Clinical trial NCT02457819
Conditions: Attention Deficit Hyperactivity Disorder
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2015-06-30; Completion date: 2017-02-02
Enrollment: 237 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label 26 week extension study for subjects who completed SEP360-202.

Detailed description:
This is an open-label, flexibly-dosed, 26 week extension study in children and adolescents with ADHD who have completed 6 weeks of double-blind treatment in the core study (SEP360 202). This study will evaluate the long-term safety and tolerability of dasotraline in this population.

Arms: arm 1: Dasotraline 2, 4, 6 mg
Interventions: intervention 1: Dasotraline
Intervention descriptions: intervention 1: Dasotraline 2 mg, 4 mg, 6 mg, once daily, flexibly dosed

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
Dasotraline 
 
Protocol SEP360-310 
 
An Open-label, Flexibly-dosed, 26-Week Extension Safety Study 
of Dasotraline in Children and Adolescents with Attention Deficit 
Hyperactivity Disorder (ADHD) 
 
IND No. 71,283 
 
Version 3.00 
Incorporates Amendment No. 2 
 
20 Jan 2016 
 
SUNOVION PHARMACEUTICALS INC. 
84 Waterford Drive 
Marlborough, MA 01752, USA 
(508) 481-6700 
 


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RESTRICTED DISTRIBUTION OF PROTOCOLS 
This protocol and the data gathered during the conduct of this protocol contains information that 
is confidential and/or of proprietary interest to Sumitomo Dainippon Pharma Co. Ltd. and/or 
Sunovion Pharmaceuticals Inc. (including their predecessors, subsidiaries or affiliates). The 
information cannot be disclosed to any third party or used for any purpose other than the purpose 
for which it is being submitted without the prior written consent of the appropriate Sumitomo 
Dainippon Pharma company. 
This information is being provided to you for the purpose of conducting a clinical study for 
Sunovion Pharmaceuticals Inc. You may disclose the contents of this protocol to the study 
personnel under your supervision and to your Institutional Review Board or Independent Ethics 
Committee for the above purpose. You may not disclose the contents of this protocol to any 
other parties, unless such disclosure is required by government regulations or laws, without the 
prior written permission of Sunovion Pharmaceuticals Inc. 
Any data gathered during the conduct of this protocol and supplemental information (eg, a 
protocol amendment) that may be added to this document is also proprietary to Sunovion 
Pharmaceuticals Inc, and should be handled consistently with that stated above. 


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EMERGENCY CONTACTS 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Responsible Physician 
  
Telephone:  
Fax:  
Email: 
Medical Monitor 
 
Office Telephone: 
 Mobile Telephone: 
Fax: 
Email: 
SAE/Pregnancy Reporting 
 Fax: 
Email: 
 


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1. 
SYNOPSIS 
Name of Sponsor: Sunovion Pharmaceuticals Inc. 
Name of Investigational Product: Dasotraline (SEP-225289) 
Title of Study: An Open-label, Flexibly-dosed, 26-Week Extension Safety Study of Dasotraline in 
Children and Adolescents with Attention Deficit Hyperactivity Disorder (ADHD) 
Proposed Indication: Attention Deficit Hyperactivity Disorder (ADHD) 
Study Centers: Approximately 40 centers in the United States 
Phase of Development: 3 
Study Objectives:  
Primary: To evaluate the long-term safety and tolerability of flexibly-dosed dasotraline in children and 
adolescents with ADHD by the incidence of adverse events (AEs; or serious AEs), and AEs (or serious 
AEs) leading to discontinuation. 
Secondary:  
• 
To evaluate the long-term safety and tolerability of flexibly-dosed dasotraline in children and 
adolescents with ADHD by assessing clinical laboratory evaluations, vital signs, physical 
examinations, body height and weight, 12-lead electrocardiograms (ECG), Tanner Staging, 
Children's Sleep Habits Questionnaire (CSHQ), and the frequency and severity of suicidal 
ideation and suicidal behavior using the Columbia – Suicide Severity Rating Scale (C-SSRS) 
Children’s Assessment. 
• 
To assess the long-term effectiveness of dasotraline in children and adolescents with ADHD 
using the following assessments: 
o ADHD Rating Scale Version IV - Home Version (modified for investigator 
administration) (ADHD-RS-IV HV) 
o Clinical Global Impression – Severity (CGI-S) 
o Conners 3rd Edition Parent (Conners 3-P) 
• 
To evaluate health-related quality of life and functional impairment in children and adolescents 
with ADHD using the Weiss Functional Impairment Rating Scale – Parent Report (WFIRS-P). 
• 
To assess potential withdrawal symptoms following discontinuation of dasotraline treatment 
using the following assessments (administered during the withdrawal period): 
o Discontinuation-Emergent Signs and Symptoms (DESS) Scale 
o Physician Withdrawal Checklist (PWC) 
Study Design:  
This is an open-label, flexibly-dosed, 26-week extension study in children and adolescents with ADHD 
who have completed 6 weeks of double-blind treatment in the core study (SEP360-202). This study 
will evaluate the long-term safety and tolerability of dasotraline in this population. In addition, several 
measures of effectiveness will be included. Subjects who have completed the core study (ie, completed 
6-week visit) will be eligible to enroll in this extension study; subjects who discontinue from the core 
study will not be eligible to enroll in this study. Subjects will be evaluated for eligibility in this 


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extension study during the Week 6 visit of the core study. Informed assent by the subject and informed 
consent from at least one of the subject’s parents or legal guardians will be obtained before any study 
procedures are performed for this study. 
Subjects who meet all eligibility criteria will transition directly from the core study and will not need to 
complete the End of Study (EOS) visit in the core study. Subjects will take the first dose of open-label 
study drug in this extension study on Day 1, the morning following the open-label (OL) Baseline visit. 
Subjects will continue to take study drug for 26 weeks, at approximately the same time each morning 
including on the days when clinic visits occur. Dasotraline will be dosed at 2 mg/day for the first week 
of the study (Days 1 – 7). Subjects will then be flexibly dosed (2, 4, or 6 mg/day) thereafter beginning 
on Day 8 based on the investigator’s assessment of effectiveness and tolerability. All changes in study 
drug dose will begin the morning after the visit at which the dose change decision is made using the 
new package of study drug. Additional dose adjustment is allowed during the study at the discretion of 
the investigator; the dose may be increased or decreased by 2 mg/day, as necessary for effectiveness or 
tolerability reasons. Total daily dose will not exceed 6 mg/day. There is no limit on the number of dose 
increments or reductions during the study. A minimum of 7 days is required between dose increases. 
Dose decreases may be made at less than 7 day intervals for safety/tolerability reasons, at the 
investigator’s discretion. Subjects wishing to take study drug at an alternate time of day require 
investigator and medical monitor approval. 
After the OL Baseline visit, subjects will return to the clinic weekly for the first 2 weeks, once every 
2 weeks for the next 4-weeks, then once every 4 weeks for the remainder of the treatment period for 
clinical evaluation, and once at the end of the withdrawal period (Visit 13E). At the approximate 
midpoint between the scheduled monthly visits (ie, 14 ± 2 days after a visit) during the treatment 
period, the site staff will contact the subject’s parent/legal guardian via telephone, text, or email in 
order to evaluate the safety of the subjects as well as to remind subject/parent/legal guardian about 
adherence to study drug administration and upcoming visits, following which, if necessary, an 
unscheduled visit can be arranged. 
Safety and tolerability will be monitored throughout the study by collection of AEs, clinical laboratory 
evaluations, vital signs, physical examinations, body height and weight, 12-lead ECG, Tanner Staging, 
CSHQ, and the frequency and severity of suicidal ideation and suicidal behavior using C-SSRS. The 
measures of effectiveness, ADHD-RS-IV HV, CGI-S, and Conners 3-P, and assessment of health-
related quality of life and functional impairment, WFIRS-P, will be completed as scheduled (Table 2). 
A Data and Safety Monitoring Board (DSMB) will review safety and clinical outcome data including 
data on AEs and serious AEs at regular intervals. 
Assessment of potential withdrawal effects will be conducted via administration of the DESS and PWC 
at the end of study drug treatment (Visit 10E) and upon the completion of the withdrawal period 
(Visit 13E). In addition, the subject/parent/legal guardian will be called by the clinical site staff once a 
week (Day 189 ± 3 and Day 196 ± 3) during the withdrawal period to complete the DESS. Phone 
contacts may be made up to 3 times per day if the clinical site staff is unable to contact the 
subject/parent/legal guardian on the first 2 attempts. If the subject/parent/legal guardian cannot be 
contacted on a given day, during the next contact the study site staff will retrospectively collect the 
missed DESS, in addition to the current day’s DESS, as necessary. Clinical site staff will record the 
responses in the subject’s source information and in the CRF with the contact date and time. As noted 
above, all subjects will return to the clinic 3 weeks (± 7 days) after the final dose of study drug for 
withdrawal (DESS and the PWC) and EOS safety assessments (Visit 13E).  
Subjects who discontinue from the study prior to completion will be asked to return to the clinical site 
and complete the Early Termination assessments within 3 days of discontinuation and complete all 
withdrawal period assessments (calls) and EOS visit. 
After the EOS visit or upon discontinuation of study drug, all subjects will be referred for continuation 
of their care as determined by the investigator. 


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Number of Subjects (planned): This study is projected to enroll up to 330 subjects based on the 
number of subjects who complete the core study. 
Diagnosis and Main Criteria for Subject Inclusion:  
Eligibility criteria will be assessed at the OL Baseline visit (Week 6 in the core study). Assessments 
performed as part of the Week 6 visit in the core study do not need to be repeated. 
Inclusion Criteria: 
1. At least one of the subject’s parents/legal guardians must give written informed consent, 
including privacy authorization, prior to study participation. The subject will complete an 
informed assent prior to study participation. 
2. Subject and subject’s parent/legal guardian are judged by the investigator to be willing and 
able to comply with the study procedures and visit schedules. 
3. Subject has completed all required assessments for Week 6 of the core study. 
4. Subject has not taken any medication other than the study drug for the purpose of controlling 
ADHD symptoms during the core study. 
5. Subject, if female, must not be pregnant or breastfeeding. 
6. Female subject: 
• 
must be unable to become pregnant (eg, premenarchal, surgically sterile, etc); 
-OR- 
• 
practice true abstinence (consistent with lifestyle) and must agree to remain abstinent from 
signing informed consent/assent to at least 14 days after the last dose of study drug has 
been taken; 
-OR- 
• 
is sexually active and willing to use a medically effective method of birth control (see 
Appendix IV, Section 23) from signing informed consent/assent to at least 14 days after 
the last dose of study drug has been taken. 
7. Male subject must be willing to remain sexually abstinent (consistent with lifestyle) or use an 
effective method of birth control (see Appendix IV, Section 23) from signing informed 
consent/assent to at least 14 days after the last dose of study drug has been taken. 
8. Any subject whose weight is < 21 kg at the OL Baseline visit should be discussed with the 
medical monitor prior to enrollment. 
9. Subject and subject’s parent/legal guardian must be able to fully comprehend the informed 
consent/assent form (as applicable), understand all study procedures, and be able to 
communicate satisfactorily with the Investigator and study coordinator. 
Exclusion Criteria: 
1. Subject is considered by the investigator to be at imminent risk of suicide, injury to self or to 
others, or damage to property. 
2. Subject answers “yes” to “Suicidal Ideation” item 4 (active suicidal ideation with some intent 
to act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) 
for any lifetime history on the C-SSRS Children’s “Since Last Visit” assessment at OL 


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Baseline. 
3. Subject has a clinically significant abnormality including physical examination, vital signs, 
ECG, or laboratory tests that the investigator in consultation with the medical monitor 
considers to be inappropriate to allow participation in the study. 
4. Subject has a positive urine drug screen (UDS) or breath alcohol test at OL Baseline. 
5. Subject or parents/legal guardian has commitments during the study that would interfere with 
attending study visits. 
6. Subject is at high risk of non-compliance in the investigator’s opinion. 
Investigational Product, Dosage and Mode of Administration: Dasotraline 2, 4, and 6 mg capsules 
for oral administration will be supplied. One capsule of study drug will be taken once daily for 
26 weeks (Day 1 through Day 182), at approximately the same time each morning without regard for 
food including on the days when clinic visits occur. If morning dosing is not tolerated then dosing may 
be at another time of day with prior medical monitor approval; however, if there is a time of day dosing 
change, subjects should administer study drug at the same time of day for the remainder of the study. 
Dose schedule and adjustment are described under Study Design. 
Duration of Treatment: 26 weeks 
Reference Therapy, Dosage and Mode of Administration: Not applicable 
Concomitant Medications: 
Disallowed Medications During Study 
Use of any of the following medications is not permitted during the study through EOS: lithium (any 
lithium preparation or formulation); alpha-2 adrenergic receptor agonists (including clonidine and 
guanfacine), modafinil, armodafinil, atomoxetine, or any stimulant class (methylphenidate- or 
amphetamine-based) agent; antidepressant medications and St. John’s Wort; anticonvulsant 
medications and antipsychotic medications; pseudoephedrine-containing medications for treatment of 
allergies or flu-like symptoms; medications with significant effect on blood pressure or heart rate 
(Intermittent use of asthma treatments is permitted but should be discussed with the medical monitor.); 
sleep aids (with the exception of melatonin ≤ 5 mg/day); any medications for the treatment of ADHD; 
and CYP2B6 substrates or inhibitors or inducers of CYP2B6. 
Subjects who require persistent asthma treatment during the study should be discussed with the medical 
monitor as they may be required to be discontinued from the study. 
Other Treatment Restrictions: 
Subjects undergoing cognitive behavioral therapy (CBT) are excluded from entering the study. In 
addition, a new course of CBT specifically for ADHD is not allowed during the study. Unavoidable 
changes in school-based interventions that occur during study participation will not be exclusionary, 
but should be documented by the investigator, to the extent possible. 
Study Endpoints:  
Primary Endpoint: The incidence of overall AEs (or serious AEs), and AEs (or serious AEs) leading 
to discontinuation. 
Secondary Endpoints:  
• Clinical laboratory evaluations (serum chemistry, hematology, lipid panel, thyroid function 
panel, urinalysis, sex hormones). 
• Clinical evaluations (vital signs, physical examination, body height and weight, Tanner 


