treatment 
or worsen in severity during treatment. These AEs will be tabulated, listed and analyzed. 
The incidence of AESIs based on AE data will be summarized for each treatment group 
by MedDRA SOC and PT. Supporting subject listing of AESI will be presented. For 
AESIs, percentages of subjects experiencing visual/ocular disturbances, oligohydrosis, 
hyperthermia, metabolic acidosis (serum bicarbonate), hyperammonemia, 
nephrolithiasis, and hepatic injury will be summarized using descriptive statistics by 
treatment and collection time point. Clinical laboratory values will be summarized by visit 
and treatment group using descriptive statistics. For quantitative laboratory parameters, 
both actual values and change from baseline (values collected at Screening) will be 
summarized. 
Vital signs will be summarized by visit by treatment group using descriptive statistics. 
Both actual values and change from baseline will be summarized. 
ECG results will be summarized by visit by treatment group using descriptive statistics 
(for quantitative ECG parameters) and frequency tables (for qualitative ECG parameters, 
including the overall ECG finding). 
C-SSRS outcomes will be summarized using number and percent of subjects by 
categories for suicidal ideation only, suicidal behavior only and suicidality (ideation and 
behavior combined). The summary will be presented by treatment groups. 
For physical, neurological, and eye examinations, change in status from baseline to the 
EOS will be summarized by body system for each treatment group.  
Cognitive function will be assessed by evaluating the responses from subject responses to 
the cognitive questionnaire. Responses to the questions will be presented in subject listing 
and summarized by study visit and treatment group.    

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8 
DOCUMENTATION 
8.1 
Adherence to the Protocol 
The Investigator agrees, when signing the protocol, to adhere to the instructions and 
procedures described within and to the principles of ICH GCP as well as all governing 
local regulations and principles for medical research. 
The protocol, ICF/IAF, and appropriate related documents must be reviewed and 
approved by an IRB constituted and functioning in accordance with ICH E6 and any local 
regulations. Documentation of IRB compliance with the ICH and any local regulations 
regarding constitution and review conduct will be provided to the Sponsor. 
A signed letter of study approval from the IRB must be sent to the Investigator with a 
copy to the Sponsor prior to study start and the release of SM to the site by the Sponsor 
or its designee. If the IRB decides to suspend or terminate the study, the Investigator will 
immediately send the notice of study suspension or termination by the IRB to the 
Sponsor. 
8.2 
Changes to the Protocol 
Changes to the protocol will not be made without written approval from the Sponsor. 
Any change to the protocol requires a written protocol amendment or administrative 
change that must be approved by the Sponsor before implementation. Amendments 
specifically affecting the safety of subjects, the scope of the investigation, or the 
scientific quality of the study require additional approval by the applicable IRB, and in 
some cases, filings to the regulatory authority. These requirements should in no way 
prevent any immediate action from being taken by the Investigator, or by the Sponsor, in 
the interest of preserving the safety of all subjects included in the study. If an immediate 
change to the protocol is felt by the Investigator to be necessary for safety reasons, the 
Medical Monitor and IRB must be notified promptly. 
Changes to the protocol that are administrative in nature do not require formal protocol 
amendments or IRB approval, but the IRB must be kept informed of such changes. In 
these cases, the Sponsor will send a letter to the IRB detailing such changes. 
8.3 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines. Site visit 
audits may be made periodically by the Sponsor’s Quality Assurance team or qualified 
designee, which is an independent function from the study conduct team. 
8.3.1 Data Collection 
The primary source document will be the subject’s medical record. If separate research 
records are maintained by the Investigator(s), both the medical record and the research 

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record will be considered the source documents for the purposes of monitoring and 
auditing the study. 
Electronic data collection techniques will be used to collect data directly from the study 
sites using eCRFs. The electronic data will be stored centrally in a fully validated clinical 
database. 
Data recorded on source documents will be transcribed into the eCRFs in accordance 
with the eCRF Completion Instructions that are provided to the study sites. The 
Investigator is responsible for ensuring that all sections of each eCRF are completed 
correctly, and that entries can be verified against source documents. The eCRFs will be 
monitored for completeness and accuracy against the source documents by the CRA(s) 
on a regular basis. Inconsistencies between the eCRFs and source documents will be 
resolved in accordance with the principles of GCP. 
8.3.2 Clinical Data Management 
Data from eCRFs and other external data (e.g., laboratory data) will be entered into or 
merged with a clinical database as specified in the data management plan. Quality 
control and data validation procedures will be applied to ensure the validity and accuracy 
of the clinical database.  
8.3.3 Database Quality Assurance 
In accordance with the vendor’s procedures, the clinical database will be reviewed and 
checked for omissions, apparent errors, and values requiring further clarification using 
computerized and manual procedures. The procedure for handling missing data will be 
addressed in the SAP. Data queries requiring clarification will be documented and 
returned to the study site for resolution. Only authorized personnel will make corrections 
to the clinical database, and all corrections will be documented in an audit trail.  
8.3.4 Bioanalytical Sample Handling 
Topiramate (TPM) concentrations in plasma samples will be determined using a 
validated chromatographic method. Details on the analytical methodology, the method of 
validation, and the analytical within-study quality control procedures will be included in 
the clinical study report for this study.  
8.4 
Retention of Records 
The Investigator has the responsibility to retain all study “essential documents”, as 
described in ICH E6 for at least 2 years after approval of a marketing application or after 
formal discontinuation of the clinical program. Essential documents include but are not 
limited to the protocol, eCRFs, source documents, laboratory test results, SM inventory 
records, Investigator's Brochure, regulatory agency registration documents (e.g., FDA 
form 1572, ICFs, and IRB correspondence). The Investigator must obtain written 
permission from Supernus prior to the destruction of any study document.  

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8.5 
Auditing Procedures 
In addition to the routine monitoring procedures, the Sponsor’s Corporate Quality 
Assurance department or qualified designee may conduct audits of clinical research 
activities in accordance with the Sponsor’s written SOPs to evaluate compliance with the 
principles of ICH GCP and all applicable local regulations. A government regulatory 
authority may also wish to conduct an inspection (during the study or after its 
completion). If an inspection is requested by a regulatory authority, the Investigator must 
inform the Sponsor immediately that this request has been made. 
These records must be made available at reasonable times for inspection and 
duplication, if required, by a properly authorized representative of the US FDA in 
accordance with the US 21 CFR 312.68 or other national or foreign regulatory authorities 
in accordance with regulatory requirements. 
8.6 
Publication of Results 
Any presentation or publication of data collected as a direct or indirect result of this trial 
will be considered as a joint publication by the Investigator(s) and the appropriate 
personnel at the Sponsor’s site. Authorship will be determined by mutual agreement. All 
manuscripts, abstracts or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the Sponsor, prior to submission for 
publication or presentation. No publication or presentation with respect to the study shall 
be made until Sponsor comments on the proposed publication or presentation have 
been addressed to the Sponsor’s satisfaction. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be outlined in the 
agreement between each Investigator and the Sponsor or designee. 
8.7 
Financing and Insurance 
Financing and Insurance information will be set forth in a separate document between 
the Investigator and Sponsor (provided by the Sponsor or designee). 
8.8 
Disclosure and Confidentiality 
The contents of this protocol, any amendments, and results obtained during the course 
of this study will be kept confidential by the Investigator, the Investigator’s staff, and the 
IRB and will not be disclosed in whole or in part to others or used for any purpose other 
than reviewing or performing the study without the written consent of the Sponsor. No 
data collected as part of this study will appear in any written work, including publications, 
without the written consent of Sponsor. 
All persons assisting in the performance of this study must be bound by the obligations 
of confidentiality and non-use set forth in the Confidentiality Agreement between the 
Investigator and Sponsor. 

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8.9 
Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for medical or administrative 
reasons at any time. The Investigator will be reimbursed for reasonable expenses 
covering subjects, use of live-in facilities, laboratory tests, and other professional fees. 
The Investigator will refund the excess of payments made in advance. 
The Investigator reserves the right to discontinue the study as per his/her judgment. The 
Investigator will notify the IRB in case of study discontinuation. Study records must be 
retained as noted above. 
9 
ETHICS 
9.1 
Institutional Review Boards 
The IRB that approved this study and the approval letters will be included in the clinical 
study report for this protocol. 
The protocol, any protocol amendments, and the ICF/IAF will be reviewed and approved 
by the appropriate IRB before subjects are enrolled. The Investigators or Sponsor will 
submit, depending on local regulations, periodic reports and inform the IRB of any 
reportable AEs per ICH guidelines and local IRB standards of practice.  
9.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with SOPs from both the Sponsor. These 
SOPs are designed to ensure adherence to GCP guidelines as required by: 
• 
Declaration of Helsinki, 1964 (“Recommendations Guiding Physicians in 
Biomedical Research Involving Human Patients”), and all its accepted 
amendments to date concerning medical research in humans. 
• 
ICH Guideline for GCP (Committee for Proprietary Medicinal 
Products/ICH/135/95) of the European Agency for the Evaluation of Medicinal 
Products, Committee for Proprietary Medicinal Products, ICH of Pharmaceuticals 
for Human Use. 
• 
United States (US) CFR dealing with clinical studies (21 CFR, including parts 50 
and 56 concerning Patient Informed Consent/Assent and IRB regulations). 
• 
Local, national legal guidelines. 
9.3 
Investigators and Study Personnel 
This study will be conducted by qualified Investigators under the sponsorship of 
Supernus Pharmaceuticals, Inc. (Sponsor). 
Contact persons at the Sponsor and the qualified personnel from the site or designee 
are listed in the reference binder provided to each investigational site. The study will be 
monitored by qualified personnel from the Sponsor or their designees. Medical writing, 
data management, and statistical analyses will be performed by the qualified personnel 

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or designee. Laboratory tests will be conducted by a central laboratory as designated in 
the reference binder.  
The study will be monitored by qualified personnel from Supernus or designee for data 
management and biostatistics groups.  
9.4 
Subject Information and Consent 
The Investigator (or designee) will inform the caregiver and subject of all aspects 
pertaining to the subject’s participation in the study and will provide oral and written 
information describing the nature and duration of the study, the procedures involved, the 
expected duration, the potential risks and benefits involved, and any potential 
discomfort. 
The process for obtaining informed consent/assent will be in accordance with all 
applicable regulatory requirements. The Investigator (or designee) and subject/caregiver 
must sign and date the ICF/IAF before the subject can participate in the study. The 
caregiver/subject will be given a copy of the signed and dated ICF/IAF and the original 
will be retained in the investigational site study records. 
The decision regarding subject participation in the study is entirely voluntary. The 
Investigator (or designee) must emphasize to the subject/caregiver that consent, 
regarding study participation, may be withdrawn at any time without penalty or loss of 
benefits to which the subject is otherwise entitled. 
If the ICF/IAF is amended during the study, the Investigator must follow all applicable 
regulatory requirements pertaining to approval of the amended ICF/IAF by the IRB and 
use the amended ICF (including ongoing subjects). 
 