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Staging, and 12-lead ECG). 
• Frequency and severity of suicidal ideation and suicidal behavior using the C-SSRS. 
• Change in CGI-S score. 
• Change in ADHD-RS-IV HV total score. 
• Change in the inattentiveness and hyperactivity subscales of the ADHD-RS-IV HV. 
• Change in Conners 3-P total score and subscale scores (Oppositional, Cognitive problems, 
Hyperactivity, and ADHD Index). 
• Change in CSHQ total score and 8 subscale scores (bedtime resistance, sleep onset delay, sleep 
duration, sleep anxiety, night wakings, parasomnias, sleep disordered breathing, and daytime 
sleepiness). 
• Change in WFIRS-P total score and 6 domain scores (family, school learning behavior, life 
skills, child's self-concept, social activities, and risky activities). 
• Symptoms of withdrawal using: 
o PWC score 
o DESS score 
Statistical Methods:  
No statistical inference will be performed for treatment comparisons as this is a single arm, open-label, 
extension study. Continuous variables will be summarized using descriptive statistics of number of 
subjects, mean, standard deviation, median, minimum and maximum values. Categorical variables will 
be reported as frequencies and percentages. All statistical summaries will be presented by treatment 
group in the double-blind study as well as all subjects in the extension study. Changes from baseline in 
safety and effectiveness endpoints will be calculated from both the double-blind (DB) baseline in the 
core study and the OL baseline in the extension study, which is Week 6 endpoint in the core study. 
The summary of AEs and serious AEs will be limited to treatment emergent AEs (TEAE). The TEAEs 
will be summarized by system organ class (SOC) and preferred term (PT) by presenting the number 
and percentage of subjects with any TEAE. Descriptive statistics also will be provided by visit based 
on observed values and changes from baselines for the following safety variables: laboratory tests 
(hematology, chemistry, urinalysis, lipid panel, thyroid function panel, and sex hormones), vital signs, 
ECG parameters, Tanner staging, and CSHQ. Shift tables comparing OL baseline to end of study will 
be presented, as appropriate. In addition, the markedly abnormal post-baseline results will be 
summarized for certain safety parameters, as appropriate. The frequency and percentage by visit will be 
summarized for all C-SSRS responses. 
The long-term effectiveness data will be summarized descriptively for the changes from baseline in 
ADHD-RS-IV HV total score and subscale scores, CGI-S score, and Conners 3-P total score and 
subscale scores. 
The change from baseline in the WFIRS-P total score and its domain scores will be summarized. 
The PWC and DESS will be summarized using descriptive statistics by visit for the total score. 
Sample Size: 
This study is projected to enroll up to 330 subjects based on the number of subjects who complete the 
core study. 


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Table 2: 
Schedule of Assessments 
 
OL Baselinea 
Treatment Period 
Withdrawal Period 
Visit  
1E 
2E 
3E 
4E 
5E 
6E 
7E 
8E 
9E 
10E/ET 
11E 
Call 
12E 
Call 
13E/EOS 
Week 
 
Week 
1 
Week 
2 
Week 
4 
Week 
6 
Week 
10 
Week 
14 
Week 
18 
Week 
22 
Week 
26b 
Week 
27b 
Week 
28b 
Week 29b 
Day 
Day 0 
Day 7 
± 3 
Day 
14 ± 3 
Day 
28 ± 3 
Day 
42 ± 3 
Day 70 
± 3 
Day 98 
± 3 
Day 
126 ± 3 
Day 
154 ± 3 
Day 182 
± 3 
Day 189 
± 3 
Day 
196 ± 3 
Day 203 
± 7 
Obtain informed 
consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense study drugc  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Study drug accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Between visit contactd 
 
 
 
 
 
At the approximate midpoint between Visits 5E and 
6E, Visits 6E and 7E, Visits 7E and 8E, Visits 8E 
and 9E, and Visits 9E and 10E. 
 
 
 
Medical and Psychiatric 
History 
X (carried 
over) 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
review 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Physical examination 
X (carried 
over) 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Neurological examination 
X (carried 
over) 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Height (measured by 
stadiometer)  
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Weight (including body 
mass index) 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Vital signs 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Electrocardiogram (ECG) 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 


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Table 2:  
 
 
Schedule of Assessments (Continued) 
 
OL Baselinea 
Treatment Period 
Withdrawal Period 
Visit  
1E 
2E 
3E 
4E 
5E 
6E 
7E 
8E 
9E 
10E/ET 
11E 
Call 
12E 
Call 
13E/EOS 
Week 
 
Week 
1 
Week 
2 
Week 
4 
Week 
6 
Week 
10 
Week 
14 
Week 
18 
Week 
22 
Week 
26b 
Week 
27b 
Week 
28b 
Week 29b 
Day 
Day 0 
Day 7 
± 3 
Day 
14 ± 3 
Day 
28 ± 3 
Day 
42 ± 3 
Day 70 
± 3 
Day 98 
± 3 
Day 
126 ± 3 
Day 
154 ± 3 
Day 182 
± 3 
Day 189 
± 3 
Day 
196 ± 3 
Day 203 
± 7 
Adverse event monitoring 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Tanner Staging  
X (carried 
over) 
 
 
 
 
 
 
 
 
X 
 
 
 
Columbia Suicide Severity 
Rating Scale (C-SSRS) 
Children’s Assessmente  
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Clinical Global Impression – 
Severity (CGI-S) 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ADHD Rating Scale 
Version IV - Home Version 
(modified for investigator 
administration) (ADHD-RS-
IV HV) 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Conners 3rd Edition Parent 
(Conners 3-P) 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Children's Sleep Habits 
Questionnaire (CSHQ) 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Weiss Functional 
Impairment Rating Scale – 
Parent Report (WFIRS-P) 
X (carried 
over) 
 
 
 
 
 
X 
 
 
X 
 
 
 
Physician Withdrawal 
Checklist (PWC)j 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Discontinuation-Emergent 
Signs and Symptoms 
(DESS) Scale j 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 


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Table 2:  
 
 
Schedule of Assessments (Continued) 
 
OL Baselinea 
Treatment Period 
Withdrawal Period 
Visit  
1E 
2E 
3E 
4E 
5E 
6E 
7E 
8E 
9E 
10E/ET 
11E 
Call 
12E 
Call 
13E/EOS 
Week 
 
Week 
1 
Week 
2 
Week 
4 
Week 
6 
Week 
10 
Week 
14 
Week 
18 
Week 
22 
Week 
26b 
Week 
27b 
Week 
28b 
Week 29b 
Day 
Day 0 
Day 7 
± 3 
Day 
14 ± 3 
Day 
28 ± 3 
Day 
42 ± 3 
Day 70 
± 3 
Day 98 
± 3 
Day 
126 ± 3 
Day 
154 ± 3 
Day 182 
± 3 
Day 189 
± 3 
Day 
196 ± 3 
Day 203 
± 7 
Hematology/Chemistry 
X (carried 
over) 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Thyroid panelf 
X (carried 
over) 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Lipid panelg  
X (carried 
over) 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Sex hormone testsh 
X (carried 
over) 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Serum β-hCG (in females)i 
X (carried 
over) 
 
 
 
 
 
 
 
 
 
 
 
X 
Urinalysis 
X (carried 
over) 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Urine drug screen  
X (carried 
over) 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
Urine β-hCG (in females)i 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Breath alcohol test 
X (carried 
over) 
 
 
 
 
 
X 
 
 
 
 
 
X 
Abbreviations: β-hCG = beta-human chorionic gonadotropin, EOS = end of study, ET = early termination, OL = open label 
a Week 6 in core study. Baseline assessments indicated as “carried over” are performed as part of Week 6 visit in the core study (with the exception of medical 
and psychiatric history from screening in the core study) and do not need to be repeated; the data will be duplicated from Week 6 visit in the core study. 
b Subjects who discontinue from the study prior to completion will be asked to return to the site and complete the ET assessments within 3 days of 
discontinuation and complete all withdrawal period assessments (calls) and EOS visit. 
 
Footnotes are continued on the next page. 


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c Subjects will take the first dose of study drug in this study on Day 1, the morning following the baseline visit; there will be no break in study drug treatment 
between the core study and this extension study. All study drug will be administered by the subject in the morning. Subjects wishing to take study drug at an 
alternate time of day require investigator and medical monitor approval. 
d At the approximate midpoint between the scheduled monthly visits during the treatment period, the site staff will contact the subject’s parent/legal guardian via 
telephone, text, or email in order to evaluate the safety of the subject, as well as to remind subject/parent/legal guardian about adherence to study drug 
administration and upcoming visits, following which an unscheduled visit may be scheduled, if necessary. The date and time of these contacts will be 
documented in the case report form (CRF). 
e Subjects who have significant findings for suicidal ideation upon completion of the C-SSRS at any time during the study must be referred to the investigator for 
follow-up evaluation. 
f Thyroid-stimulating hormone (TSH), free T4, and free T3 will be evaluated. 
g Subjects should be fasted (no food or drink except water at least 8 hours prior to blood draws for the lipid panel). Blood samples should be drawn in the 
morning followed by a snack or meal. 
h For females: estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). For males: testosterone. 
i Females ≥ 8 years of age. Any positive urine β-hCG test should be confirmed by serum β-hCG. 
j Clinical site staff will call the subject/parent/legal guardian each week (Day 189 ± 3 and Day 196 ± 3) during the study medication withdrawal period in order to 
complete the Discontinuation-Emergent Signs and Symptoms (DESS). Clinical site staff may call up to 3 times per day if the clinical site staff are unable to 
contact the subject/parent/legal guardian on the first 2 attempts. If the subject/parent/legal guardian cannot be contacted on a given day, during the next contact 
the study site staff will retrospectively collect the DESS from the missed day and the current day, as necessary.


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
RESTRICTED DISTRIBUTION OF PROTOCOLS ......................................................................2 
EMERGENCY CONTACTS...........................................................................................................3 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............13 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
4. 
INTRODUCTION ......................................................................................................22 
4.1. 
Background .................................................................................................................22 
4.2. 
Study Conduct Rationale ............................................................................................23 
4.3. 
Risk-Benefit Assessment ............................................................................................23 
5. 
STUDY OBJECTIVES ..............................................................................................25 
5.1. 
Primary Objectives .....................................................................................................25 
5.2. 
Secondary Objectives .................................................................................................25 
6. 
STUDY ENDPOINTS ................................................................................................26 
6.1. 
Primary Endpoint ........................................................................................................26 
6.2. 
Secondary Endpoints ..................................................................................................26 
7. 
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design ..................................................................................................27 
7.2. 
Rationale .....................................................................................................................28 
7.2.1. 
Rationale for the Study Design ...................................................................................28 
7.2.2. 
Rationale for the Dosages ...........................................................................................29 
7.2.3. 
Rationale for the Study Population .............................................................................29 
7.2.4. 
Rationale for the Endpoints ........................................................................................29 
7.2.5. 
Prevention of Missing Data ........................................................................................29 
8. 
SELECTION OF SUBJECTS ....................................................................................31 
8.1. 
Subject Inclusion Criteria ...........................................................................................31 
8.2. 
Subject Exclusion Criteria ..........................................................................................32 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................33 
9.1. 
Description of Study Drug ..........................................................................................33 


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9.2. 
Study Drug Packaging and Labeling ..........................................................................33 
9.2.1. 
Package Description ...................................................................................................33 
9.2.2. 
Labeling Description ..................................................................................................33 
9.3. 
Study Drug Storage .....................................................................................................34 
9.4. 
Dispensing of Study Drug ..........................................................................................34 
9.5. 
Study Drug Accountability .........................................................................................34 
9.6. 
Study Drug Handling and Disposal ............................................................................35 
10. 
TREATMENT OF SUBJECTS ..................................................................................36 
10.1. 
Study Medication ........................................................................................................36 
10.2. 
Dose Adjustment Criteria ...........................................................................................36 
10.3. 
Concomitant Medications and Therapies ...................................................................36 
10.3.1. 
Prohibited Medications ...............................................................................................36 
10.3.2. 
Prohibited Therapies ...................................................................................................37 
10.3.3. 
Permitted Medications ................................................................................................37 
10.4. 
Guidance for Overdose ...............................................................................................37 
10.5. 
Cautions ......................................................................................................................38 
10.6. 
Dietary Guidelines ......................................................................................................38 
10.7. 
Treatment Compliance ................................................................................................38 
10.8. 
Treatment Assignment and Blinding ..........................................................................38 
10.8.1. 
Treatment Assignment ................................................................................................38 
10.8.2. 
Blinding ......................................................................................................................38 
11. 
STUDY ASSESSMENTS ..........................................................................................39 
11.1. 
Demographics and Baseline Characteristics ...............................................................39 
11.2. 
Efficacy Assessments .................................................................................................39 
11.2.1. 
Efficacy Scales ............................................................................................................39 
11.3. 
Safety Assessments .....................................................................................................40 
11.3.1. 
Adverse Events ...........................................................................................................40 
11.3.2. 
Clinical Laboratory Tests ...........................................................................................40 
11.3.3. 
Physical and Neurological Examinations ...................................................................41 
11.3.4. 
Vital Signs ..................................................................................................................41 
11.3.5. 
ECGs ...........................................................................................................................41 
11.3.6. 
Safety Scales ...............................................................................................................41 
11.4. 
Study Visits and Assessments ....................................................................................42 