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10 APPENDICES 
10.1 Study Definitions and ICHD-3 Diagnostic Criteria 
Study Definitions 
ICHD-3 outlines special features that are characteristic of migraine headaches in 
children and adolescents (aged under 18 years), including the following: 
• 
In children and adolescents, migraine attacks may last 2-72 hours. 
• 
In children and adolescents, migraine headache is often bilateral; unilateral pain 
usually emerges in late adolescence or early adult life.  
• 
In children and adolescents, aura may be represented by less typical bilateral 
visual symptoms. 
• 
In children, migraine headache is usually frontotemporal. Occipital headache is 
rare and calls for diagnostic caution.  
• 
In young children, photophobia and phonophobia may be inferred from their 
behavior.  
Migraine episode is defined as the occurrence of any migraine that starts, ends or 
recurs within a 24-hour period. Migraine episodes that persist or recur within a 24-hour 
period are considered the same episode. 
Monthly migraine is measured by the number of migraine days within 28 days. A 
migraine day is defined as a calendar day (12:00 am to 11:59 pm) in which the subject 
experiences a migraine attack that starts, ends or recurs within 24 hours and lasts for ≥ 
1 hour (if untreated) or ≥ 30 minutes (if interrupted with rescue medication). Pain 
persisting for more than 1 calendar day (≥ 24 hours) after initial onset will be considered 
as a new, distinct headache day. 
Headache Day is any calendar day in which the subject experiences one of the 
following: a qualified migraine headache, a non-migraine headache that lasts 
continuously for more than 30 minutes, or a headache of any duration for which acute 
medication was used. 
ICHD-3 Diagnostic Criteria 
Per the IHS Criteria for Classification of Migraines in Children and Adolescents (aged 
less than 18 years) (https://www.ichd-3.org/; Headache Classification Committee of the 
International Headache (IHS), Cephalalgia, 2018, 38 (1): 1-211). 
Migraine Without Aura 
Previously used terms:  
Common migraine; hemicrania simplex. 

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Description: 
Recurrent headache disorder manifesting in attacks lasting 4-72 hours. Typical 
characteristics of the headache are unilateral location, pulsating quality, moderate or 
severe intensity, aggravation by routine physical activity and association with nausea 
and/or photophobia and phonophobia. 
Diagnostic criteria: 
A. At least five attacks Note #1 fulfilling criteria B-D 
B. Headache attacks lasting 4-72 h (untreated or unsuccessfully treated) Notes #2; #3 
C. Headache has at least two of the following four characteristics: 
• 
unilateral location 
• 
pulsating quality 
• 
moderate or severe pain intensity 
• 
aggravation by or causing avoidance of routine physical activity (e.g., 
walking or climbing stairs) 
D. During headache at least one of the following: 
• 
nausea and/or vomiting 
• 
photophobia and phonophobia 
E. Not better accounted for by another ICHD-3 diagnosis. 
Notes: 
1. One or a few migraine attacks may be difficult to distinguish from symptomatic 
migraine-like attacks. Furthermore, the nature of a single or a few attacks may be 
difficult to understand. Therefore, at least five attacks are required. Individuals 
who otherwise meet criteria for 1.1 Migraine without aura but have had fewer 
than five attacks should be coded 1.5.1 Probable migraine without aura. 
2. When the patient falls asleep during migraine and wakes up without it, duration of 
the attack is reckoned until the time of awakening. 
3. In children and adolescents (aged under 18 years), attacks may last 2-72 hours 
(the evidence for untreated durations of less than two hours in children has not 
been substantiated). 
Migraine With Aura 
Previously used terms:  
Classic or classical migraine; ophthalmic, hemiparaesthetic, hemiplegic or aphasic 
migraine; migraine accompagnée; complicated migraine. 

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Description: 
Recurrent attacks, lasting minutes, of unilateral fully reversible visual, sensory or other 
CNS symptoms that usually develop gradually and are usually followed by headache 
and associated migraine symptoms. 
Diagnostic criteria: 
A. At least two attacks fulfilling criteria B and C 
B. One or more of the following fully reversible aura symptoms: 
• 
visual 
• 
sensory 
• 
speech and/or language 
• 
motor 
• 
brainstem 
• 
retinal 
C. At least three of the following six characteristics: 
• 
at least one aura symptom spreads gradually over ≥5 minutes 
• 
two or more aura symptoms occur in succession 
• 
each individual aura symptom lasts 5-60 minutes Note #1 
• 
at least one aura symptom is unilateral Note #2 
• 
at least one aura symptom is positive Note #3 
• 
the aura is accompanied, or followed within 60 minutes, by headache 
D. Not better accounted for by another ICHD-3 diagnosis. 
Notes: 
1. When for example three symptoms occur during an aura, the acceptable maximal 
duration is 3×60 minutes. Motor symptoms may last up to 72 hours. 
2. Aphasia is always regarded as a unilateral symptom; dysarthria may or may not 
be. 
3. Scintillations and pins and needles are positive symptoms of aura. 
 
 
 
 
 
 
 
 

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10.2 Headache Diary – Preventive Therapies (Version 2.0) 
 

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10.3 Pediatric Migraine Disability Assessment Questionnaire (PedMIDAS) 
 
 

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10.4 Pediatric Quality of Life Inventory, Version 4.0 (PedsQL, 4.0) 
 
 

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10.6 Columbia-Suicide Severity Rating Scale 
10.6.1 C-SSRS - Children’s Baseline 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Children’s Baseline 
Version 6/23/10 
 
 Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc. 

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10.6.2 C-SSRS - Children’s Since Last Visit 
 

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10.8.1 Wall Snellen Chart 
 
 

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10.8.2 Amsler Grid Test 
 

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10.11 Summary of Changes 
 
Protocol Number, Version, and Date: 
Protocol 538P401, Version 4.0, dated 14 Dec 2022 
Protocol Title:  
A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Parallel Group Study to 
Evaluate the Efficacy and Safety of SPN-538 as a Therapy for the Prevention of 
Migraine in Subjects Ages 6-11 Years 
 
Version 
Version Number 
Version Date 
Amended Protocol 
4.0 
14 Dec 2022 
Old Protocol  
(prior to amendment) 
3.0 
29 Jun 2021 
 
Section and page numbers are references to the amended protocol. 
Administrative changes: Minor changes involving grammar, wordsmithing, 
punctuation, spelling, formatting, correction of typographical errors, and other editorial 
changes for further clarification and/or consistency have been made throughout the 
document. This includes changes to document version number and date, all that is 
related to abbreviations/spelling out of abbreviations in the list of abbreviations as well 
as synopsis and main text, all that is related to references and citations, all things related 
to cross reference and hyperlinks, and personnel changes (Sponsor, Investigator, and/or 
Vendors/Consultants). Movement of intact sections (e.g., an appendix to main text or 
renumbering of appendices) are also considered administrative. All these changes 
except formatting changes are identified in the track-changes version of the amendment. 
 

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Section 
Page 
Description of Change 
Rationale for Change 
Synopsis 
2.2 
5 
25 
Secondary (Objectives) 
1. Responder rate, with a responder defined as a subject with at least a 50% 
reduction in the average of monthly migraine days (MMDs). 
4. Onset of action, defined as the time to month of the Treatment Phase in which 
first statistically significant difference is treatment effect observed between SPN
538 and placebo in the primary endpoint maintained until the end of study (EOS). 
Major change for clarification 
Synopsis 
2.2 
5-6 
25-26 
Primary Estimand (new section) 
According to the ICH E9 Addendum, the attributes of the primary estimand 
(target of estimation) are provided below. 
1. 
Treatment: To compare the treatment effect of SPN-538 vs Placebo. 
2. 
Population: The population targeted for the scientific question is 
defined via the inclusion and exclusion criteria in children 6 to 11 years old 
(inclusive) with a history of migraine.  
3. 
Variable: The primary efficacy endpoint is the change from baseline in 
the monthly (28-day) rate of migraine days during the last 4 weeks of the 20-
week double-blind Treatment Phase relative to the Prospective Baseline Period 
based on the Full Analysis Set (FAS).  
4. 
Intercurrent Events: For subjects discontinued due to adverse event (AE) 
or lack of efficacy, missing data will be imputed using multiple imputation (MI) 
under the missing not at random (MNAR) assumption. For all other missing data 
due to intercurrent event (ICE), missing data will not be imputed following the 
treatment policy strategy, which assumes that ICE did not occur.  
5. 
Population level summary: The difference in the mean change from 
baseline in the monthly (28-day) rate of migraine days during the last 4 weeks of 
the Treatment Phase between the SPN-538 and placebo groups will be analyzed 
using a Mixed Model for Repeated Measures (MMRM). 
Changed to align with statistical 
analysis plan (SAP) per FDA request  
Synopsis 
2.3 
6 
26 
Safety (Objectives) 
4. 
C-SSRS assessment. 
5. 
Cognitive assessment. 
Minor change for clarification 
Synopsis 
2.4 
6 
26 
 
 
 
. 
Minor change for clarification 

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Section 
Page 
Description of Change 
Rationale for Change 
Synopsis 
 
7 
 
Treatment Schedule 
Throughout the duration of the study, rescue medications will be allowed for 
symptomatic relief of headaches (migraine and non-migraine) if the pattern of use 
remains stable and does not meet the criteria for medication overuse. (i.e., > 10 
treatment days/month for ergot-containing medication or triptans; >15 
treatment days/month for simple analgesics/nonsteroidal anti-inflammatory 
drugs (NSAIDs). Simple analgesics (e.g., ibuprofen, acetaminophen) are allowed, 
but use of narcotics is not permitted (Section 4.7).   
Clarified the definition of overdose 
Synopsis 
 
7 
 
Screening/Wash Out Period (Visit 1, up to 8 weeks before Visit 3)  
Prospective subjects who meet initial eligibility criteria will be instructed to 
discontinue any preventive medications for a 14 day wash out period before 
returning to the clinic for Visit 2. 
Prophylactic migraine treatments including daily NSAIDs, antihistamines, 
corticosteroids, antiemetics, high-dose magnesium supplements (≥600 mg/day), 
high-dose riboflavin (≥100 mg/day), coenzyme Q10, omega-3, melatonin, muscle 
relaxants, and β-blockers will be allowed if on a stable dose for at least 12 weeks 
prior to the Screening visit.  The dose must remain stable (7 days/week) 
throughout the duration of the study (Appendix 10.9). 
Prospective subjects who meet eligibility criteria at Visit 1 will be instructed to 
discontinue the following preventive medications 14 days prior to Visit 2 (see 
Exclusion Criterion #8): antipsychotics, antimanics, barbiturates, 
benzodiazepines, sedatives, serotonin selective reuptake inhibitors (SSRIs), non-
selective reuptake inhibitor (NSRIs), amitriptyline, tricyclic antidepressants, 
lithium, valproic acid, AEDs, calcium channel blockers, cannabidiol (CBD) oil, 
calcitonin gene-related peptide (CGRP) receptor antagonists, herbal 
preparations/supplements such as feverfew or St John’s Wort and/or any 
medications that could impair or decrease thinking and concentration. It is 
recommended to taper off antipsychotics, barbiturates, benzodiazepine, tricyclic 
antidepressants, lithium, amitriptyline, valproic acid, SSRIs and NSRIs as 
applicable (Appendix 10.10). 
Re-screening is not permitted, however subjects who screen failed due to a 
PedMIDAS Total score > 50 under any prior version of the protocol, may be 
rescreened if they still meet the study eligibility criteria under this version of the 
protocol (Version 4.0, 14 Dec 2022). 
Major change to facilitate study 
conduct 

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Section 
Page 
Description of Change 
Rationale for Change 
Synopsis 
3.1 
8 
30-31 
Maintenance Period (Visits 6 to 8, Weeks 9 through 20)  
Once the target dose or MTD is reached, treatment at that dose will continue for 
the 12 weeks of the maintenance period; up to one dose reduction will be allowed 
for safety and tolerability during this period. Additional dose titration related to 
body weight changes will be reviewed and approved by the Medical Monitor and 
the Sponsor on a case by case basis. The Headache Diary will be completed daily 
during this period. Clinic visits will be scheduled every 4 weeks for safety, 
headache disability, and HRQoL assessments (Section 5.1.5). 
 
 
 
 
Minor change per site clarification 
Synopsis 
2.5 
10 
26 
The primary efficacy outcome measure is the mean change in the monthly (28-day) 
rate of MMDs during the last 4 weeks of the 20-week double-blind Treatment 
Phase relative to the Prospective Baseline Period based on the Full Analysis Set 
(FAS). 
Minor change for clarification 
Synopsis 
2.6 
10 
26-27 
Secondary Endpoints  
2. Percentage of responders Responder, defined as a subject with a ≥ 50% 
reduction in the average of monthly MMDs during the last 4 weeks of the 
Treatment Phase relative to baseline Prospective Baseline Period.  
7. Change from baseline in the mean of monthly migraine-specific acute 
rescue medication use in the last 4 weeks of the Treatment Phase.  
8. Change in the monthly rate of total headache days (migraine and non-
migraine), duration and severity. 
9. The first monthChange in the time to onset of treatment including the 
last 4 weeks of action, defined as the Treatment Phase in which a time to 
first statistically significant treatment difference in the change from 
baseline in monthly migraine days is observed between SPN 538 and 
placebo maintained until the EOS.  
Major change for clarification 
Synopsis 
2.6 
10 
27 
Safety Endpoints: 
4. 
C-SSRS assessment. 
5. 
Cognitive assessment. 
 
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Section 
Page 
Description of Change 
Rationale for Change 
Synopsis 
3.3.2 
13 
37 
Inclusion Criteria 
4. 
At Screening, a PedMIDAS Disability score of >10 ≥20 (indicating at least 
mild disruption of daily activities) and ≤ 50139 (where a score greater than 50 
indicates indicating severe disability that may require more comprehensive 
therapy). 
5. 
Weight of at least 20 kg and no more than 60 kg (inclusive) at the 
Screening and Baseline visits Randomization visit (Visit 3). 
Major change to facilitate study 
conduct 
Synopsis 
3.3.3 
13-15 
37-39 
Exclusion Criteria 
3. 
Have taken any disallowed migraine preventive medication including TPM 
within 14 days prior to the start of the Prospective Baseline Period; or used 
onabotulinumtoxin A (Botox®) within 3 months prior to entering the Screening 
period. 
8. 
Inability to washout of current Subjects treated with the following 
prophylactic medications should discontinue the treatment 14 days before 
prospective baseline including prior to the Prospective Baseline Period: 
antipsychotics, antimanics, barbiturates, benzodiazepines,  muscle relaxants, β
blockers, amitriptyline, lithium, valproic acid, tricyclic antidepressants, AEDs, 
calcium channel blockers, corticosteroids (i.e., systemic, inhaled or topical), daily 
NSAIDs, sedatives, SSRIs, NSRIs, high dose magnesium supplements (≥600 
mg/day), high dose riboflavin (≥100 mg/day), CGRP receptor antagonists,  omega
3, melatonin, CBD oil, herbal preparations/supplements such as feverfew or St 
John’s wort and/or any medications that could impair or decrease thinking and 
concentration. It is recommended to taper off antipsychotics, barbiturates, 
benzodiazepine, tricyclic antidepressants, lithium, amitriptyline, valproic acid, 
SSRIs and NSRIs as applicable.  
Note: The use of these medications should be discontinued at least 14 days before 
Prospective Baseline Period and refrain from using throughout duration of 
study.Subjects must refrain from using these medications throughout the duration 
of the study. 
11. 
Significant major psychiatric disorder (e.g., psychosis, bipolar disorder, 
major depression, and generalized anxiety disorders, ADHD), or documented 
developmental delays or impairments (e.g., autism, cerebral palsy, or mental 
retardation) that, in the opinion of the Investigator, would interfere with 
adherence to study requirements or safe participation in the trial. 
Note: Subjects with an established diagnosis of Attention Deficit Hyperactivity 
Disorder (ADHD), will be allowed if they are taking a stable dose (7 days/week) 
Major change to facilitate study 
conduct  

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Section 
Page 
Description of Change 
Rationale for Change 
of ADHD stimulant medication (extended or controlled release) for at least 12 
weeks prior to the Screening visit and refrain from changing the dose or the 
ADHD medication during the study duration. 
16. 
Known neurological disorder or a structural disorder of the brain from 
birth; head trauma or past infection (within 6 months prior to Screening) 
infectious disease resulting in migraine or worsening of the migraine symptoms; 
or previous central nervous system (CNS), or previous CNS surgery.   
18. 
Evidence of suicidal ideation and/or suicidal behaviors within 6 months 
prior to Screening or during the Screening period Pre-treatment Phase. 
Note: Abnormal results on screening laboratory tests and/or ECG may be repeated 
once per test at the discretion of the Investigator. 
1 
24 
Introduction 
These include ophthalmologic side effects (acute myopia, secondary angle closure 
glaucoma, and visual field defects), oligohydrosis and hyperthermia, treatment-
related laboratory abnormalities (e.g., metabolic acidosis, hyperammonemia, and 
changes in complete blood count values), nephrolithiasis, negative effects on 
growth, and suicidal behavior and ideation. 
Changed to provide additional safety 
information 
3.1 
27-28 
Pre-treatment Phase 
Screening/Wash Out Period (Visit 1, up to 8 weeks before Visit 3) 
Prospective subjects who meet initial eligibility criteria will discontinue any 
preventive Subjects treated with the following prophylactic medications for a 14
day wash out period. All ongoing pharmacological therapies used for migraine 
prophylaxis (except should discontinue the treatment 14 days prior to the 
Prospective Baseline Period: antipsychotics, antimanics, barbiturates, 
benzodiazepines amitriptyline, lithium, valproic acid, tricyclic antidepressants, 
AEDs, calcium channel blockers, sedatives, serotonin selective reuptake 
inhibitors (SSRIs), non-selective reuptake inhibitor (NSRIs), calcitonin gene-
related peptide (CGRP) receptor antagonists, cannabidiol (CBD) oil, herbal 
preparations/supplements such as feverfew or St John’s wort and/or any 
medications that could impair or decrease thinking and concentration. It is 
recommended to taper off antipsychotics, barbiturates, benzodiazepine, tricyclic 
antidepressants, lithium, amitriptyline, valproic acid, SSRIs and NSRIs as 
applicable. (Appendix 10.10)  
Note: Subjects must refrain from using these medications throughout the 
duration of the study. 
Major change to facilitate study 
conduct 