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11.4.1. 
Open-label Baseline: Visit 1E (Day 0) .......................................................................42 
11.4.2. 
Visit 2E: Week 1 (Day 7 ± 3) .....................................................................................43 
11.4.3. 
Visit 3E: Week 2 (Day 14 ± 3) ...................................................................................43 
11.4.4. 
Visit 4E: Week 4 (Day 28 ± 3) ...................................................................................44 
11.4.5. 
Visit 5E: Week 6 (Day 42 ± 3) ...................................................................................44 
11.4.6. 
Visit 6E: Week 10 (Day 70 ± 3) .................................................................................44 
11.4.7. 
Visit 7E: Week 14 (Day 98 ± 3) .................................................................................45 
11.4.8. 
Visit 8E: Week 18 (Day 126 ± 3) ...............................................................................45 
11.4.9. 
Visit 9E: Week 22 (Day 154 ± 3) ...............................................................................45 
11.4.10. 
Visit 10E: Week 26 (Day 182 ± 3) / Early Termination .............................................46 
11.4.11. 
Withdrawal Period ......................................................................................................46 
11.4.11.1. Visit 11E /Telephone Contact: Week 27 (Day 189 ± 3) .............................................46 
11.4.11.2. Visit 12E /Telephone Contact: Week 28 (Day 196 ± 3) .............................................47 
11.4.11.3. Visit 13E / End of Study: Week 29 (Day 203 ± 7) .....................................................47 
11.4.12. 
Between Visit Contacts ...............................................................................................47 
12. 
SAFETY REPORTING ..............................................................................................48 
12.1. 
Definitions ..................................................................................................................48 
12.1.1. 
Adverse Events ...........................................................................................................48 
12.1.2. 
Serious Adverse Events ..............................................................................................48 
12.2. 
Objective Findings ......................................................................................................49 
12.3. 
Collection and Recording Adverse Events .................................................................50 
12.4. 
Immediately Reportable Events ..................................................................................51 
12.4.1. 
Serious Adverse Event ................................................................................................51 
12.4.2. 
Pregnancy ...................................................................................................................52 
12.5. 
Data Monitoring Committee/Data and Safety Monitoring Board ..............................52 
13. 
TERMINATION OF SUBJECT FROM STUDY/DISCONTINUATION OF 
STUDY DRUG ...........................................................................................................53 
13.1. 
Criteria for Subject Termination .................................................................................53 
14. 
STUDY TERMINATION ..........................................................................................54 
15. 
STATISTICS ..............................................................................................................55 
15.1. 
Sample Size Determination ........................................................................................55 
15.2. 
Analysis Populations ..................................................................................................55 
15.3. 
Data Analysis ..............................................................................................................55 


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15.3.1. 
Subject Disposition .....................................................................................................55 
15.3.2. 
Drug Exposure and Compliance .................................................................................55 
15.3.3. 
Important Protocol Deviations ....................................................................................55 
15.3.4. 
Demographic and Baseline Characteristics ................................................................56 
15.3.5. 
Effectiveness Analysis ................................................................................................56 
15.3.5.1. 
Effectiveness Endpoint Analyses ...............................................................................56 
15.3.5.2. 
Subgroup Analysis ......................................................................................................56 
15.3.6. 
Safety Analysis ...........................................................................................................56 
15.3.6.1. 
Adverse Events ...........................................................................................................56 
15.3.6.2. 
Clinical Laboratory Assessments ...............................................................................57 
15.3.6.3. 
Centrally-read ECG ....................................................................................................57 
15.3.6.4. 
Vital Signs ..................................................................................................................57 
15.3.6.5. 
Neurological Examination ..........................................................................................57 
15.3.6.6. 
Tanner Staging ............................................................................................................58 
15.3.6.7. 
Breath Alcohol Test ....................................................................................................58 
15.3.6.8. 
Prior and Concomitant Medications ...........................................................................58 
15.3.6.9. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................58 
15.3.6.10. Children's Sleep Habits Questionnaire (CSHQ) .........................................................58 
15.3.6.11. Physician Withdrawal Checklist (PWC), and Discontinuation-Emergent 
Signs and Symptoms (DESS) Scale ...........................................................................58 
15.3.6.12. Subgroup Analyses .....................................................................................................58 
16. 
PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL /DATA 
COLLECTION, MANAGEMENT, AND QUALITY ASSURANCE ......................59 
16.1. 
Data Collection/Electronic Data Capture (EDC) ........................................................59 
16.2. 
Computerized Systems Used for Source Data ............................................................59 
16.3. 
Study Monitoring ........................................................................................................61 
16.4. 
Audits ..........................................................................................................................61 
16.5. 
Study Documentation .................................................................................................61 
16.6. 
Clinical Laboratory Certification and Normal Values ................................................61 
17. 
ETHICAL AND REGULATORY OBLIGATIONS..................................................62 
17.1. 
Study Conduct ............................................................................................................62 
17.2. 
Institutional Review Board/Independent Ethics Committee ......................................62 
17.3. 
Informed Consent .......................................................................................................63 


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17.4. 
Subject Privacy ...........................................................................................................64 
17.5. 
Protocol Amendments and Emergency Deviations ....................................................64 
17.6. 
Records Retention .......................................................................................................64 
17.7. 
Inspection of Records .................................................................................................64 
17.8. 
Financial Disclosure ...................................................................................................64 
17.9. 
Publication Policy .......................................................................................................65 
18. 
INVESTIGATOR APPROVAL .................................................................................66 
19. 
REFERENCES ...........................................................................................................67 
20. 
APPENDIX I. CARDIAC SAFETY MONITORING (ECG) ....................................69 
21. 
APPENDIX II. CLINICALLY RELEVANT CYP2B6 SUBSTRATES OR 
INDUCERS OR INHIBITORS (GENERIC NAMES) ..............................................70 
22. 
APPENDIX III. CLINICAL LABORATORY TESTS ..............................................71 
23. 
APPENDIX IV. ACCEPTABLE CONTRACEPTIVE PROCEDURES 
DURING THE STUDY ..............................................................................................72 
24. 
APPENDIX V. TOTAL BLOOD VOLUMES ..........................................................73 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Assessments ..............................................................................................9 
Table 3: 
List of Abbreviations ..................................................................................................18 
Table 4: 
Definition of Key Study Terms ..................................................................................21 
Table 5: 
Investigational Product ...............................................................................................33 
Table 6: 
Between Visit Contact Timeline .................................................................................47 
Table 7: 
Computerized Systems Used for Source Data ............................................................60 
Table 8: 
Blood Collection Volumes (mL) ................................................................................73 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................28 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The abbreviations and the definition of key study terms used in the clinical study protocol are 
shown in Table 3 and Table 4. 
Table 3: 
List of Abbreviations 
Abbreviation 
Full Form 
ADHD 
Attention deficit hyperactivity disorder 
ADHD-RS-IV HV ADHD Rating Scale Version IV - Home Version (modified for 
investigator administration) 
AE 
Adverse event 
ATC 
Anatomical therapeutic chemical 
BMI 
Body mass index  
CBT 
Cognitive behavioral therapy 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression–Severity of Illness 
CIMS 
Clinical Inventory Management System 
Conners 3-P 
Conners 3rd Edition Parent 
CRF 
Case report form 
CRO 
Contract research organization 
CSHQ 
Children's Sleep Habits Questionnaire 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTM 
Clinical trial material 
DAT 
Dopamine transporter 
DBL 
Database lock 
DESS 
Discontinuation-Emergent Signs and Symptoms 
DHPG 
3, 4-dihydroxyphenylglycol 
DNRI 
Dopamine and norepinephrine, reuptake inhibitor 
DSM-5 
Diagnostic and Statistical Manual for Mental Disorders Fifth 
Edition 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOS 
End of study 
FDA 
US Food and Drug Administration 


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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
GCP 
Good Clinical Practice 
HR 
Heart rate  
IAF 
Informed assent form 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISI 
Insomnia Severity Index 
ITT 
Intention-to-Treat 
IXRS 
Interactive response system 
K-SADS-PL 
Schedule for Affective Disorders and Schizophrenia for School-
Age Children Present and Lifetime Version 
MAO 
Monoamine oxidase 
MDD 
Major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
NET 
Norepinephrine transporter 
ODD 
Oppositional defiant disorder  
OL 
Open-label 
PK 
Pharmacokinetic(s) 
PR 
Time between P wave and QRS in electrocardiography 
PT 
Preferred term 
PWC 
Physician Withdrawal Checklist 
QRS 
Electrocardiographic wave (complex or interval) 
QT 
Electrocardiographic interval from the beginning of the QRS 
complex to the end of the T wave 
QTc 
QT interval corrected for heart rate 
RR 
RR interval 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SNRI 
Serotonin norepinephrine reuptake inhibitor 
SSRI 
Selective serotonin reuptake inhibitor 


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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
UDS 
Urine drug screen 
WFIRS-P 
Weiss Functional Impairment Rating Scale – Parent Report 
WHODRUG 
World Health Organization drug dictionary 
 


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Table 4: 
Definition of Key Study Terms  
Terms 
Definition of terms 
CRF 
A printed, optical, or electronic document designed to record all 
of the protocol required information to report to the Sponsor for 
each study subject. 
Study Drug (or 
Study medication) 
Term to cover investigational drug. 
Treatment Period 
The period of the study in which the study drug is administered. 
Completed Subject 
Any subject who participated throughout the duration of the 
study, up to and including the last on-treatment visit (Week 26). 
Early Termination 
Subject 
Any subject who was successfully screened and enrolled into the 
treatment period of the study, but did not complete the study. 
End of Treatment 
The day that the subject receives protocol-defined last dose of the 
study drug. 
End of Study 
The day that the subject completes the study per the study design. 
 


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4. 
INTRODUCTION 
4.1. 
Background 
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized 
by persistent inattention, hyperactivity, and impulsivity that is more severe or frequent when 
compared to individuals of the same developmental stage. There are a number of characteristics 
related to cognition that distinguish people with ADHD from people without ADHD including 
deficits in response inhibition (Aron-2005, Goto-2010, Luna-2004) and reward sensitivity 
(Passarotti-2011), as well as working memory, attention, planning, and behavioral inhibition 
(Hervey-2004, Boonstra-2005, Willcutt-2005). ADHD is prevalent in approximately 8% to 10% 
of school-aged children and approximately 2% to 5% of adults (Ferri-2014). Symptoms 
experienced in childhood often persist into adolescence and adulthood, though the hyperactivity 
component tends to diminish over time (Ferri-2014). 
The etiology of ADHD is not fully understood, but it is believed that both genetic and non-
genetic factors are implicated in the disease. Several factors related to disturbances of neonatal 
development including premature birth, low birth weight, and perinatal complications have been 
shown to increase the risk of developing ADHD in childhood (Perricone-2013, Botting-1997, 
Amor-2005). The neurotransmitters dopamine and norepinephrine, and perhaps to a lesser degree 
serotonin, are expected to have a critical role in the development of ADHD and thus receptors 
associated with these are key drug targets (Rader-2009). Changes in serotonergic, cholinergic, 
and mostly dopaminergic functioning have been documented in children with ADHD 
(Dopheide-2011). 
Current ADHD pharmacotherapies have effects on central catecholamine neurotransmission. In 
nonclinical microdialysis studies, ADHD drugs like amphetamine, methylphenidate, and 
atomoxetine increase dopamine and norepinephrine – either by reuptake inhibition or stimulation 
of release – especially in the prefrontal cortex. At clinically-efficacious doses, 50% dopamine 
transporter (DAT) occupancies are reported with methylphenidate in adults with ADHD 
(Volkow-1998). 
Adrenergic signaling in the prefrontal cortex is thought to control attentional processes and thus 
contribute to working memory and executive functions (Arnsten-2011, Gamo-2011). Consistent 
with this neuronal circuitry, norepinephrine transporter (NET) inhibition (eg, atomoxetine) alone 
is sufficient for clinical efficacy in ADHD. The stimulants amphetamine and methylphenidate 
both increase norepinephrine concentrations centrally, and methylphenidate achieves 50% NET 
occupancy in human subjects at doses clinically efficacious in ADHD (Hannestad-2010). 
Dasotraline (also known as SEP-225289) is a new chemical entity that is thought to produce its 
therapeutic effects in ADHD by inhibition of the presynaptic dopamine transporter (DAT) and 
NET, as determined by receptor occupancy and microdialysis studies. Pharmacologically, 
dasotraline is consistent with dopamine and norepinephrine, reuptake inhibitor (DNRI) effects. 
Dasotraline is a diastereomer of the major metabolite of the selective serotonin reuptake inhibitor 
sertraline, but is not a metabolite of sertraline, nor is it converted to the desmethylated metabolite 
of sertraline in vivo. Unlike amphetamines, dasotraline does not increase the release of these 
monoamines into the extraneuronal space. Dasotraline's pharmacokinetic profile, unique among 