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Description of Change 
Rationale for Change 
Non-pharmacologic approaches involving life-style modifications are allowed if 
initiated more than 1 month prior to Screening. 
For subjects who met the eligibility criteria, prophylactic migraine treatments will 
be discontinued allowed if on a stable dose for at least 14 days before the start of 
the Prospective Baseline Period. If a subject does not need to wash out from any 
medications, he/she may enter the Prospective Baseline Period within a 12 weeks 
prior to the Screening Visit including daily nonsteroidal anti-inflammatory drugs 
(NSAIDs), antiemetics, antihistamines, corticosteroids (i.e., systemic inhaled, or 
topical), high-dose magnesium supplements (≥600 mg/day), high-dose riboflavin 
(≥100 mg/day), coenzyme Q10, omega-3, melatonin, muscle relaxants and β-
blockers (Appendix 10.9). 
Note: The dose and the medication must remain stable (7 days/week) during the 
duration of Visit 1 if the laboratory test results are normal the study. 
During Screening, acute rescue medications (e.g., ibuprofen, acetaminophen, Non
Steroidal Anti Inflammatory Drugs (NSAIDs), ergot derivates and triptans) will be 
allowed for symptomatic relief of headaches (migraine and non-migraine) as long 
as the pattern of use remains stable and does not meet the criteria for medication 
overuse (i.e., > 10 treatment days/month for ergot-containing medication or 
triptans; >15 treatment days/month for simple analgesics/NSAIDs). The use of 
narcotics is not permitted. 
Re-screening is not permitted, however subjects who screen failed due to a 
PedMIDAS Total score > 50 under any prior version of the protocol, may be 
rescreened if they still meet the study eligibility criteria under this version of the 
protocol (Version 4.0, 14 Dec 2022). 
3.1 
29 
Randomization (Visit 3, Day 1) 
All eligible subjects will be randomized in a blinded fashion by the interactive web 
response system (IWRS) in a 1:1 ratio of placebo or SPN-538. Subjects will receive a 
4 week supply of their assigned study medication (SM). Safety evaluations 
including AEs, vital signs and suicidality evaluation (using the C-SSRS), eye 
examinations, concomitant medications, urine pregnancy test (FOCP only), 
headache disability, HRQoL, and cognitive assessments will be obtained at the visit. 
SM accountability and resupply will occur at each subsequent study visit. 
 
Minor changes for completeness 

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Section 
Page 
Description of Change 
Rationale for Change 
3.1 
30 
Titration Period (Visits 4 to 5, Weeks 1 through 8) 
• 
During the visits (Visit 4 and Visit 5), SM supply will be provided, and SM 
compliance, and the Headache Diary will be reviewed. Safety assessment including 
AEs, vital signs, concomitant medications, clinical laboratory tests, urine pregnancy 
test (FOCP only) and suicidality evaluation (using the C-SSRS) will be obtained. 
Physical and neurological evaluations will be performed, and a refresher placebo 
training will be administered will be performed.  
• 
During the last visit of the titration period (Visit 5), in SM supply will be 
provided, SM compliance and the Headache Diary will be reviewed. In addition to 
safety evaluations (i.e., AEs, vital signs and concomitant medications), ECG, 
headache disability, HRQoL, C-SSRS and cognitive assessments will be performed; 
urine pregnancy test (FOCP only), clinical laboratory tests, and a urine drug 
screen sample will be collected. 
Minor changes for completeness 
and/or clarification 
3.1 
30-31 
Maintenance Period (Visits 6 to 8, Weeks 9 to 20) 
Once the target dose or MTD is reached, treatment at that dose will continue for 
the 12 weeks of the maintenance period; up to one dose reduction will be allowed 
for safety and tolerability during this period. Additional dose titration related to 
body weight changes will be reviewed and approved by the Medical Monitor and 
the Sponsor on a case by case basis. The number, severity, and symptoms of all 
headaches, as well as the type and dose of rescue medication and SM compliance 
will be recorded daily in the Headache Diary. During the Maintenance Period, clinic 
visits will be scheduled every 4 weeks. During each clinic visit, a 4-week supply of 
SM will be provided, and SM compliance and the Headache Diary will be reviewed. 
Safety evaluations, including vital signs, concomitant medications, cognitive 
assessment, C-SSRS, clinical laboratory tests (only at Visit 8), urine pregnancy test 
(FOCP only), urine drug screen, physical and neurological evaluations will also be 
performed.
 
 
 
During Visit 6, the eye exam will be performed, and another refresher placebo 
training will be administered. 
Telephone contacts will occur at the intervening 2-week periods [Days 71, 99 and 
127 (±2 days)] between clinic visits for safety assessment and to provide guidance 
on dose reduction (as needed). 
Minor changes for completeness 
and/or clarification 

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Section 
Page 
Description of Change 
Rationale for Change 
3.1 
30-31 
Tapering Period (Weeks 21 to 23):  
During the following 3 weeks the dose of SM will be gradually reduced until the 
subject is no longer taking the SM, so that by the end of Week 23 the subject is out 
of capsulesSM. Dose tapering will also be required for subjects who discontinue 
early during the titration period (Week 3 through Week 8) or maintenance period 
(Week 9 through Week 20). Subjects who discontinue early at an MTD of 25 
mg/day will not undergo a dose tapering period but will return to the clinic to 
complete the end of study (EOS) procedures (all procedures scheduled to be 
performed at Visit 9) within 1 week after discontinuation of SM. 
Minor changes for clarification 
3.1 
31 
End of Study (Visit 9): 
All subjects who complete the study (Week 20) will return to the clinic for a final 
safety evaluation at the end of the Tapering Period (Visit 9). During this visit, 
subjects will complete the EOS procedures: clinical laboratory tests, AE 
assessments, vital signs, concomitant medications review, ECG, physical and 
neurological evaluations, eye exam, urine pregnancy test (FOCP only) and urine 
drug screen, headache disability, HRQoL, C-SSRS and cognitive assessments. The 
remaining SM and the Headache Diary device, if applicable, will be collected, and 
safety follow-up instructions will be provided to caregivers. 
Minor changes for completeness 
and/or clarification 
3.1 
32 
Safety Follow-up Telephone Call (Weeks 24 to 26):  
Safety follow-up over the telephone will take place 1 to 3 weeks after the 
EOS/early termination (ET) visit. During the telephone call, all concomitant 
medications, cognitive assessment and AEs will be evaluated and recorded. Any 
subject who experiences an AE (whether serious or non-serious) or has a clinically 
significant abnormal laboratory test value will be followed by the Investigator for 
up to 30 days after the EOS/ET visit. These subjects will be treated and/or followed 
up until the symptoms or laboratory values return to normal/baseline or 
acceptable levels, as determined by the Investigator. 
Minor changes for completeness 
and/or clarification 
3.1 
33 
Figure 1 (Study Schematic) Footnote 
1. 
Dosing will be based on weight and is flexible. 
 
 
 
whichever is less. The total daily dose will not exceed 100 mg/day (or 4 × 25 mg 
capsules/day). In the event of tolerability problems during titration, the 
Investigator may reduce the dose 
 During 
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maintenance, up to one dose reduction will be allowed for safety and tolerability 
during this period. Additional dose titration related to body weight changes will 
be reviewed and approved by the Medical Monitor and the Sponsor on a case by 
case basis. 
3.4.1 
39 
Discontinuation of Subjects 
Reasons for subject discontinuation may include: 
• 
Withdrawal of consent and assent 
• 
Non-compliance with study procedures 
• 
Lack of efficacy 
• 
Investigator decision 
• 
Occurrence of unmanageable AEs 
• 
Lost to follow-up 
• 
Other (study is terminated by the Sponsor, blind is broken, subject has 
relocated or death etc.) 
Minor change for completeness 
and/or clarification 
4.3 
41-42 
Study Medication Dosing 
During maintenance, up to one dose reduction will be allowed for safety and 
tolerability. Additional dose titration related to body weight changes will be 
reviewed and approved by the Medical Monitor and the Sponsor on a case-by-
case basis.   
Minor change per site clarification 
4.7 
44 
Concomitant Medications 
Subjects may not be on any prohibited medication as indicated in the 
Inclusion/Exclusion Criteria. 
Throughout the duration of the study, rescue migraine treatments such as simple 
analgesics (e.g., ibuprofen and acetaminophen) are allowed for symptomatic relief 
of acute headache episodes as long as their use does not exceed 3 times per week 
(or 15 treatment days/month) and the pattern of use remains stable. Use of 
narcotics is not permitted (Appendix 10.9). 
Stimulant medications (extended or controlled release formulation) for the 
treatment of ADHD will be allowed if initiated and maintained on a stable dose 
(7 days/week) for at least 12 weeks prior to the Screening Visit and continued on 
the same dose during the study duration (Appendix 10.9).  
Prophylactic treatment for migraine is permitted if on a stable dose for at least 
12 weeks prior to the Screening Visit including: daily NSAIDs, antiemetics, 
antihistamines, corticosteroids (i.e., systemic inhaled, or topical), high-dose 
Major change to facilitate study 
conduct 

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magnesium supplements (≥600 mg/day), high-dose riboflavin (≥100 mg/day), 
coenzyme Q10, omega-3, melatonin, muscle relaxants and β-blockers. The dose 
and the medication must be maintained during the duration of the study 
(Appendix 10.9). 
Triptans, ketorolac, antiemetics, and ergotamines must be used with caution and 
with a frequency that does not exceed 10 treatment days/month. Subjects will be 
asked to be consistent in the use of their preferred acute migraine medication and 
encouraged not to initiate new therapies during the course of the trial (Appendix 
10.9). 
Anti-asthma medication: Albuterol sulfate is the only antiasthma medication 
allowed as needed (PRN) to keep any respiratory conditions under control 
(Appendix 10.9). 
Treatment for AEs other than minor transient ailments is permitted only in 
consultation with the Medical Monitor or his/her designee with the exception of 
required treatments for acute conditions in the emergency room/hospital and/or 
office visit as indicated.  
No additional concomitant medications are allowed during the study, with the 
following exceptions: 
• 
Nutritional supplements (e.g., multivitamins), except those listed in 
Section 4.8 • 
EMLA® or other numbing cream for venipuncture • Routine 
childhood vaccinations 
• 
Mydriatics are allowed on as needed basis per PI’s discretion 
Additional concomitant medications allowed during the study include: 
nutritional supplements (e.g., multivitamins), EMLA® or other numbing cream for 
venipuncture, routine childhood vaccinations, Coronavirus Disease 2019 (COVID-
19) vaccine and mydriatics (as needed per Principal Investigator (Winner et al.) 
discretion). 
4.8 
44-45 
The following complementary and alternative prophylactic approaches to migraine 
are prohibited during the participation in this study (and as applicable, should be 
recorded as part of the subject’s retrospective headache history):  
• 
Acupuncture 
• 
Manual therapies (chiropractic spinal manipulation, occipital nerve block, 
massage therapy, physical therapy) 
Minor change 

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• 
Herbal and nutritional supplement therapies for migraine prevention 
(butterbur, feverfew, high dose magnesium supplements, riboflavin, and 
coenzyme Q10) and St. John’s Wort) 
• 
Cognitive-behavioral therapy, biofeedback, hypnosis 
• 
Neuromodulation devices 
4.8.1 
45 
4.8.1 Prohibited Medications (new section) 
Subjects may not be on any prohibited medication as indicated in the 
Inclusion/Exclusion Criteria. 
Subjects treated with the following prophylactic medications should discontinue 
the treatment 14 days prior to the Prospective Baseline Period: antipsychotics, 
antimanics, barbiturates, benzodiazepines amitriptyline, lithium, valproic acid, 
tricyclic antidepressants, AEDs, calcium channel blockers, sedatives, SSRIs, NSRIs, 
CGRP receptor antagonists, CBD oil, herbal preparations/supplements such as 
feverfew or St John’s wort and/or any medications that could impair or decrease 
thinking and concentration. It is recommended to taper off antipsychotics, 
barbiturates, benzodiazepine, tricyclic antidepressants, lithium, amitriptyline, 
valproic acid, SSRIs and NSRIs as applicable. (Appendix 10.10).  
Note: Subjects must refrain from using these medications throughout the 
duration of the study.  
Non-stimulant ADHD medications (e.g., clonidine, atomoxetine, viloxazine and 
guanfacine) must be discontinued 14 days prior the Prospective Baseline Period 
(Appendix 10.10). 
Major change for consistency/study 
conduct facilitation 
5.1 
46 
Study Visits and Procedures 
Study visits must be scheduled according to the Schedule of Events relative to the 
Baseline Randomization Visit (Visit 3). Visits must not be scheduled relative to the 
previous visit. Bi-weekly telephone contacts will occur between study visits, at 
Days 14, 43, 71, 99, 127, and 148 (± 2 days). 
Major change to provide clarification 
on telephone contacts and add 
telephone contact at Day 148 
 
Table 2 
47-49 
The Schedule of Events and Assessments was updated for consistency with 
changes to the protocol, especially those detailed in Sections 3.1 and 5. The 
following changes were made to the table footnotes. 
* Visit 5 is end of titration and beginning of Maintenance Period of the 
Treatment Phase hence included within Section 5.1.5 for clarification. 
a. 
Subjects who had used TPM or any disallowed prophylactic migraine 
therapy within 4 weeks prior to Screening must complete a washout period of 
Major and minor changes for 
completeness and/or clarification and 
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discontinue the treatment at least 2 weeks before the start of the Prospective 
Baseline Period, with an appropriate taper when applicable.  
b. 
Bi-weekly telephone contacts will occur between study visits, at Days 14, 
43, 71, 99, and 127, and 148 (± 2 days).   
c. 
Informed consent/assent to be obtained prior to performing any study 
procedures.  
d. 
Physical examination (excluding genitourinary system) includes height and 
weight and a special assessment for the occurrence of decreased sweating and 
elevation in body temperature above normal. Neurological examination includes 
evaluation for impaired reflexes, balance problems, muscle weakness, 
paresthesia/numbness and tingling, speech difficulties, mental confusion or 
excessive fatigue.  
e. 
Seated (5 min) pulse rate, blood pressure, temperature, and respiratory 
rate. The vital signs’ readings, except prior to dosing, will be performed within 
approximately 10 minutes prior to scheduled blood draws, where applicable.  
F 
 Concomitant medication includes headache rescue medicine (also 
recorded in the Headache Diary).  
g. 
Headache Diary training will be provided at Visit 2.  
h. 
Subjects will start the first dose on the same day of Visit 3 at the clinical 
site, instructions for dose titration will be provided.  
i. 
Provide instructions for dose tapering at Visit 8. 
j. 
Any subject who experiences an AE (whether serious or non-serious) or 
has a clinically significant abnormal laboratory test value will be followed by the 
Investigator for up to 30 days after the EOS visit.  These subjects will be treated 
and/or followed up until the symptoms or value(s) return to normal/baseline or 
acceptable levels, as determined by the Investigator. 
l. 
Safety Follow Up (by Phone) is not a site visit and falls within a range of 
1-3 weeks after Visit 9/ET Visit occurs. 
m. 
Placebo training refresher Subjects who discontinue from the study 
earlier than the EOS visit (visit 9) should undergo all EOS procedures included in 
visit 9 during the ET visit. 
Note: Besides the testing specified during the respective visits in the Table 2 
above, repeat testing for clinical laboratory parameters, vital signs, and/or ECG 
may be permitted, at the discretion of the Investigator. However, these repeat 

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testing will require justification from the site and agreement with the Medical 
Monitor and the Sponsor on a case-by-case basis prior to conducting the tests. 
5.1.1 
50 
Visit 1 – Screening (Day -56) 
All reasons for screening failure will be recorded. If the subject passes screening 
but fails eligibility at baseline Randomization visit (Visit 3), the reason(s) will also 
be recorded in the eCRF. 
For subjects provisionally eligible for study participation, a Prospective Baseline 
Visit will be scheduled allowing for at least a 2-week/14-day washout of any 
disallowed migraine preventative drug therapy medications the subject was 
receiving at Screening. 
Major change to provide clarification 
5.1.3 
51 
Visit 3 (+2 days) – Randomization (Day 1) 
The following assessments will be conducted at this visit:  
• 
Review inclusion/exclusion criteria 
• 
Record vital signs (pulse rate, BP, temperature, and RR) 
• 
Collect urine sample for pregnancy test (FOCP only) 
• 
Administer C-SSRS 
• 
Review and record concomitant medications 
• 
Review Headache Diary for eligibility  
• 
Administer PedMIDAS, PedsQL 4.0 scales 
• 
Perform cognitive assessment 
• 
Perform eye exam 
• 
Record AEs 
• 
Randomization  
• 
Dispense SM (4-week supply) and provide instructions for dose titration 
 
 
 
 
 
 
 
Minor change for completeness 

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5.1.4 
51-52 
Titration Period (Days 1 to 56, Week 1 to end of Week 8) 
Visit 4 (Day 29 ± 7 days) 
During Treatment Phase (Visits 4 through 9), sample collection and testing have 
been specified for respective visits by the Sponsor. Besides the testing specified 
during these respective visits, repeat testing for clinical laboratory parameters, 
vital signs, and/or ECG may be permitted, at the discretion of the Investigator. 
However, these repeat testing will require justification from the site and 
agreement with the Medical Monitor and the Sponsor on a case-by-case basis 
prior to conducting the tests.  
The following assessments will be conducted at this visit:  
• 
Perform physical examination (excluding genitourinary system) including 
height and weight, and neurological examination 
• 
Record vital signs (pulse rate, BP, temperature, and RR) 
• 
Collect blood samples for hematology and serum chemistry 
• 
Collect urine sample for urinalysis and for pregnancy test (FOCP only) 
• 
Administer C-SSRS 
• 
Review and record concomitant medications 
• 
Review Headache Diary 
• 
Record AEs 
• 
Collect SM and assess adherence; retrain as needed  
• 
Dispense SM (4-week supply) and review medication instructions with 
subject and caregiver 
• 
Placebo training refresher 
 
 
 
 
 
 
 
 
 
Minor change for completeness 
and/or clarification 

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5.1.5 
52-53 
Maintenance Period (Days 57 to 140, Week 9 to the end of Week 20) 
Visits 6 (Day 85 ± 7 days) and Visit 7 (Day 113 ± 7 days) 
The following assessments will be conducted at these visits:  
• 
Perform physical examination (excluding genitourinary system) including 
height and weight, and neurological examination  
• 
Record vital signs (pulse rate, BP, temperature, and RR) 
• 
Collect blood samples for hematology and serum chemistry 
• 
Collect urine sample for urinalysis and for pregnancy testing (FOCP only) 
• 
Collect urine sample for drug screen 
• 
Perform eye exam (only at Visit 6)  
• 
Administer C-SSRS 
• 
Perform cognitive assessment 
• 
Review and record concomitant medications 
• 
Review Headache Diary 
• 
Record AEs 
• 
Collect SM and assess adherence; retrain as needed 
• 
Dispense SM (4-week supply) and review medication instructions with 
subject and caregiver 
• 
Placebo training refresher (only at Visit 6) 
Minor change to align with Table 2 
5.1.5 
53 
Maintenance Period (Days 57 to 140, Week 9 to the end of Week 20) 
Intervening Phone Calls 
At Days 71 (± 2 days), 99 (± 2 days) and 127 (± 2 days), there will be telephone calls 
to subjects to assess the tolerability of SM treatment.   
The following assessments will be made during these telephone contacts:  
• 
Review and record concomitant medications 
• 
Record AEs 
• 
Provide guidance (as needed) on dose reduction, up to one dose 
reduction will be allowed for safety and tolerability during this period. Additional 
dose titration related to body weight changes will be reviewed and approved by 
the Medical Monitor and the Sponsor on a case by case basis. 
 