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ADHD treatments, allows plasma concentrations to remain in a therapeutic range over the 
24 hour dosing interval at steady state. 
The evaluation of the pharmacokinetics and safety of dasotraline in pediatric and adolescent 
subjects is currently ongoing (Study SEP360-105). Study SEP360-105 will evaluate the safety, 
tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of dasotraline in 
subjects 6 – 17 years old with ADHD. It is a multicenter, open-label study in which subjects are 
assigned to study drug in a dose-escalating manner. The doses planned to be evaluated range 
from 1 - 32 mg. Additionally, the safety and efficacy of dasotraline in 6 – 12 year old subjects 
with ADHD is ongoing in a randomized, double-blind, multicenter, placebo-controlled, 
parallel-group, outpatient study (SEP360-202). 
Further information on nonclinical and clinical studies is provided in the Investigator’s Brochure. 
As there is a considerable unmet medical need for ADHD medications in children and 
adolescents that may warrant long-term treatment, Sunovion believes dasotraline, a novel 
inhibitor of NET and DAT, may be a useful addition to the current treatment armamentarium. 
Based on the available data dasotraline may provide steady, full-day coverage of DAT and NET 
inhibition. Dasotraline is being evaluated as a once daily treatment for children, adolescents and 
adults with ADHD with possible therapeutic coverage across the 24-hour dosing interval. 
4.2. 
Study Conduct Rationale 
ADHD is prevalent in approximately 8% to 10% of school-aged children (Ferri-2014) and causes 
substantial impairments in everyday functioning that may warrant long-term treatment. A 
medication such as dasotraline that may provide therapeutic coverage across a 24-hour dosing 
interval may prove beneficial for the treatment of ADHD. 
This is an open-label extension study to evaluate the safety and effectiveness of flexibly-dosed 
dasotraline over 26 weeks of treatment in children and adolescents with ADHD who completed 
6 weeks of double-blind treatment in Study SEP360-202 (ie, the core study). 
4.3. 
Risk-Benefit Assessment 
Two studies were recently completed to support dasotraline as a safe and efficacious treatment 
for adults with ADHD with minimal abuse potential. 
The first study, SEP360-201, a randomized, double-blind, parallel-group, outpatient study at 
30 sites, evaluated the efficacy and safety of dasotraline in adults with ADHD using 2 doses 
(4 mg/day or 8 mg/day) versus placebo over a 4-week treatment period. In this study, clinically 
meaningful treatment effects were observed for both dasotraline 4 mg/day and 8 mg/day 
compared to placebo. For the primary efficacy endpoint, change from baseline in ADHD RS-IV 
with adult prompts total score at week 4, statistical significance was achieved for dasotraline 
8 mg/day compared to placebo (adjusted p = 0.019) with a strong trend for dasotraline 4 mg/day 
(adjusted p = 0.076). Efficacy with both doses was observed for the secondary endpoint change 
from baseline in CGI-S (4 mg group p = 0.021; 8 mg group p = 0.013). A dose response 
relationship was observed supporting pharmacological activity in ADHD. Decreases in 
3, 4-dihydroxyphenylglycol (DHPG) concentrations indicated the presence of central NET 
inhibition. Treatment-emergent AEs (TEAEs) were consistent with dasotraline pharmacology, ie, 
insomnia, decreased appetite, dry mouth, and headache. Worsening of insomnia associated with 


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dasotraline was characterized by TEAEs, and shifts in Insomnia Severity Index (ISI) total score, 
particularly with dasotraline 8 mg/day. TEAEs, particularly insomnia, were the most frequent 
reason for discontinuation of dasotraline 8 mg/day. Decreases in mean body weight were 
generally greater for dasotraline 8 mg/day than 4 mg/day. Increases in mean supine and standing 
heart rate observed during treatment and follow-up were generally higher on dasotraline 
8 mg/day than 4 mg/day. 
No signs or symptoms of withdrawal upon discontinuation of dasotraline were observed for 
either dose. In addition, there was no evidence of drug liking or deterioration of psychiatric 
symptoms associated with either dose of dasotraline. No misuse or diversion of dasotraline was 
detected through the abuse potential monitoring plan 
A second study, SEP360-101, evaluated dasotraline’s abuse liability and was conducted in 
recreational stimulant users; results indicated that dasotraline has low abuse liability. All doses of 
dasotraline (8, 16, 36 mg) demonstrated significantly lower drug liking scores than 
methylphenidate (40, 80 mg) and were no greater than placebo. 
Four previous clinical studies in healthy adult subjects using single doses ranging from 0.2 mg to 
36 mg and doses of 1 mg/day to 3 mg/day for durations up of 21 days, and 1 study in adult 
subjects with major depressive disorder (MDD) using doses of 0.5 mg/day and 2 mg/day for up 
to 8 weeks (56 days) have been completed. In these clinical studies, dasotraline was generally 
safe and well tolerated at the doses studied and there was no evidence of abuse or diversion and 
no symptoms of withdrawal. 


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5. 
STUDY OBJECTIVES 
5.1. 
Primary Objectives 
To evaluate the long-term safety and tolerability of flexibly-dosed dasotraline in children and 
adolescents with ADHD by the incidence of adverse events (AEs; or serious AEs [SAEs]), and 
AEs (or SAEs) leading to discontinuation. 
5.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the long-term safety and tolerability of flexibly-dosed dasotraline in 
children and adolescents with ADHD by assessing clinical laboratory evaluations, 
vital signs, physical examinations, body height and weight, 12-lead 
electrocardiograms (ECG), Tanner Staging, Children's Sleep Habits Questionnaire 
(CSHQ), and the frequency and severity of suicidal ideation and suicidal behavior 
using the Columbia – Suicide Severity Rating Scale (C-SSRS) Children’s 
Assessment. 
• To assess the long-term effectiveness of dasotraline in children and adolescents with 
ADHD using the following assessments: 
− the ADHD Rating Scale Version IV - Home Version (modified for investigator 
administration) (ADHD-RS-IV HV) 
− the Clinical Global Impression – Severity (CGI-S) 
− the Conners 3rd Edition Parent (Conners 3-P) 
• To evaluate health-related quality of life and functional impairment in children and 
adolescents with ADHD using the Weiss Functional Impairment Rating Scale – 
Parent Report (WFIRS-P). 
• To assess potential withdrawal symptoms following discontinuation of dasotraline 
treatment using the following assessments (administered during the withdrawal 
period): 
− Discontinuation-Emergent Signs and Symptoms (DESS) Scale 
− Physician Withdrawal Checklist (PWC) 


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6. 
STUDY ENDPOINTS 
6.1. 
Primary Endpoint 
The incidence of overall AEs (or SAEs), and AEs (or SAEs) leading to discontinuation. 
6.2. 
Secondary Endpoints 
The secondary endpoints are: 
• Clinical laboratory evaluations (serum chemistry, hematology, lipid panel, thyroid 
function panel, urinalysis, sex hormones). 
• Clinical evaluations (vital signs, physical examination, body height and weight, 
Tanner Staging, and 12-lead ECG). 
• Frequency and severity of suicidal ideation and suicidal behavior using the C-SSRS. 
• Change in CGI-S score. 
• Change in ADHD-RS-IV HV total score. 
• Change in the inattentiveness and hyperactivity subscales of the ADHD-RS-IV HV. 
• Change in Conners 3-P total score and subscale scores (Oppositional, Cognitive 
problems, Hyperactivity, and ADHD Index). 
• Change in CSHQ total score and 8 subscale scores (bedtime resistance, sleep onset 
delay, sleep duration, sleep anxiety, night wakings, parasomnias, sleep disordered 
breathing, and daytime sleepiness). 
• Change in WFIRS-P total score and 6 domain scores (family, school learning 
behavior, life skills, child's self-concept, social activities, and risky activities). 
• Symptoms of withdrawal using: 
− PWC score 
− DESS score 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is an open-label, flexibly-dosed, 26-week extension study in children and adolescents with 
ADHD who have completed 6 weeks of double-blind treatment in the core study. This study will 
evaluate the long-term safety and tolerability of dasotraline in this population. In addition, 
several measures of effectiveness will be included. Subjects who have completed the core study 
(ie, completed Week 6 visit) will be eligible to enroll in this extension study; subjects who 
discontinue from the core study will not be eligible to enroll in this study. Subjects will be 
evaluated for eligibility in this extension study during the Week 6 visit of the core study. 
Informed assent by the subject and informed consent from at least one of the subject’s parents or 
legal guardians will be obtained before any study procedures are performed for this study. 
Subjects who meet all eligibility criteria will transition directly from the core study and will not 
need to complete the End of Study (EOS) visit in the core study. Subjects will take the first dose 
of open-label study drug in this extension study on Day 1, the morning following the open-label 
(OL) Baseline visit. Subjects will continue to take study drug for 26 weeks, at approximately the 
same time each morning including on the days when clinic visits occur. Dasotraline will be 
dosed at 2 mg/day for the first week of the study (Days 1 - 7). Subjects will then be flexibly 
dosed (2, 4, or 6 mg/day) thereafter beginning on Day 8 based on the investigator’s assessment 
of effectiveness and tolerability. All changes in study drug dose will begin the morning after the 
visit at which the dose change decision is made using the new package of study drug. Additional 
dose adjustment is allowed during the study at the discretion of the investigator; the dose may be 
increased or decreased by 2 mg/day, as necessary for effectiveness or tolerability reasons. Total 
daily dose will not exceed 6 mg/day. There is no limit on the number of dose increments or 
reductions during the study. A minimum of 7 days is required between dose increases. Dose 
decreases may be made at less than 7 day intervals for safety/tolerability reasons, at the 
investigator’s discretion. Subjects wishing to take study drug at an alternate time of day require 
investigator and medical monitor approval. 
After the OL Baseline visit, subjects will return to the clinic weekly for the first 2 weeks, once 
every 2 weeks for the next 4 weeks, then once every 4 weeks for the remainder of the treatment 
period for clinical evaluation, and once at the end of the withdrawal period (Visit  13E). At the 
approximate midpoint between the scheduled monthly visits (ie, 14 ± 2 days after a visit) during 
the treatment period, the site staff will contact the subject’s parent/legal guardian via telephone, 
text, or email in order to evaluate the safety of the subjects as well as to remind 
subject/parent/legal guardian about adherence to study drug administration and upcoming visits, 
following which, if necessary, an unscheduled visit can be arranged.  
Safety and tolerability will be monitored throughout the study by collection of AEs, clinical 
laboratory evaluations, vital signs, physical examinations, body height and weight, 12 lead ECG, 
Tanner Staging, CSHQ, and the frequency and severity of suicidal ideation and suicidal behavior 
using C-SSRS. The measures of effectiveness, ADHD-RS-IV HV, CGI-S, and Conners 3-P, and 
assessment of health-related quality of life and functional impairment, WFIRS-P, will be 
completed as scheduled (Table 2). 


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A Data and Safety Monitoring Board (DSMB) will review safety and clinical outcome data 
including data on AEs and serious AEs at regular intervals. 
Assessment of potential withdrawal effects will be conducted via administration of the DESS 
and PWC at the end of study drug treatment (Visit 10E) and upon the completion of the 
withdrawal period (Visit 13E). In addition, the subject/parent/legal guardian will be called by the 
clinical site staff once a week (Day 189 ± 3 and Day 196 ± 3) during the withdrawal period to 
complete the DESS. Phone contacts may be made up to 3 times per day if the clinical site staff is 
unable to contact the subject/parent/legal guardian on the first 2 attempts. If the 
subject/parent/legal guardian cannot be contacted on a given day, during the next contact the 
study site staff will retrospectively collect the missed DESS, in addition to the current day’s 
DESS, as necessary. Clinical site staff will record the responses in the subject’s source 
information and in the CRF with the contact date and time. As noted above, all subjects will 
return to the clinic 3 weeks (± 7 days) after the final dose of study drug for withdrawal (DESS 
and the PWC) and EOS safety assessments (Visit 13E). 
Subjects who discontinue from the study prior to completion will be asked to return to the 
clinical site and complete the Early Termination assessments within 3 days of discontinuation 
and complete all withdrawal period assessments (calls) and EOS visit. 
After the EOS visit or upon discontinuation of study drug, all subjects will be referred for 
continuation of their care as determined by the investigator. 
A study schematic is presented in Figure 1. Details of the study assessments and other 
procedures to be performed at each visit are presented in Table 2 Schedule of Assessments, and 
Section 11, Study Assessments. 
 
Figure 1: 
Study Schematic 
 
 
 
 
 
 
 
 
 
7.2. 
Rationale 
7.2.1. 
Rationale for the Study Design 
This is an open-label study to evaluate the long-term safety and effectiveness of flexibly-dosed 
dasotraline consistent with the intended long-term use of the compound in this population. 
Dasotraline 2, 4 or 6 mg/day 
(flexibly dosedb) 
a There will be no break in study drug treatment between the core study and this extension study . 
b Dasotraline will be dosed at 2 mg/day for the first week of the study (Days 1 - 7). Subjects will then be flexibly dosed (2, 4, 
or 6 mg/day) thereafter beginning on Day 8 based on the investigator’s assessment of effectiveness and tolerability. 
26 Weeks 
Study SEP360-202a 
Core Study 
Open Label Treatment 
Study Drug 
Withdrawal Period 
3 Weeks 


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7.2.2. 
Rationale for the Dosages 
Given the similarities observed in pharmacokinetics between adult and pediatric subjects, 
predictions from a population pharmacokinetic (PK) model of dasotraline previously established 
in adult subjects were evaluated against the observed single-dose pharmacokinetics in pediatric 
subjects enrolled in Study SEP360-105. Model predictions of the observed dasotraline single-
dose pharmacokinetics in Study SEP360-105, using subjects (smaller) body sizes in the 
combined population PK model, corresponded well with the observed pharmacokinetics in Study 
SEP360-105. Thus, available dasotraline concentration data collected from pediatric subjects 
enrolled in Study SEP360-105 (1, 2, 4, and 8 mg cohorts, ages 6 to 17 years old) were pooled 
together with the previously developed population PK dataset and when the model was 
re-evaluated good model fit was demonstrated for all subjects encompassing a broad range of 
body sizes. 
The dose range to be used in this study (2, 4, and 6 mg/day) was selected based on evaluation of 
data from a combined dasotraline population pharmacokinetic (PK) model. This analysis 
demonstrated that the model-based predictions for dose-exposure distributions in pediatric 
subjects for the doses of 2 mg/day and 4 mg/day fall within the dose-exposure distributions 
observed for adults following treatment with dasotraline 4 mg/day and 8 mg/day, which 
demonstrated clinically significant efficacy after 4 weeks of treatment in an adult ADHD 
population. The 6 mg/day dose was included to allow for flexibility of dosing in this long-term 
trial and to evaluate the safety and tolerability of this dose in the pediatric population. 
Dasotraline has been shown to be generally safe and well-tolerated at equivalent doses in adults. 
All subjects in the current study will initially be started at 2 mg/day and then be flexibly dosed 
(2, 4, or 6 mg/day) thereafter. 
7.2.3. 
Rationale for the Study Population 
The subject population includes males and females ranging from 6 to 12 years of age (at time of 
consent/assent and at Baseline in the core study SEP360-202); and in concert with standard 
practice guidelines, will be required to have a diagnosis of ADHD established by a 
comprehensive psychiatric evaluation that reviewed Diagnostic and Statistical Manual for 
Mental Disorders Fifth Edition (DSM-5) criteria for a primary diagnosis of ADHD (inattentive, 
hyperactive, or combined presentation); diagnosis was confirmed at screening for the core study 
using the Schedule for Affective Disorders and Schizophrenia for School-Age Children Present 
and Lifetime Version (K-SADS-PL). 
7.2.4. 
Rationale for the Endpoints 
The safety assessments and their timing are considered appropriate to assess the long-term safety 
of dasotraline, taking into account known pharmacology and adverse events based on previous 
studies. The symptom, functional, and quality of life assessments were selected to address the 
potential effectiveness of dasotraline on these parameters. 
7.2.5. 
Prevention of Missing Data 
In an effort to minimize the number of subjects who are terminated from the study prior to study 
completion, the following study design and conduct elements are implemented; (i) allowance of 
dose adjustment throughout the study based on effectiveness and tolerability, (ii) study site 


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contact with subjects between the monthly study visits during the treatment period, (iii) site 
training on the importance of continued follow-up and on the informed consent process, ensuring 
subject/parent/legal guardian understand the commitment they are making, including the intent to 
complete the trial, and (iv) data monitoring for adherence during the study. 


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8. 
SELECTION OF SUBJECTS 
Eligibility criteria will be assessed at the open-label (OL) Baseline visit (Week 6 in the core 
study). Assessments performed as part of the Week 6 visit in the core study do not need to be 
repeated. 
8.1. 
Subject Inclusion Criteria 
1. At least one of the subject’s parents/legal guardians must give written informed consent, 
including privacy authorization, prior to study participation. The subject will complete an 
informed assent prior to study participation. 
2. Subject and subject’s parent/legal guardian are judged by the investigator to be willing 
and able to comply with the study procedures and visit schedules. 
3. Subject has completed all required assessments for Week 6 of the core study. 
4. Subject has not taken any medication other than the study drug for the purpose of 
controlling ADHD symptoms during the core study. 
5. Subject, if female, must not be pregnant or breastfeeding. 
6. Female subject: 
• must be unable to become pregnant (eg, premenarchal, surgically sterile, etc); 
-OR- 
• practice true abstinence (consistent with lifestyle) and must agree to remain abstinent 
from signing informed consent/assent to at least 14 days after the last dose of study 
drug has been taken; 
-OR- 
• is sexually active and willing to use a medically effective method of birth control (see 
Appendix IV, Section 23) from signing informed consent/assent to at least 14 days 
after the last dose of study drug has been taken. 
7. Male subject must be willing to remain sexually abstinent (consistent with lifestyle) or 
use an effective method of birth control, (Appendix IV, Section 23), from signing 
informed consent/assent to at least 14 days after the last dose of study drug has been 
taken. 
8. Any subject whose weight is < 21 kg at the OL Baseline visit should be discussed with 
the medical monitor prior to enrollment. 
9. Subject and subject’s parent/legal guardian must be able to fully comprehend the 
informed consent/assent form (as applicable), understand all study procedures, and be 
able to communicate satisfactorily with the Investigator and study coordinator. 


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8.2. 
Subject Exclusion Criteria 
1. Subject is considered by the investigator to be at imminent risk of suicide, injury to self 
or to others, or damage to property. 
2. Subject answers “yes” to “Suicidal Ideation” item 4 (active suicidal ideation with some 
intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan 
and intent) for any lifetime history on the C SSRS Children’s “Since Last Visit” 
assessment at OL Baseline. 
3. Subject has a clinically significant abnormality including physical examination, vital 
signs, ECG, or laboratory tests that the investigator in consultation with the medical 
monitor considers to be inappropriate to allow participation in the study. 
4. Subject has a positive urine drug screen (UDS) or breath alcohol test at OL Baseline. 
5. Subject or parents/legal guardian has commitments during the study that would interfere 
with attending study visits. 
6. Subject is at high risk of non-compliance in the investigator’s opinion. 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Description of Study Drug 
The study medication is described in Table 5. 
 
Table 5: 
Investigational Product 
Attribute 
Study Medication 
Product name 
Dasotraline 2 mg 
Dasotraline 4 mg 
Dasotraline 6 mg 
Dosage form 
capsules 
capsules 
capsules 
Unit dose 
capsule 
capsule 
capsule 
Route of administration 
oral 
oral 
oral 
Physical description 
Swedish orange, size #4 
Swedish orange, size #4 
Swedish orange, size #4 
 
In addition to dasotraline, the active ingredient, each capsule contains: Mannitol United States 
Pharmacopeia (USP), Sodium Starch Glycolate NF, Talc USP, and Magnesium Stearate NF. 
9.2. 
Study Drug Packaging and Labeling 
9.2.1. 
Package Description 
Study drug will be provided in 1 week blister cards containing 10 capsules of dasotraline 2 mg, 
4 mg, or 6 mg capsules (7 days + 3 extra days). 
9.2.2. 
Labeling Description  
All packaging for the study medications will be labeled with: 
• Protocol number 
• Sponsor’s name and address 
• Content (eg number of capsules) 
• Investigational New Drug statement 
• Instructions for use and storage 
• Blank space for subject number (if needed) 
• Batch number 
• Blank space to record visit number identifier 
• Unique medication number (if needed) 


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9.3. 
Study Drug Storage 
All study medication should be stored at United States Pharmacopeia (USP) Controlled Room 
Temperature: 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F). 
The subject’s parent/legal guardian will be instructed to store the study medication at room 
temperature. 
In addition, the subject’s parent/legal guardian will be instructed to store the study medication in 
a location where it cannot be inadvertently accessed and consumed by the subject and to remove 
all previous ADHD treatments from the subject’s access. 
9.4. 
Dispensing of Study Drug 
An Interactive Response System (IXRS) will be used to manage subject enrollment. The IXRS is 
an integrated web based subject and drug management system. 
The IXRS will be used to assign subject numbers that will be linked via IXRS to the subject’s 
previous core study subject number. 
Study medication blister cards will be assigned by the IXRS based on the treatment schedule 
determined by the investigator. The IXRS will generate instructions on which medication 
number to assign to a subject. Each subject will be dispensed one to four 10-day blister cards per 
scheduled visit, based on the expected next visit date. 
Under supervision from the subject’s parent/legal guardian, subjects will self-administer the 
study drug daily on an outpatient basis (see Section 10.1). The daily dosage will be clearly 
labeled on the study drug blister card. 
9.5. 
Study Drug Accountability 
The Investigator or designee is responsible for storing the study drug in a secure location and for 
maintaining adequate records of study drug disposition that includes the dates, quantity, and use 
by subjects. If the study is stopped for any reason or completed, all unused supplies of study drug 
will be returned to the Sponsor, unless other instructions are provided in writing by Sponsor/ 
contract research organization (CRO). 
Upon receipt of clinical trial material (CTM) the Principal Investigator, or designee, will 
inventory the supplies and verify receipt of supplies. The site will send an Acknowledgement of 
Receipt to Sunovion Pharmaceuticals, or designee, confirming date of receipt, inventory, and 
condition of CTM received. 
The Clinical Inventory Management System (CIMS) will be used for the accountability of the 
supplies at the clinical site. The Investigator, or designee, will maintain the inventory for 
accountability within CIMS, including CTM disposition, return and availability of CTM 
received. The Investigator, or designee, agrees to collect and document all used and unused study 
medication from study subjects at appropriate study visits. 


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9.6. 
Study Drug Handling and Disposal 
The Investigator or designee, on an ongoing basis, must maintain a study drug inventory record 
of supplied, received, dispensed, and returned study drug. Access will be provided to the 
Sponsor’s CIMS to document study drug inventory records. 
The study drug will not be dispensed for use by any person who is not a study subject under this 
protocol. 
The Investigator or designee is required to return all used and unused study drug to the Sponsor 
or designee as instructed. The Investigator or designee is required to maintain copies of study 
drug shipping receipts, study drug accountability records, and records of return or final disposal 
of the study drug. 


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10. 
TREATMENT OF SUBJECTS 
10.1. 
Study Medication  
Dasotraline 2, 4, and 6 mg capsules for oral administration will be supplied for the study as 
described in Section 9.1. 
Under supervision from the subject’s parent/legal guardian, subjects will self-administer the 
study drug on an outpatient basis beginning on Day 1, the morning following the OL Baseline 
visit. All dasotraline doses will consist of 1 capsule taken orally once a day for 26 weeks (Day 1 
through Day 182) at approximately the same time each morning including on the days when 
clinic visits occur. If morning dosing is not tolerated then dosing may be at another time of day 
with prior medical monitor approval; however, if there is a time of day dosing change, subjects 
should administer study drug at the same time of day for the remainder of the study. 
Subjects may take study drug with or without food. 
Study drug capsules should not be opened or tampered with in any way; the active ingredient is 
an ocular irritant. 
10.2. 
Dose Adjustment Criteria 
Dasotraline will be dosed at 2 mg/day for the first week of the study (Days 1 - 7). Subjects will 
then be flexibly dosed (2, 4, or 6 mg/day) thereafter beginning on Day 8 based on the 
investigator’s assessment of effectiveness and tolerability. All changes in study drug dose will 
begin the morning after the visit at which the dose change decision is made and using the new 
package of study drug. Additional dose adjustment is allowed during the study at the discretion 
of the investigator; the dose may be increased or decreased by 2 mg/day, as necessary for 
effectiveness or tolerability reasons. Total daily dose will not exceed 6 mg/day. There is no limit 
on the number of dose increments or reductions during the study. A minimum of 7 days is 
required between dose increases. Dose decreases may be made at less than 7 day intervals for 
safety/tolerability reasons, at the investigator’s discretion. 
Subjects wishing to take study drug at an alternate time of day require investigator and medical 
monitor approval. 
10.3. 
Concomitant Medications and Therapies 
The following information on all medication, other than study drug, taken by or administered to 
the subject between OL Baseline and End of Study or at discontinuation will be recorded on the 
case report form (CRF): 
Medication name, dose, frequency, route, start date, stop date, and indication. 
10.3.1. 
Prohibited Medications 
Use of any of the following medications is not permitted during the study through EOS: 
• Lithium (any lithium preparation or formulation). 


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• Alpha-2 adrenergic receptor agonists (including clonidine and guanfacine), modafinil, 
armodafinil, atomoxetine, or any stimulant class agent (methylphenidate- or 
amphetamine-based). 
• Antidepressant medications (eg, bupropion, selective serotonin reuptake inhibitor 
[SSRI]/ serotonin norepinephrine reuptake inhibitor [SNRI], monoamine oxidase 
[MAO] blocker, tricyclic, etc) and St. John’s Wort. 
• Anticonvulsant medications (eg, phenytoin, carbamazepine, lamotrigine, valproic 
acid, etc) and antipsychotic medications. 
• Pseudoephedrine-containing medications for treatment of allergies or flu-like 
symptoms. 
• Medications with significant effect on blood pressure or heart rate. Intermittent use of 
asthma treatments is permitted but should be discussed with the medical monitor. 
• Sleep aids with the exception of melatonin (see Section 10.3.3). 
• Any medications for the treatment of ADHD. 
• CYP2B6 substrates or inhibitors or inducers of CYP2B6 (see Appendix II, 
Section 21). 
Subjects who require persistent asthma treatment during the study should be discussed with the 
medical monitor as they may be required to be discontinued from the study. 
10.3.2. 
Prohibited Therapies 
Subjects undergoing cognitive behavioral therapy (CBT) are excluded from entering the study. 
In addition, a new course of CBT specifically for ADHD is not allowed during the study.  
Unavoidable changes in school-based interventions that occur during study participation will not 
be exclusionary, but should be documented by the investigator, to the extent possible. 
10.3.3. 
Permitted Medications 
Use of medications not listed under prohibited medications in Section 10.3.1 are permitted 
during the study. 
Melatonin (≤ 5 mg/day) may be administered at bedtime for insomnia, as needed. For those 
subjects taking melatonin, over the counter melatonin should be used; combination melatonin 
products are not allowed. Subjects should avoid taking these products within 8 hours prior to 
scheduled study assessments. 
Contraception requirements are described in Appendix IV (Section 23). 
10.4. 
Guidance for Overdose 
There is no overdose experience with dasotraline in humans. Signs and symptoms of overdose in 
nonclinical studies were consistent with exaggerated pharmacology and included hyperactivity, 
stereotypy, aggressiveness, and reduced food intake and body weight loss. 