Minor change per site clarification 

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5.1.6 
54 
Taper Period (Days 141 to 161, Week 21 to the end of Week 23) 
Intervening Phone Call 
At Day 148 (± 2 days) there will be a telephone call to subjects to assess the 
tolerability of the SM treatment.   
The following assessments will be made during these telephone contacts:  
• 
Review and record concomitant medications 
• 
Record AEs 
• 
Provide guidance (as needed) on dose reduction 
Visit 9 (Day 162 ± 7 days) – End of Study (EOS) Visit 
The following assessments will be conducted at this visit:  
• 
Perform physical examination (excluding genitourinary system) including 
height and weight, and neurological examination  
• 
Perform 12-lead ECG 
• 
Record vital signs (pulse rate, BP, temperature, and RR) 
• 
Collect blood samples for hematology and serum chemistry 
• 
Collect urine sample for urinalysis and for pregnancy testing (FOCP only) 
• 
Collect urine sample for drug screen 
• 
Perform visual neurological exam 
• 
Perform eye exam  
• 
Administer C-SSRS 
• 
Review and record concomitant medications 
• 
Review Headache Diary  
• 
Remove app from caregiver’s phone 
• 
Administer PedMIDAS, PedsQL 4.0 scales 
• 
Perform cognitive assessment 
• 
Record AEs 
• 
Collect SM and assess adherence 
Minor change for completeness and 
clarification 
5.1.7 
54 
Added 3rd bullet to assessments at Safety Follow-up Telephone Call (Weeks 24 
through 26) 
Perform cognitive assessment (Appendix 10.5) 
 
Major change 

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6.6 
58 
Adverse Events 
An AE can be: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
• 
Any new disease, intercurrent injuries, or exacerbation of an existing 
disease. 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG) 
that results in symptoms, a change in treatment, or discontinuation from SM. 
• 
Recurrence of an intermittent medical condition (e.g., headache muscle 
pain) not present at baseline. 
Minor change 
6.6.2 
59 
Recording and Evaluation of Adverse Events 
The Investigator is responsible for evaluating AEs and determining the following: 
• 
Serious vs. Non-serious: Is the event an SAE? 
• 
Causality: Was AE related or possibly not related to the SM? 
• 
Severity: How pronounced is the incapacity/discomfort caused by an AE? 
Major change 
6.6.9 
62-63 
Adverse Events of Special Interest 
Several AEs are known to be associated with the long-term use of TPM and can be 
expected with treatment with SPN-538 ("National Institutes of Health-DailyMed- 
Trokendi XR- Prescribing Information.," 2022). Consistent monitoring is required 
for the following AESIs: 
• 
Metabolic acidosis (serum bicarbonate) 
• 
Hyperammonemia 
• 
Oligohydrosis and hyperthermia 
• 
Clinically significant increase in alkaline phosphatase, creatinine, or 
eosinophils (specifically, for patients 6 to 11 years, these were noted to be 
abnormally increased more frequently with TPM than with placebo) 
• 
Clinically significant decrease in total white cell count or neutrophils  
• 
Visual changes: subjects presenting with blurry vision, ocular pain, and 
visual field defects subjects must be discontinued early and closely followed to 
ensure a prompt resolution of ocular AEs.   
• 
Suicidal behavior and ideation 
Major change to align with the 
updated Prescribing Information 

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• 
Serious skin reactions (TPM should be discontinued at the first sign of 
rash, unless rash is not drug-related) 
• 
Negative effect on growth (weight and height) 
• 
Cognitive and memory function impairments 
• 
Nephrolithiasis 
6.8.6 
66 
Eye Exam 
Equipment at the site necessary to perform the visual neurological and eye exam 
consists of the following:  
• 
Near card 
• 
Wall Snellen Chart (optional, at Investigator’s discretion based on 
outcome from routine eye exam) 
• 
Penlight  
• 
Hand help Ophthalmoscope (direct or Panoptic) 
• 
Amsler grid (optional, at Investigator’s discretion based on outcome 
from routine eye exam) 
The Wall Snellen Chart uses a geometric scale to measure visual acuity, with 
normal vision at a distance being set at 20/20. The numerator represents the 
distance that the patient is standing from the chart (in feet), while the 
denominator represents the distance from which a person with perfect eyesight 
is still able to read the smallest line that the patient can clearly visualize.  
The Amsler grid could be used to help detect early signs of retinal disease and 
monitor changes in vision after diagnosis. 
Note: The Sponsor has appended Snellen chart (Appendix 10.8.1) and Amsler grid 
(Appendix 10.8.2) for every participating site as a tool to be used by the 
investigator if further examination is deemed necessary after a routine eye exam 
outcome. 
Major change for completeness 
and/or clarification 
6.8.7 
67 
Cognitive Assessment 
Changes in cognitive function will be assessed at Visit 3, Visits 65 through 9 and at 
the safety follow-up phone call after the EOS. 
 
 
 
Major change 

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7.1 
69 
All data analyses will be performed by qualified personnel as identified by the 
Sponsor after the study is completed and the database is released. All data will be 
analyzed using SAS® (SAS Institute, Inc., Version 9.3 or later). 
In general, continuous variables will be summarized using standard descriptive 
statistics including number of subjects (n), mean, standard deviation (SD), median, 
interquartile range (Q1, Q3), minimum, and maximum. Categorical variables will 
be summarized with frequencies and percentages. 
The data summaries will be accompanied by individual subject data listings, as 
specified in Sections 16.2 and 16.4 of ICH Guidance E3, sorted by unique subject 
identifier. All data available from the electronic CRFs will be listed. Unscheduled 
measurements will be excluded from the descriptive statistics and statistical 
analysis but will be included in listings. 
Categorical variables will be analyzed using categorical response statistical 
methods such as Pearson’s Chi-square test or Fisher’s exact test as appropriate.  
Treatment comparison for all efficacy variables will be evaluated based on a two-
sided significance level of 0.05 and the interaction effects at 0.10. 
Unless specified otherwise, baseline is defined as the non-missing value collected 
most recent to and before the time of the very first dose of the SM. 
Subject baseline measurements are assumed to be comparable at the start of the 
study, as randomization is designed to ensure balance between the groups on the 
baseline characteristics, so no formal statistical group comparisons will be 
conducted on the subject characteristics. 
The test for the normality of the change in the monthly migraine days during the 
last 4 weeks of the Treatment Phase relative to the Prospective Baseline Period will 
be checked using the Shapiro Wilks test. If the test does not detect departures 
from normality, then the primary and sensitivity analyses will be performed using 
parametric methods for estimation and hypothesis testing. Otherwise, the primary 
and sensitivity analysis endpoints will be analyzed using the non parametric 
Wilcoxon rank sum test to compare the median SPN 538 dose with the median of 
the Placebo. The Hodges Lehmann estimate of the difference (SPN 538 minus 
placebo) and the associated 95% confidence interval (CI) around the difference will 
be calculated. 
Complete details of the statistical analysis will be provided in a separate statistical 
analysis plan (SAP). The statistical analysis methods described in the SAP will 
supersede the statistical methods described in this protocol. 
Changed to align with SAP per FDA 
request  

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7.2 
69-70 
Baseline: 
For baseline, missing baseline data will not to be imputed.  
Primary and Secondary Efficacy Endpoints:  
For the primary efficacy endpoint, monthly migraine days during the treatment 
period will be calculated over the number of days with non missing migraine 
diary data in the Treatment Phase.  
Missing diary data for the analysis in the calculations of monthly measurements 
about subjects’ migraine will be handled by the following method: 
1. 
Monthly intervals with diary compliance ≥ 50% (i.e., ≥ 14 days of diary 
days out of 28 days during the Treatment Phase):  
a)  
Monthly measurements (including migraine days, headaches days 
duration of migraine, or acute medication use) will be prorated to 28 day 
equivalents.  
b)  
Monthly average severity of migraine pain, migraine related symptoms 
and monthly average scale of migraine interference with daily activity will be 
calculated as the average of observed scores.  
2.  
Monthly intervals with diary compliance < 50% (i.e., < 14 days of diary 
days out of 28 days); all monthly measurements will be set as missing.  
Missing endpoint values in this study may result from subjects discontinuing 
from the study prematurely or missing intermediate assessments while 
remaining on study. The primary efficacy analysis method will be based on a 
Mixed Model for Repeated Measures (MMRM) which utilizes all available data 
(complete and partial) from subjects included in an analysis set. The MMRM-
based approach assumes that missing diary data are MAR. MAR refers to a 
missingness mechanism that is independent of missing responses, conditionally 
on observed response history and covariates. That is, given the observed data, 
the reason for the missing data does not depend on the underlying unseen data.   
For primary analysis, missing 28-day MMDs for subjects discontinued due to AE 
or lack of efficacy will be explicitly imputed by the mean values obtained from MI 
under the missing not at random (MNAR) assumption before implementing the 
MMRM. Missing 28-day MMDs for subjects discontinued due to reasons other 
than AE or lack of efficacy will not be imputed for the primary efficacy analysis. 
Sensitivity analyses of the primary endpoint to investigate robustness to missing 
primary endpoint data will be performed by assuming that missing diary data are 
MNAR, meaning that the probability that an observation is missing may depend 
Changed to align with SAP per FDA 
request  