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Activated charcoal may be of value if administered very soon after a dasotraline overdose (ie, 
during the absorption process). 
10.5. 
Cautions 
Dasotraline is a severe ocular irritant. Therefore appropriate precautions should be taken to avoid 
ocular exposure to the contents of the dasotraline capsules. 
10.6. 
Dietary Guidelines 
Study drug may be taken without regard for food. 
10.7. 
Treatment Compliance 
Compliance with study drug will be monitored closely and determined at each visit during 
treatment. Subjects and their parents/legal guardians will be instructed to bring all unused study 
drug with them to each visit. Compliance will be assessed by counting capsules and dividing the 
actual number of doses taken (per capsule count) by the number of doses the subject should have 
taken within a visit period and multiplying by 100. Subjects who miss more than 25% of 
scheduled doses or take more than 125% of the scheduled doses will be considered 
noncompliant. Evidence of noncompliance must be immediately reported to the Medical 
Monitor. Potential noncompliance will be discussed with subject and their parent/legal guardian, 
and at the investigator’s discretion may result in termination of the subject from the study. All 
subjects and their parents/legal guardians will be reminded of the importance of strict 
compliance with taking study drug for the effectiveness of treatment and for the successful 
outcome of the study. 
10.8. 
Treatment Assignment and Blinding 
10.8.1. 
Treatment Assignment 
This is a single-arm, open-label study. All subjects will receive dasotraline flexibly dosed at 2, 4, 
or 6 mg/day. 
10.8.2. 
Blinding 
Blinding of study treatment is not applicable; this is an open-label study. 


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11. 
STUDY ASSESSMENTS 
A study schematic is presented in Figure 1. A summary of assessments to be conducted at each 
visit is presented in Table 2. 
Training, as appropriate, will be provided for study site staff that did not participate in the core 
study and will be administering any of the effectiveness and safety assessments in this study. In 
an effort to improve the consistency of subject assessment across sites, an independent rater 
qualification service, Bracket, will provide training on the ADHD-RS-IV HV, Conners 3-P, 
CGI-S, CSHQ, Tanner staging, WFIRS-P, DESS, and PWC. In an effort to improve rater 
consistency and precision, Bracket, in collaboration with the sponsor, will develop a credential 
and experience survey to identify raters with appropriate experience. The sponsor has final 
discretion regarding allowing raters to participate in the study. 
11.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics obtained for the core study including date of birth, sex, 
ethnicity, race, weight, height, BMI, physical and brief neurological examination results, and 
medical and psychiatric history will be carried over for this study and duplicate assessments will 
not be conducted. 
11.2. 
Efficacy Assessments 
11.2.1. 
Efficacy Scales 
ADHD Rating Scale Version IV - Home Version (modified for investigator administration) 
(ADHD-RS-IV HV) 
The ADHD-RS-IV HV was developed to measure the behaviors of children with ADHD. The 
ADHD-RS-IV HV is a validated scale that consists of 18 items designed to reflect current 
symptomatology of ADHD based on Diagnostic and Statistical Manual for Mental Disorders 
Fourth Edition; Text Revision (DSM-IV-TR) criteria and is also consistent with DSM-5 criteria. 
Each item is scored from a range of zero (reflecting no symptoms) to 3 (reflecting severe 
symptoms) with total scores ranging from zero to 54. The 18 items may be grouped into 
2 subscales: hyperactivity/impulsivity (even number items 2 through 18) and inattentiveness 
(odd number items 1 through 17). The ADHD-RS-IV HV will be administered to the caregiver 
by a qualified rater at the site. The same study site rater should perform all ADHD-RS-IV HV 
assessments for a given subject whenever possible. 
Clinical Global Impression–Severity of Illness (CGI-S) 
Following a clinical interview, the CGI-S can be completed in 1 – 2 minutes. The CGI-S 
modified (Guy-1976) asks the clinician one question: “Considering your total clinical experience 
with this population, how mentally ill is the subject at this time?” The clinician’s answer is rated 
on the following 7 point scale: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly 
ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill 
subjects. 


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This rating is based upon observed and reported ADHD symptoms, behavior, and function in the 
past 7 days. Clearly, symptoms and behavior can fluctuate over a week; the score should reflect 
the average severity level across the 7 days. 
The Conners 3rd Edition Parent (Conners 3-P) 
The Conners 3–P assesses behaviors and other concerns in children between the ages of 6 and 18, 
inclusive. The full-length version of the Conners 3–P will be used. The full-length version 
provides a thorough assessment of ADHD and addresses comorbid disorders such as 
oppositional defiant disorder (ODD) and conduct disorder. Responses to the Conners 3-P will be 
used to calculate the total score and subscale scores (Oppositional, Cognitive problems, 
Hyperactivity, and ADHD Index). 
At each timepoint the review will include the past month. 
Weiss Functional Impairment Rating Scale – Parent Report (WFIRS-P) 
The WFIRS-P is an ADHD-specific instrument completed by the parent/legal guardian to 
evaluate domains of daily functioning that are likely to be impaired in ADHD. The WFIRS-P 
comprises 50 items used to provide measures of impairment in 6 domains (family, learning and 
school, life skills, child’s self-concept, social activities and risky activities) and overall (total 
score). The items are scored using a 4-point Likert scale: 0 (never or not at all); 1 (sometimes or 
somewhat); 2 (often or much); or 3 (very often or very much). At all visits the WFIRS-P version 
for evaluation of the previous one-month period will be used. 
11.3. 
Safety Assessments 
The Investigator or appropriate designee will review results of safety assessments on a regular 
basis and the Sponsor must be kept fully informed of any clinically significant findings during 
study conduct. 
11.3.1. 
Adverse Events 
Adverse events will be collected for each subject. Subjects should be queried in a non-leading 
manner, without specific prompting (eg, “Has there been any change in your health status since 
your last visit?”). See Section 12, Safety Reporting. 
AEs and SAEs will be monitored throughout the study at all visits including telephone 
assessments. 
11.3.2. 
Clinical Laboratory Tests 
The clinical laboratory tests required by protocol are listed in Appendix III (Section 22). See 
Appendix V (Section 24) for estimated blood volumes to be collected from the subject during the 
course of the study. 
Blood and urine samples will be collected for clinical laboratory tests. Use of a dermal anesthetic 
to prevent pain associated with blood sampling is permitted. All clinical laboratory tests will be 
performed centrally. For detailed instructions regarding clinical laboratory procedures, sampling, 
and shipping guidelines refer to the Laboratory Manual. Samples will be processed at a central 
laboratory to ensure consistency. All clinical laboratories must be College of American 


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Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA) (or equivalent) 
certified. 
11.3.3. 
Physical and Neurological Examinations 
Clinically significant physical and neurological examination findings, as judged by the 
investigator, will be recorded as AEs. 
Body weight while wearing street clothes and without shoes will be recorded in kilograms (kg). 
Height without shoes will be measured by stadiometer and recorded in centimeters (cm). 
11.3.4. 
Vital Signs 
Respiratory rate and oral temperature will be measured following 5 minutes of supine rest.  
An appropriately sized blood pressure cuff should be used based on the subject’s size. Blood 
pressure and pulse rate should first be taken with the subject in the supine position after resting 
for ≥ 5 minutes. Blood pressure and pulse rate will be taken again after the subject has been 
standing for ≥ 5 minutes. The same arm should be used during each assessment of blood pressure 
and pulse rate throughout the study. If a subject develops symptoms consistent with orthostatic 
hypotension (light-headedness, dizziness, or changes in sensorium upon standing) at any point, 
his or her supine and standing blood pressure and pulse rate should be collected at that time in 
the manner described above. Vital signs will be obtained prior to clinical laboratory collection 
and performance of an ECG. 
11.3.5. 
ECGs 
All ECGs will be obtained in the supine position, after the subject has been resting supine for at 
least 5 minutes. ECGs will be 12-lead with a 10-second rhythm strip. ECGs should be obtained 
prior to drawing blood samples. All attempts should be made to use the same ECG recorder for 
all visits within individual subjects. ECGs will be centrally read at a core laboratory according to 
established quality assurance procedures for inter/intra reader variability. Refer to Appendix I 
(Section 20) for additional information. 
Standard 12 lead ECG parameters heart rate (HR), PR interval, RR interval, QT interval, QTcB 
and QTcF intervals, and QRS duration will be assessed. 
11.3.6. 
Safety Scales 
Columbia Suicide Severity Rating Scale (C-SSRS) Children’s Assessment 
The C-SSRS (Posner-2007) is a tool designed to systematically assess and track suicidal AEs 
(suicidal behavior and suicidal ideation) throughout the study. The strength of this suicide 
classification system is in its ability to comprehensively identify suicidal events while limiting 
the over identification of suicidal behavior. The scale takes approximately 5 minutes to 
administer. The C-SSRS will be administered by a trained rater at the site. 
For all visits the “Since Last Visit” version of the C-SSRS will be administered. 
Subjects who have significant findings for suicidal ideation upon completion of the C-SSRS at 
any time during the study must be referred to the investigator for follow-up evaluation. 


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Children's Sleep Habits Questionnaire (CSHQ) 
The CSHQ is a retrospective, 45-item parent questionnaire that is used to examine sleep behavior 
in young children (Owens-2000). The CSHQ includes items relating to a number of key sleep 
domains that encompass the major presenting clinical sleep complaints in this age group: 
bedtime behavior and sleep onset; sleep duration; anxiety around sleep; behavior occurring 
during sleep and night wakings; sleep-disordered breathing; parasomnias; and morning 
waking/daytime sleepiness. Parents are asked to recall sleep behaviors occurring over a “typical” 
recent week. Items are rated on a 3-point scale: “usually” if the sleep behavior occurred 5 to 
7 times/week; “sometimes” for 2 to 4 times/week; and “rarely” for 0 to 1 time/week. Some items 
were reversed in order to consistently make a higher score indicative of more disturbed sleep. 
For the purposes of further psychometric evaluation analysis, some of the CSHQ items were 
eliminated as redundant or ambiguous, and the remaining 35 numbered items on the scale were 
conceptually grouped into 8 subscale scores reflecting the following sleep domains: (1) Bedtime 
Resistance; (2) Sleep Onset Delay; (3) Sleep Duration; (4) Sleep Anxiety; (5) Night Wakings; 
(6) Parasomnias; (7) Sleep-Disordered Breathing; (8) Daytime Sleepiness. Responses to the 
CSHQ will be used to calculate the total score and 8 domain scores. 
Tanner Staging 
The Tanner scale is a scale of physical development in children, adolescents, and adults. The 
scale defines physical measurements of development based on external primary and secondary 
sex characteristics, such as the size of the breasts, genitalia, testicular volume, and development 
of pubic and axillary hair. 
Discontinuation--Emergent Signs and Symptoms (DESS) Scale 
The DESS Scale (Rosenbaum-1998) is a clinician-rated instrument of 43 items used to evaluate 
signs and symptoms associated with discontinuation or interruption of monoamine reuptake 
inhibitor treatment.  
On non-clinic days, the DESS Scale will be completed by site staff during a call to the 
subject/parent/legal guardian. 
Physician Withdrawal Checklist (PWC)  
The Physician Withdrawal Checklist (PWC) is used to evaluate symptoms of withdrawal after 
discontinuation of study drug. Symptoms are assessed as present or absent and if present then 
intensity is assessed as mild, moderate, or severe. 
11.4. 
Study Visits and Assessments 
11.4.1. 
Open-label Baseline: Visit 1E (Day 0) 
Subjects will be evaluated at the Open-label Baseline Visit to determine their eligibility to enroll 
in the study. The following study-related procedures will be performed at Open-label Baseline in 
the following order: 
• Obtain informed consent/assent 
• Review inclusion/exclusion criteria 
• Dispense study drug 


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The following study-related procedures will be carried over from the core study Week 6 visit and 
do not need to be performed for the Open-label Baseline visit: 
• Medical and psychiatric histories 
• Physical and neurological examinations 
• Concomitant medications 
• Vital signs, height, weight, and BMI 
• AEs 
• ECG 
• Tanner Staging 
• C-SSRS, CGI-S, ADHD-RS-IV HV, Conners 3-P, CSHQ 
• WFIRS-P 
• Clinical laboratories (hematology, chemistry, lipid panel, thyroid panel, sex hormone 
tests, urinalysis), UDS, and serum pregnancy test for females of child bearing 
potential 
• Breath alcohol test 
11.4.2. 
Visit 2E: Week 1 (Day 7 ± 3) 
• Record concomitant medications 
• Collect vital signs, height, weight, and BMI 
• Perform ECG 
• Record AEs 
• Administer C-SSRS, CGI-S, ADHD-RS-IV HV, Conners 3-P, CSHQ 
• Perform study drug accountability 
• Dispense study drug 
11.4.3. 
Visit 3E: Week 2 (Day 14 ± 3) 
• Record concomitant medications 
• Collect vital signs, height, weight, and BMI 
• Perform ECG 
• Record AEs 
• Administer C-SSRS, CGI-S, ADHD-RS-IV HV, Conners 3-P, CSHQ 
• Collect sample for UDS 
• Perform study drug accountability 
• Dispense study drug 


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11.4.4. 
Visit 4E: Week 4 (Day 28 ± 3) 
• Record concomitant medications 
• Collect vital signs, height, weight, and BMI 
• Perform ECG 
• Record AEs 
• Administer C-SSRS, CGI-S, ADHD-RS-IV HV, Conners 3-P, CSHQ 
• Perform study drug accountability 
• Dispense study drug 
11.4.5. 
Visit 5E: Week 6 (Day 42 ± 3) 
• Record concomitant medications 
• Collect vital signs, height, weight, and BMI 
• Perform ECG 
• Record AEs 
• Administer C-SSRS, CGI-S, ADHD-RS-IV HV, Conners 3-P, CSHQ 
• Collect sample for UDS and urine pregnancy test for females of childbearing 
potential 
• Perform study drug accountability 
• Dispense study drug 
At the approximate midpoint between Visit 5E (Week 6) and Visit 6E (Week 10), contact the 
subject to evaluate safety (See Section 11.4.12). 
11.4.6. 
Visit 6E: Week 10 (Day 70 ± 3) 
• Record concomitant medications 
• Collect vital signs, height, weight, and BMI 
• Perform ECG 
• Record AEs 
• Administer C-SSRS, CGI-S, ADHD-RS-IV HV, Conners 3-P, CSHQ 
• Collect sample for UDS and urine pregnancy test for females of childbearing 
potential 
• Perform study drug accountability 
• Dispense study drug 
At the approximate midpoint between Visit 6E (Week 10) and Visit 7E (Week 14), contact the 
subject to evaluate safety (See Section 11.4.12). 


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11.4.7. 
Visit 7E: Week 14 (Day 98 ± 3) 
Subjects should be fasted (no food or drink except water at least 8 hours prior to blood draws for 
the lipid panel). Blood samples should be drawn in the morning followed by a snack or meal. 
• Record concomitant medications 
• Perform physical and neurological examination 
• Collect vital signs, height, weight, and BMI 
• Perform ECG 
• Record AEs 
• Administer C-SSRS, CGI-S, ADHD-RS-IV HV, Conners 3-P, CSHQ 
• Parent/legal guardian completes WFIRS-P 
• Collect sample for clinical laboratories (hematology, chemistry, thyroid, lipid panel, 
thyroid function panel, urinalysis), UDS, urine pregnancy test for females of 
child bearing potential, sex hormone tests 
• Perform breath alcohol test 
• Perform study drug accountability 
• Dispense study drug 
At the approximate midpoint between Visit 7E (Week 14) and Visit 8E (Week 18), contact the 
subject to evaluate safety (See Section 11.4.12). 
11.4.8. 
Visit 8E: Week 18 (Day 126 ± 3) 
• Record concomitant medications 
• Collect vital signs, height, weight, and BMI 
• Perform ECG 
• Record AEs 
• Administer C-SSRS, CGI-S, ADHD-RS-IV HV, Conners 3-P, CSHQ 
• Collect sample for UDS, and urine pregnancy test for females of childbearing 
potential 
• Perform study drug accountability 
• Dispense study drug 
At the approximate midpoint between Visit 8E (Week 18) and Visit 9E (Week 22), contact the 
subject to evaluate safety (See Section 11.4.12). 
11.4.9. 
Visit 9E: Week 22 (Day 154 ± 3) 
• Record concomitant medications 
• Collect vital signs, height, weight, and BMI 


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• Perform ECG 
• Record AEs 
• Administer C-SSRS, CGI-S, ADHD-RS-IV HV, Conners 3-P, CSHQ 
• Collect sample for UDS and urine pregnancy test for females of childbearing 
potential 
• Perform study drug accountability 
• Dispense study drug 
At the approximate midpoint between Visit 9E (Week 22) and Visit 10E (Week 26), contact the 
subject to evaluate safety (See Section 11.4.12). 
11.4.10. 
Visit 10E: Week 26 (Day 182 ± 3) / Early Termination 
Subjects should be fasted (no food or drink except water at least 8 hours prior to blood draws for 
the lipid panel). Blood samples should be drawn in the morning followed by a snack or meal. 
• Record concomitant medications 
• Perform physical and neurological examination 
• Collect vital signs, height, weight, and BMI 
• Perform ECG 
• Record AEs 
• Perform Tanner Staging 
• Administer C-SSRS, CGI-S, ADHD-RS-IV HV, Conners 3-P, CSHQ, DESS, PWC 
• Parent/legal guardian completes WFIRS-P 
• Collect sample for clinical laboratories (hematology, chemistry, thyroid function 
panel, lipid panel, urinalysis), UDS, urine pregnancy test for females of childbearing 
potential, sex hormone tests 
• Perform study drug accountability 
11.4.11. 
Withdrawal Period 
11.4.11.1. Visit 11E /Telephone Contact: Week 27 (Day 189 ± 3) 
• Administer DESS 
Clinical site staff may call up to 3 times per day if the clinical site staff are unable to contact the 
subject/parent/legal guardian on the first 2 attempts. If the subject/parent/legal guardian cannot 
be contacted on a given day, during the next contact the study site staff will retrospectively 
collect the DESS from the missed day and the current day, as necessary. 
 


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11.4.11.2. Visit 12E /Telephone Contact: Week 28 (Day 196 ± 3) 
• Administer DESS  
Clinical site staff may call up to 3 times per day if the clinical site staff are unable to contact the 
subject/parent/legal guardian on the first 2 attempts. If the subject/parent/legal guardian cannot 
be contacted on a given day, during the next contact the study site staff will retrospectively 
collect the DESS from the missed day and the current day, as necessary. 
11.4.11.3. Visit 13E / End of Study: Week 29 (Day 203 ± 7) 
Subjects should be fasted (no food or drink except water at least 8 hours prior to blood draws for 
the lipid panel). Blood samples should be drawn in the morning followed by a snack or meal. 
• Record concomitant medications 
• Perform physical and neurological examination 
• Collect vital signs, height, weight, and BMI 
• Perform ECG 
• Record AEs 
• Administer C-SSRS, DESS, PWC 
• Collect sample for clinical laboratories (hematology, chemistry, thyroid function 
panel, lipid panel, urinalysis), UDS, serum pregnancy test for females of childbearing 
potential, sex hormone tests 
• Perform breath alcohol test 
11.4.12. 
Between Visit Contacts 
A member of the study site staff will contact the subject/parent/legal guardian via telephone, text, 
or email between monthly visits during the treatment period according to the timeline in Table 6. 
These contacts will be used to monitor for clinical symptoms and adverse events, as well as to 
remind subjects about adherence to study drug administration and upcoming visits. The date and 
time of these contacts will be documented in the CRF. 
 
Table 6: 
Between Visit Contact Timeline 
Study Visit Timinga 
Approximate midpoint between Visits 5E and 6E (ie, 14 ± 2 days after visit) 
Approximate midpoint between Visits 6E and 7E (ie, 14 ± 2 days after visit) 
Approximate midpoint between Visits 7E and 8E (ie, 14 ± 2 days after visit) 
Approximate midpoint between Visits 8E and 9E (ie, 14 ± 2 days after visit) 
Approximate midpoint between Visits 9E and 10E (ie, 14 ± 2 days after visit) 
a The exact timing of each contact will be determined based on the actual timing of the scheduled visits. 


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12. 
SAFETY REPORTING 
12.1. 
Definitions 
12.1.1. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a study subject administered a 
medicinal (investigational) product and which does not necessarily have a causal relationship 
with this treatment. 
An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease occurring after the administration of a medicinal (investigational) 
product, whether or not considered related to the medicinal (investigational) product. AEs may 
include the onset of new illness and the exacerbation of pre-existing conditions. AEs will be 
collected from the time the informed consent is obtained to the last study visit. 
Lack of efficacy may be an expected potential outcome and should not be reported as an AE 
unless the event is unusual in some way. 
New signs and symptoms of underlying disease, or signs and symptoms of emerging disease 
must be recorded as AEs. 
The Investigator should attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis should be documented as the AE 
and not the individual signs/symptoms. 
12.1.2. 
Serious Adverse Events 
A serious adverse event (SAE) is an AE that meets one or more of the following criteria: 
• Results in death. 
• Is life-threatening (ie, a patient is at immediate risk of death at the time of the event, 
not an event where occurrence in a more severe form might have caused death). 
• Requires hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is an important medical event that may jeopardize the subject or may require a 
medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization. 
The term "severe" is often used to describe the severity of a specific event (as in mild, moderate, 
or severe myocardial infarction) (see Section 12.3); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 


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"serious," which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject's life or functioning as defined by the criteria above. 
During the study, if a subject has a hospitalization or procedure (eg, elective surgery) that was 
scheduled before the study entry, ie, before informed consent for an event/condition that 
occurred before the study, the hospitalization is considered a therapeutic intervention and not the 
result of a SAE. However, if the event/condition worsens during the study, it should be reported 
as an AE (or SAE, if the event/condition results in a serious outcome such as prolongation of 
hospitalization). 
Life-threatening means that the subject was, in the view of the Investigator, at immediate risk of 
death from the event as it occurred. This definition does not include an event that had it occurred 
in a more severe form might have caused death. 
12.2. 
Objective Findings 
Clinically significant abnormal objective findings (eg, clinical laboratory value, ECG value, and 
physical examination observation) will also be recorded as AEs. 
When a clear diagnosis is available that explains the objective findings, this diagnosis will be 
recorded as the AE, and not the abnormal objective finding (eg, viral hepatitis will be recorded as 
the AE, not transaminase elevation). If a definite diagnosis is not available, then record the sign 
(eg, clinically significant elevation of transaminase levels) or symptom (eg, abdominal pain) as 
the AE. 
Clinical laboratory test results will be reviewed by the Investigator. The Investigator must 
determine the clinical significance of all out of range values. Clinical laboratory test with 
possibly drug-related or clinically relevant abnormal values of uncertain causality may be 
repeated. Any abnormal values that persist should be followed at the discretion of the 
Investigator. Laboratory reports will be initialed and dated on all pages by the Investigator. 
Clinical Laboratory Tests Outside the Normal Range: Any value outside the normal range will be 
flagged for the attention of the Investigator or appropriate designee at the clinical site. The 
Investigator or appropriate designee will indicate whether or not the value is of clinical 
significance. If the result of any test (or repeat test, if done) from the samples taken during the 
Screening phase is indicated as clinically significant and is not covered by the eligibility criteria 
in Section 8, the subject will not be allowed into the study. Additional testing during the study 
may be done if medically indicated. If a clinically significant abnormality is found in the 
samples taken after dosing, during the study, and/or at the End of Study Visit, this should be 
recorded as an AE and the subject will be followed until the test(s) has (have) normalised or 
stabilised. 
All on site ECG tracings and ECG over-read reports will be reviewed by the Investigator. The 
Investigator must determine the clinical significance of all abnormal ECGs. ECG with possibly 
drug-related or clinically relevant abnormal findings of uncertain causality may be repeated. Any 
abnormal ECGs that persist should be followed at the discretion of the Investigator. ECG 
tracings will be initialed and dated on all pages by the Investigator. 


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12.3. 
Collection and Recording Adverse Events 
All AEs must be collected and recorded in the subject’s study records/source documents, in 
accordance with the Investigator’s normal clinical practice, and on the CRF from the time the 
informed consent/assent is signed through the last study visit or discontinuation. All AEs will be 
followed up until resolution, stabilization of the condition, the event is otherwise explained, or 
the subject is lost to follow-up. 
Each AE is to be evaluated for duration, severity, frequency, seriousness, action taken with the 
study treatment, outcome, and causal relationship to the study treatment. Definitions for severity, 
frequency, action taken with the study treatment, outcome, and causal relationship to the study 
treatment are presented below. 
The severity of AE: 
• Mild - Ordinarily transient symptoms that do not influence performance of subject’s 
daily activities. Other treatment is not ordinarily indicated. 
• Moderate - Marked symptoms sufficient to make the subject uncomfortable. 
Moderate influence on performance of subject’s daily activities. Other treatment may 
be necessary. 
• Severe - Symptoms cause considerable discomfort. Substantial influence on subject’s 
daily activities. May be unable to continue the study, and other treatment may be 
necessary. 
The frequency of AE: 
• Once – an isolated episode. 
• Intermittent – occurs on two or more separate occasions. 
• Continuous – does not abate from date of onset to date of resolution. 
The action taken with the study treatment: 
• Drug Interrupted – Study drug stopped temporarily. 
• Drug Withdrawn – Study drug stopped permanently. 
• Dose Reduced. 
• Dose Increased. 
• Dose Not Changed. 
• Not Applicable. 
The outcome of the AE: 
• Recovered/Resolved. 
• Recovering/Resolving. 
• Not Recovered/Not Resolved. 
• Recovered/Resolved with Sequelae. 


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• Fatal. 
• Unknown. 
The causal relationship of the AE to the study treatment: 
• Not related   
o Not related - Improbable temporal relationship and is plausibly related to 
other drugs or underlying disease. 
o Unlikely - occurred within a reasonable time frame after 
administration/discontinuation of the study drug, but there is a likely 
association of an intercurrent/underlying medical condition or other drugs. 
• Related 
o Possible - occurred in a reasonable time after study drug administration, but 
could be related to concurrent drugs or underlying disease. 
o Probable - occurred in a reasonable time after study drug administration, is 
unlikely to be attributable to concurrent drugs or underlying disease, and there 
is a plausible mechanism to implicate the study drug. 
o Definite - occurred in a reasonable time after study drug administration and 
cannot be explained by concurrent drugs or underlying disease. The adverse 
event should respond to dechallenge/rechallenge, however, this is not 
mandatory before assigning a definite causality. 
The Medical Monitor is the initial contact person for protocol-related questions or discussion of 
AEs. The contact information for the Medical Monitor as well as other emergency contact 
information can be found in Table 1 of this protocol. 
12.4. 
Immediately Reportable Events 
The following medical events must be immediately reported to the Sponsor: 
• SAE 
• Pregnancy 
Emergency contact information can be found in Table 1. 
12.4.1. 
Serious Adverse Event 
If the Investigator or study site staff becomes aware of SAE that occurs in a study subject from 
the time that informed consent/assent is signed through 30 days following the last dose of the 
study medication, this must be reported immediately to the Sponsor whether considered related 
or unrelated to the study drug. SAEs occurring from the time of informed consent to through 
14 days following last dose of the study medication must be recorded on the CRF and the data 
recorded should match that on the SAE form. 
Following the end of subject participation in the study, the Investigator or an authorized delegate 
should report SAEs “spontaneously” to PPD-PVG if considered at least possibly related to the 
study drug. 