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on its underlying unobserved value. Missing data handling for safety data will be 
described in the SAP. 
7.3 
70 
The Per-Protocol (PP) Population is the subset of Set (PPS) includes all subjects in 
the FAS who are free of major have completed Visits 1-8 with no missing MMDs 
and no important protocol deviations. Analysis of PPS will be used as 
supplementary analysis of the primary and secondary efficacy endpoints with 
treatment classification based on the PP Population is not a sensitivity analysis, 
but it will be used to support the primary analysis to describe the treatment effects 
under idealized conditions of full or partial compliance. Subjects will be analyzed 
according to the treatment received.  
The Safety Analysis Set (SAS) includes all subjects randomized into the study who 
received at least 1 dose of SM. study medication. Subjects Data will be analyzed 
according to the treatment received. 
Changed to align with SAP per FDA 
request  
7.4 
70 
Demographic/baseline variables including age, sex, ethnicity, race, height and 
weight at screening, and medical and neurological histories will be summarized 
using descriptive statistics for continuous variables and counts and percentages for 
categorical variables. Descriptive summaries will be presented by treatment group 
for the FAS, PP Population PPS, and SAS Safety Analysis Set. 
Minor changes 
7.5 
70-71 
A disposition of subjects will include the number and percentage of subjects in 
each of the following categories: 
• 
Subjects in the Randomized Population 
• 
Subjects in the FAS  
• 
Subjects in the PP Population Analysis Set 
• 
Subjects in the SASSafety Analysis Set 
Within each of the previous categories, the number and percentage of subjects 
who completed and discontinued from the study and primary reason for early 
discontinuation will be summarized. The reason for early discontinuation may 
include any of the following: 
• 
Withdrawal of consent and assent 
Changed to align with SAP per FDA 
request  

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• 
Lack of efficacy 
• 
Investigator decision 
• 
Noncompliance with study procedures 
• 
Occurrence of unmanageable AEs 
• 
Lost to follow-up 
• 
Other Other (study is terminated by the Sponsor, blind is broken, subject 
has relocated or death etc.) 
7.6 
71 
Duration of exposure is defined as the total number of days a subject is exposed to 
any study treatment. This will be calculated for each subject by taking the 
difference between the date of last dose minus the date of the first dose, plus 1 
(date of last dose minus date of first dose +1). 
Duration of treatment exposure will also be summarized using descriptive statistics 
(n, mean, SD, median, minimum, and maximum). 
Percent of study drug SM Compliance is calculated as % compliance is defined as 
{(number of capsules dispensed minus number of capsules returned) / (date of last 
dose minus date of first dose + 1)}* 100% *(Num/Den), where 
If the date of last dose is not available, then it will be imputed by the subject’s last 
visit in the study. 
𝑵𝒖𝒎= ∑#  𝐨𝐟 𝐜𝐚𝐩𝐬𝐮𝐥𝐞𝐬 𝐝𝐢𝐬𝐩𝐞𝐧𝐬𝐞𝐝 𝐚𝐭 𝒗𝒊𝒔𝒊𝒕𝒊
𝟕
𝒊=𝟑
−# 𝐨𝐟 𝐜𝐚𝐩𝐬𝐮𝐥𝐞𝐬 𝐫𝐞𝐭𝐮𝐫𝐧𝐞𝐝 𝐚𝐭  𝒗𝒊𝒔𝒊𝒕 𝒊+𝟏  
𝑫𝒆𝒏= ∑𝒙𝒊× (#  𝐨𝐟 𝐝𝐚𝐲𝐬 𝐛𝐞𝐭𝐰𝐞𝐞𝐧 𝒗𝒊𝒔𝒊𝒕𝒊 𝐚𝐧𝐝 𝒗𝒊𝒔𝒊𝒕𝒊+𝟏)
𝟕
𝒊=𝟑
, 𝒘𝒉𝒆𝒓𝒆 
 𝒙𝒊= # 𝐨𝐟 𝐜𝐚𝐩𝐬𝐮𝐥𝐞𝐬 𝐩𝐞𝐫 𝐝𝐚𝐲 𝐚𝐬𝐬𝐠𝐢𝐧𝐞𝐝 𝐭𝐨 𝐛𝐞 𝐚𝐝𝐦𝐢𝐧𝐢𝐬𝐭𝐞𝐫𝐞𝐝 𝐚𝐭 𝒗𝒊𝒔𝒊𝒕𝒊 
For each treatment, SM compliance will be summarized by compliance category 
(<80%, 80-120%, and >120%) and number of subjects in each compliance category. 
SM Study medication compliance will also be summarized as a continuous variable 
using descriptive statistics (n, mean, standard deviation SD, median, minimum, and 
maximum) for each treatment. 
Summaries of treatment compliance and exposure will be presented separately for 
the Titration Period, Maintenance Period, and combined Titration and 
Maintenance Periods. 
Changed to align with SAP per FDA 
request  

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7.7 
71-72 
Prior and concomitant medications will be coded according to the World Health 
Organization Drug Dictionary (WHO DD). Concomitant medications will be further 
coded to the appropriate Anatomical Therapeutic Chemical (ATC) code indicating 
therapeutic classification. A tabular summary of concomitant medications by drug 
class will be presented for the SAS and summarized descriptively by ATC 
classification level 4 and preferred term for the Safety Population. Medications 
used within 30 days prior to the start of the study and during the course of the 
study will be listed. Medications with a valid stop date prior to first dose date will 
be considered prior medications. Incidence (number and percent of subjects 
reporting the medication at least once during the study) will be summarized for all 
concomitant medications. 
Changed to align with SAP per FDA 
request 
Synopsis & 
7.8 
11, 72 
Based on the FAS, the observed value and change from baseline will be 
summarized using descriptive statistics as described in Section 7.1 and presented 
for all efficacy endpoints by study visit and treatment group. Subject listing of 
the observed value and change from baseline will be listed for all efficacy 
endpoints. The mean profile of 28-day MMDs will be presented by treatment 
group and study visit. 
Changed to align with SAP per FDA 
request 
Synopsis & 
7.8.1 
11-12, 72-73 
The primary efficacy outcome measure is the endpoint, change in the mean 
monthly (28 day) rate of migraine days (MMDs) during the last 4 weeks of the 20
week double blind Treatment Phase relative to from the Prospective Baseline 
Period based on the FAS. 
The test for the normality of the change in the monthly migraine days during the 
last 4 weeks of the Treatment Phase relative to the Prospective Baseline Period will 
be checked using the Shapiro Wilks test. If the test does not detect departures 
from normality, then the primary and sensitivity analyses will be performed using 
parametric methods for estimation and hypothesis testing. Otherwise, the primary 
and sensitivity analysis endpoints in 28-day rate MMDs, will be analyzed using the 
non parametric Wilcoxon rank sum test to compare the median SPN 538 dose 
with the median of the Placebo. The Hodges Lehmann estimate of the difference 
(SPN 538 minus placebo) and the associated 95% confidence interval (CI) around 
the difference will be calculated. 
If departures from normality in the number of migraine days per month are not 
detected, then the primary endpoint will be analyzed using a Mixed Model for 
Repeated Measures (MMRM) analysis of covariance (ANCOVA), which assumes 
that missing data are missing at random (MAR). All post-baseline study visits will 
Changed to align with SAP per FDA 
request 

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be included in the model; however, the primary comparison will be between 
SPN-538 and placebo at Month 5 (last 4 weeks of the Maintenance Period). The 
model will include fixed effect terms for the prospective baseline migraine days, 
28-day rate of MMDs for the Prospective Baseline Period, treatment group, 
Prospective Baseline monthly migraine-specific acute rescue medication (28-day 
rate) use (Yes or No), visit (5 monthly visits), and treatment-by-visit interaction as 
covariates independent variables. The model parameters will be estimated using 
restricted maximum likelihood method with an unstructured variance-covariance 
matrix and Kenward-Roger approximation to estimate denominator degrees of 
freedom. In case there is a convergence problem in the MMRM model with the 
unstructured variance covariance matrix,  
If the MMRM model with the unstructured variance-covariance matrix does not 
converge using the default Newton-Raphson fitting algorithm by PROC MIXED in 
SAS, then the Fisher scoring algorithm or the no-diagonal factor analytic 
structure will be used (Lu & Mehrotra, 2010). If the model still fails to converge, 
then the first (co)variance structure which does not have convergence problem 
will be used for the analysis from the following ordered list: a) Toeplitz, b) 
Autoregressive of order 1, c) Compound symmetry. 
The treatment differences in terms of mean change from the Prospective Baseline 
Period to the post randomization migraine days will be estimated and tested from 
this model from the treatment by visit interaction. 
6. Heterogeneous Toeplitz  
7. Heterogeneous Autoregressive of order 1  
8. Toeplitz  
9. Autoregressive of order 1  
10. Compound Symmetry   
The denominator degrees of freedom will be estimated using the BETWITHIN 
option in SAS when any of the covariance structures is used with the sandwich 
variance estimator. 
The adjusted mean (least square mean ([LS Mean]) of each treatment group 
(Pplacebo and SPN-538dose) along with the corresponding standard error, p-
values, difference in the LS Mean between the LS Mean of SPN-538 dose and 
placebo (SPN-538 dose minus Pplacebo), and 95% CIs will be computed at each 
visit. 

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Sensitivity To assess the robustness of the primary analysis under the MAR 
assumption, two sensitivity analyses will be performed based on multiply imputed 
data assuming missing data are missing not at random (MNAR). The change in the 
mean 28 day rate of migraine days during the last 4 weeks of the Treatment Phase 
relative to the Prospective Baseline first sensitivity analysis will be based on 
placebo-based MI in which missing values for the subjects in the FAS will be 
analyzed using ANCOVA with treatment as a fixed classification variable and SPN-
538 treatment group would adopt the Prospective Baseline migraine days as a 
covariate. outcome model estimated from the placebo arm. The second 
sensitivity analysis This will be implemented performed using SAS® PROC MI and 
SAS® PROC MIANALYZE (SAS/STAT Software) a ‘tipping point’ methodology to 
assess the assumption of MAR in the primary analysis. The tipping point analysis 
will progressively impose increasing shift parameters to the imputed 
observations under the MNAR assumption in the active treatment arm, not to 
the placebo arm, to assess how severe departures from MAR must be to 
overturn the conclusion from the primary analysis. 
The details for both approaches will be provided in the SAP. 
7.8.2 
73 
This is a 2 arm treatment study and hence, no multiplicity adjustment is needed. 
The overall type I error rate for the study will be preserved at the two-sided 5% 
significance level by using a sequential (hierarchical) testing for the primary and 
secondary endpoints. The details will be provided in the SAP. 
Changed to align with SAP per FDA 
request  
7.8.3 
73-74 
Secondary endpoints will be analyzed based on the FAS using appropriate 
statistical models based on the type of endpoints.  
Analyses of Secondary Endpoints 
1. 
Monthly Migraine Responders: For each subject, a binary response 
variable for change from baseline in the monthly migraine days MMDs during the 
last 4 weeks of the Treatment Phase relative to baseline will be set to 'YES' if a 
subject’s % reduction is ≥ 50% or ‘NO’ otherwise. The proportion of responders will 
be presented for each treatment group. The 2-sided 95% CI around the difference 
in proportions (SPN-538 dose minus Placebo) and the p-value from Pearson’s Chi-
squared Test or Fisher’s Exact Test will be presented. 
2. 
Migraine-Specific Acute Rescue Medication:   The change from 
Prospective Baseline in the 28-day rate of migraine-specific acute rescue 
medication use in the last 4 weeks of the Treatment Phase will be analyzed using 
the same analysis method (MMRM) as for the primary efficacy endpoint. The 
Changed to align with SAP per FDA 
request  

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contrast of interest will be at Month 5 for the SPN-538 group compared with 
placebo. Change from baseline in the number of days per month with acute rescue 
medication use in the last 4 weeks of the Treatment Phase will be analyzed using 
parametric ANCOVA, assuming normality assumption, with treatment as a fixed 
classification variable and baseline as a covariate. The SPN 538 dose will be 
compared with placebo. The p values, LS Means of the treatment groups, 
differences between the LS treatment means and placebo (SPN 538 dose minus 
Placebo), and 95% CIs for the treatment differences will be computed. If data are 
not normal, then non parametric method will be used.   
3. 
Total Headache Days, Duration, and Severity:   The change from 
Prospective Baseline in the 28-day rate of total headache days, duration of 
headache days (migraine and non-migraine) in the last 4 weeks of the Treatment 
Phase will be analyzed using the same analysis method (MMRM) as for the 
primary efficacy endpoint. The contrast of interest will be at Month 5 for the 
SPN-538 group compared with placebo. Change in the monthly rate of total 
headache days (migraine and non migraine), duration and severity will be analyzed 
using the methods described above.   
4. 
Onset of action: The time to first significant treatment effect in the 
MMDs will be based on the MMRM analysis of the primary endpoint. The first 
month at which a statistically significant difference in the change from baseline 
in 28-day MMDs is observed and maintained until the EOS between SPN-538 and 
placebo will be claimed as the first month for the onset of treatment effect.  
Change from baseline in monthly migraine days from the first month of treatment 
and the last 4 weeks of the Treatment Phase will be evaluated for a statistically 
significant difference between SPN 538 and placebo in the primary analyses.   
5. 
Headache disability: The change from baseline in the Headache Disability 
Score as measured by PedMIDAS during the last 4 weeks of the Treatment Phase 
will be summarized using descriptive statistics by visit. analyzed using the 
methodology described in item 2 above 
6. 
HRQoL: The change from baseline in the HRQoL as measured by the 
PedsQL4.0 Total Scale Score during the last 4 weeks of the Treatment Phase for the 
self-report and the parent-report will be analyzed summarized using the 
methodology described in item 2 above descriptive statistics by visit. 

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Synopsis & 
7.8.4 
12, 74 
Descriptive statistics and modeling will be used for exploratory analyses of other 
efficacy endpoints. Multiple Type 1 error rates will not be controlled. 
Administrative change resulting from 
changes to align with SAP per FDA 
request 
Synopsis 
12 
Descriptive statistics will be presented for demographics, data from the clinical 
laboratory test results, vital signs, weight, ECGs, physical, neurological and eye 
examinations, suicidal ideation, and cognitive assessment. 
Major change for completeness 
7.11 
74-75 
Safety analysis as described below will be conducted using the SAS. All safety 
analyses will be performed on the Safety Analysis Set.  
The incidence rate of AEs will be calculated by treatment group for each System 
Organ Class (SOC) and Preferred Term (PT). The severity of the AEs and the 
relationship to SM will be summarized by treatment group for each SOC and PT. 
AEs will be summarized using discrete summaries at the subject and event level by 
SOC and PT, and by severity and relationship separately for each treatment group. 
Verbatim description and Medical Dictionary for Regulatory Activities (MedDRA) 
SOCs and PTs for all AEs will be contained in the subject data listings. 
All AEs occurring after randomization and throughout the study period will be 
recorded. For subjects who receive SM, TEAEs will be collected starting after the 
first dose of SM (Visit 3) to the end of the study. These AEs include those that 
emerge during treatment or worsen in severity during treatment. These AEs will be 
tabulated, listed and analyzed. 
The incidence of AESIs based on AE data will be summarized for each treatment 
group by MedDRA SOC and PT. Supporting subject listing of AESI will be 
presented. For AESIs, percentages of subjects experiencing visual/ocular 
disturbances, oligohydrosis, hyperthermia, metabolic acidosis (serum bicarbonate), 
hyperammonemia, nephrolithiasis, and hepatic injury will be summarized using 
descriptive statistics by treatment and collection time point. 
Clinical laboratory values will be summarized by visit and treatment group using 
descriptive statistics. For quantitative laboratory parameters, both actual values 
and change from baseline (values collected at Screening) values will be 
summarized. 
Vital signs will be summarized by visit by treatment group using descriptive 
statistics. Both actual values and change from baseline will be summarized. 
Minor changes for completeness 
and/or clarification  

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ECG results will be summarized by visit by treatment group using descriptive 
statistics (for quantitative ECG parameters) and frequency tables (for qualitative 
ECG parameters, including the overall ECG finding). 
C-SSRS outcomes will be summarized using number and percent of subjects by 
categories for suicidal ideation only, suicidal behavior only and suicidality (ideation 
and behavior combined). The summary will be presented by treatment groups. 
For physical, neurological, and eye examinations, change in status from baseline to 
the end of study EOS will be summarized by body system for each treatment 
group.  
Cognitive function will be assessed by evaluating the responses from subject 
responses to the cognitive questionnaire. Responses to the questions will be 
presented in subject listing and summarized by study visit and treatment group. 
10.6 
98-103 
10.6 
(Appendix 6) Columbia-Suicide Severity Rating Scale 
10.6.1 
C-SSRS - Children’s Baseline (new section) 
10.6.2 
C-SSRS - Children’s Since Last Visit (new section) 
Major Change 
 
Version 3.0 contained only the 
Children’s Baseline version.  
Appendix 10.6 has the Children’s 
Baseline and Children’s Since Last 
Visit versions in two subsections. 
10.8 
105-107 
10.8 
(Appendix 7b) Eye Exam Checklist   
10.8.1 
Wall Snellen Chart (new section) 
10.8.2 
Amsler Grid Test (new section) 
Major Change 
 
Version 3.0 contained only the Eye 
Exam Checklist. Version 4.0 contains 
the Eye Exam Checklist and the two 
additional listed items in the 
subsections. 
10.9 
108 
10.9 
Concomitant Medications (new section) 
Major Change 
10.10 
109 
10.10 
Prohibited Medications (new section) 
 
 
 
 
Major Change 

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Section and page numbers refer to the amended protocol. 
Changes in figures and tables are described rather than reproduced as marked up text. 
 
 
Section 
Page 
Description of Change 
Rationale for Change 
10.11 
110-139 
10.11 
Summary of Changes (new section) 
Major Change – put Summary of 
Changes at the end to prevent 
pagination changes during the 
process of creating the Summary of 
Changes 

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This document is confidential. It contains proprietary information of Supernus® Pharmaceuticals, Inc. Any 
viewing or disclosure of such information that is not authorized in writing by the Sponsor is strictly prohibited. 
Such information may be used solely for the purpose of reviewing or performing this study. 
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