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SAEs will be followed until resolution, loss to follow-up, stabilization of condition, or the event 
is otherwise explained. 
In addition to the initial telephone notification, an initial SAE form as applicable must be 
completed and signed and sent via fax or email (see Table 1) to PPD-PVG within 1 business day 
of the Investigator or study site staff becoming aware of the event. The SAE report form must be 
signed by the Investigator or appropriate designee. The Sponsor provides the SAE form used to 
report SAEs. 
The Sponsor or designee will promptly notify all study sites and Investigators of a SAE that is 
determined to be expedited to the Regulatory Authorities in accordance with applicable law(s) 
and regulation(s). These SAEs must be promptly reported to the Institutional Review Board 
(IRB) or Independent Ethics Committee (IEC) by the Principal Investigator or the appropriate 
person at the site. 
12.4.2. 
Pregnancy 
Pregnancies that occur from the time that informed consent/assent is signed through 30 days 
following the last dose of the study medication will be collected and reported on the Pregnancy 
Event Form. 
If a subject becomes pregnant during the course of the study, she/parent/legal guardian will be 
instructed to discontinue the study medication. Further, the subject/parent/legal guardian (or 
female partner of male subject) will be instructed to return promptly/within 48 hours of the first 
notification of pregnancy to the research site and undergo a serum pregnancy test, as 
confirmation of pregnancy. If positive, the subject will no longer receive any additional study 
medication. All pregnancies, whether or not the subject received any additional study 
medication, will be followed until resolution (ie, termination [voluntary or spontaneous] or 
birth). 
To report a pregnancy, the Pregnancy Event Form must be completed and sent via fax to 
PPD-PVG within 1 business day of the Investigator or study site staff becoming aware of the 
pregnancy. The Sponsor provides the Pregnancy Event Form. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study drug may have 
interfered with the effectiveness of a contraceptive medication or other AEs were detected. 
12.5. 
Data Monitoring Committee/Data and Safety Monitoring Board 
The Data and Safety Monitoring Board (DSMB) will monitor safety throughout the study. The 
DSMB will be independent of the Sponsor, CRO, and the investigators and will be empowered 
to recommend stopping the study due to safety concerns. The membership of the DSMB and its 
mandate will be described in a separate DSMB charter. 


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13. 
TERMINATION OF SUBJECT FROM 
STUDY/DISCONTINUATION OF STUDY DRUG 
13.1. 
Criteria for Subject Termination  
Subjects may terminate their study participation at any time for any reason. 
The possible reasons for the termination of study participation are as follows: 
• Adverse event 
• Lack of efficacy 
• Lost to follow-up 
• Pregnancy 
• Withdrawal by subject 
• Noncompliance 
• Protocol violation 
• Other 
If at any time during the course of the study, in the opinion of the Investigator, the subject may 
no longer safely participate due to a change in medical status (eg, experiences an AE, becomes 
pregnant), the subject must be discontinued from the study treatment. 
The reason for discontinuation will be recorded on the appropriate CRF. 
Subjects who prematurely terminate the study participation will not be replaced. 
Subjects who discontinue study drug prior to completion will be asked to return to the site and 
complete the Early Termination visit assessments (Visit 10E/ET; Section 11.4.10) within 3 days 
of study drug discontinuation and complete all withdrawal period assessments (calls) and the 
EOS visit (Visit 13E; Section 11.4.11.3). 


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14. 
STUDY TERMINATION 
The Sponsor reserves the right to discontinue the study at this site or at multiple sites for safety 
or administrative reasons at any time while ensuring that early termination does not compromise 
subjects’ safety or well-being. In particular, a site that does not recruit at an acceptable rate may 
be closed. Should the study be terminated and/or the site closed for whatever reason, all 
documentation and study medications pertaining to the study must be returned to the Sponsor or 
its representative. 
If, in the opinion of the Investigator, clinical observations suggest it may be unsafe to continue, 
the Investigator may terminate part or the entire study after consultation with the Sponsor. 
In the event of study or site termination, subjects will be required to return for a final study 
assessment 3 days after their last dose of study drug and provided with access to standard care. 


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15. 
STATISTICS 
The Statistical Analysis Plan (SAP) will provide details on the statistical methods planned for 
this study and will be finalized before database lock (DBL). 
All statistical summaries will be presented by treatment group from the double-blind core study 
as well as all subjects in the extension study. 
Changes from baseline in safety and effectiveness endpoints will be calculated from both the 
double-blind (DB) baseline in the core study and the open-label (OL) baseline in the extension 
study, which is the Week 6 endpoint in the core study for most measures. No statistical inference 
will be performed for treatment comparison as this is a single arm, open-label, extension study. 
15.1. 
Sample Size Determination 
This study is projected to enroll up to 330 subjects based on the number of subjects who 
complete the core study. 
15.2. 
Analysis Populations 
Safety population: The Safety population includes all subjects who enter this study and receive at 
least one dose of study drug. All safety analyses will be performed in the Safety population. 
Intent-to-Treat (ITT) population: The ITT population is defined as all subjects who enter this 
study and receive at least one dose of study drug, and have a baseline effectiveness measure and 
at least one post baseline effectiveness measure in ADHD-RS-IV HV. The ITT population will 
be used for the effectiveness and quality of life analyses. 
15.3. 
Data Analysis 
15.3.1. 
Subject Disposition  
Subject disposition will be summarized for all enrolled subjects. Subjects who completed the 
study and discontinued early from the study will be summarized. The primary reason for 
discontinuation from the study will also be presented. 
15.3.2. 
Drug Exposure and Compliance 
A descriptive summary will be performed to summarize exposure to study drug. Treatment 
compliance will be determined and summarized descriptively. 
15.3.3. 
Important Protocol Deviations 
Protocol deviations will be collected during monitoring visits. Protocol deviations will be placed 
into the following categories: concomitant medications, dosing, enrollment criteria, laboratory, 
non-compliance, visit schedule, visit/procedure requirement, and others. Protocol deviations will 
be reviewed and determination of importance will be made prior to DBL. 
A summary of protocol deviations will be provided as number (%) of subjects with at least one 
protocol deviation and number (%) of subjects by category. 


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15.3.4. 
Demographic and Baseline Characteristics 
Demographics (sex, race, ethnicity, age [years], age group, baseline weight [kg], height [cm], 
and BMI [kg/m2]) will be summarized for the Safety population. Sex, race, age group, and 
ethnicity will be summarized using summary statistics for categorical variables (frequencies and 
percentages). Age, baseline height, baseline weight, and baseline BMI will be summarized using 
summary statistics for continuous variables (number of subjects, mean, standard deviation, 
median, minimum and maximum values). 
15.3.5. 
Effectiveness Analysis 
This is a single arm, open-label, extension study therefore no inferential statistics will be 
performed for any the effectiveness variables. 
15.3.5.1. Effectiveness Endpoint Analyses 
For effectiveness evaluations, descriptive statistics of observed value and change from both DB 
and OL baselines in the following endpoints will be summarized by visit. 
• Change in ADHD-RS-IV HV total score. 
• Change in CGI-S score. 
• Change in the ADHD-RS-IV HV inattentiveness and hyperactivity-impulsivity 
subscale scores. 
• Change in Conners 3-P score and subscale scores (Oppositional, Cognitive problems, 
Hyperactivity, and ADHD Index). 
• Change in WFIRS-P total score and 6 domain scores (family, learning and school, life 
skills, child’s self-concept, social activities, and risky activities). 
15.3.5.2. Subgroup Analysis 
Subgroup summary in change from baseline in ADHD-RS-IV HV total score will be provided by 
sex, race (eg, White, Black or African American, Asian, and Other) and age group in the 
ITT Population. 
15.3.6. 
Safety Analysis 
15.3.6.1. Adverse Events 
The summary of AEs and SAEs will be limited to TEAEs. A TEAE is any AE (or SAE) 
occurring after the first dose of study drug and before the end of the 2-week study follow-up 
period. All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 17.0 or higher. 
The TEAEs will be summarized by system organ class (SOC) and preferred term (PT) by 
presenting the number and percentage of subjects with each TEAE. The TEAE summary will be 
produced for the following categories: 
• TEAEs by SOC and PT 
• Serious TEAEs by SOC and PT 


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• TEAEs leading to discontinuation by SOC and PT 
• TEAEs by SOC, PT, and maximum severity 
• Treatment-related TEAEs by SOC and PT 
• Treatment-related serious TEAEs by SOC and PT 
• TEAE leading to death by SOC and PT 
A subject with multiple adverse events during the study will only be counted only once in a 
category per SOC and PT. The same subject may appear in different categories per SOC and PT. 
If a subject has the same AE on multiple occasions, the highest severity (severe, moderate, mild) 
recorded for the event will be presented and the highest drug relationship (Unrelated, Unlikely to 
be Related, Possibly Related, Probably Related, Definitely Related), reclassified into Related 
(Possibly Related, Probably Related, Related) or Not Related (Unrelated and Unlikely to be 
Related), will be presented on the respective tables. Percentages are based on the number of 
subjects in the Safety population. 
15.3.6.2. Clinical Laboratory Assessments 
The laboratory results collected in conventional units will be converted to SI units for the 
summaries. 
Clinical laboratory test results (hematology, chemistry, lipid panel, thyroid function panel, sex 
hormones, and urinalysis) and their changes from baseline will be summarized by visit using 
descriptive statistics. Shift tables comparing laboratory test results from OL baseline to end of 
study will be presented. In addition, the markedly abnormal post-baseline laboratory results will 
be summarized for certain laboratory tests. 
15.3.6.3. Centrally-read ECG 
Actual values and changes from baseline in ECG parameters (QTc, Bazetts corrected QTcB, 
Fridericia corrected QTcF, heart rate, PR interval, QRS interval, and RR interval) will be 
descriptively summarized by visit. The incidence of subjects with clinically abnormal QTc 
intervals and clinically significant changes in QTc intervals will also be summarized. 
15.3.6.4. Vital Signs 
Vital signs (blood pressure, pulse rate, height, weight, BMI, and respiration rate) will be 
monitored at every visit. Each vital sign parameter will be summarized at each visit for the 
observed value and change from baseline. In addition, the markedly abnormal post-baseline vital 
signs results will also be summarized for subjects with at least one markedly abnormal value 
during the 26-week treatment period. A shift table will be presented comparing shifts from the 
baseline visit to end of study. The number and percentage of subjects who experienced 
orthostatic hypotension at each time point will be summarized. 
15.3.6.5. Neurological Examination 
Neurological examination assessments will be summarized using summary statistics for 
categorical variables (normal/abnormal) by visit. 


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15.3.6.6. Tanner Staging 
Descriptive statistics will be provided by visit based on observed values and changes from 
baselines in Tanner Staging. 
15.3.6.7. Breath Alcohol Test 
Breath alcohol examination assessments will be summarized using summary statistics for 
categorical variables (negative/positive) by visit. 
15.3.6.8. Prior and Concomitant Medications 
All medications will be coded using the World Health Organization drug dictionary 
(WHODRUG) version Q32014 (September 1st, 2014 release) or higher. 
The prior medications will include medications started prior to the first dose date of study drug. 
The concomitant medications will include medications started on or after the first dose date of 
study drug. 
For the summary, the count and percentage of subjects under each anatomical therapeutic 
chemical (ATC) class and PT will be summarized. If a subject has taken one or more prior or 
concomitant medications more than once, the subject will be counted only once under any given 
drug class. 
15.3.6.9. Columbia-Suicide Severity Rating Scale (C-SSRS) 
The frequency and percentage by visit will be summarized for all C-SSRS responses. Frequency 
and severity of suicidality using the C-SSRS will be summarized using a shift table to examine 
changes in C-SSRS Scores from baseline compared to the worst (highest) category during the 
26-week treatment period by visit. 
15.3.6.10. Children's Sleep Habits Questionnaire (CSHQ) 
Changes from baseline in CSHQ total score and 8  subscale scores (bedtime resistance, sleep 
onset delay, sleep duration, sleep anxiety, night wakings, parasomnias, sleep disordered 
breathing, and daytime sleepiness) will be summarized descriptively. 
15.3.6.11. Physician Withdrawal Checklist (PWC), and Discontinuation-Emergent Signs 
and Symptoms (DESS) Scale  
The PWC will be summarized using descriptive statistics by visit for the total score. The frequency 
and percentage of subjects with a ‘Present’ response will be summarized for each of the 20 PWC 
items. In addition, responses of ‘moderate’ or ‘severe’ will be summarized separately by each visit. 
The DESS score from the last day of treatment and during the 3-week follow-up period will be 
summarized, as appropriate. 
15.3.6.12. Subgroup Analyses 
Subgroup summary analysis will be conducted on overall TEAEs to examine sex, race (eg, 
White, Black or African American, Asian, and Other), and age group in the Safety population. 


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16. 
PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL 
/DATA COLLECTION, MANAGEMENT, AND QUALITY 
ASSURANCE 
16.1. 
Data Collection/Electronic Data Capture (EDC) 
The results from baseline and data collected during the study (except clinical laboratory test 
results, electrocardiogram results, and IXRS data) will be recorded in the subject’s electronic 
CRF. The C-SSRS, CGI-S, ADHD-RS-IV HV, Conners 3-P, CSHQ, WFIRS-P, DESS, and 
PWC will be completed on paper and then entered into the electronic data capture (EDC) system. 
The study sites will use an EDC system that is compliant with relevant FDA regulatory 
requirements per 21 Code of Federal Regulations (CFR) Part 11, Medidata Rave®. Password 
protected access to the EDC system will be via a secure website. Data queries and data 
corrections will be handled through the same system. All transactions within the EDC system are 
fully documented within an electronic audit trail. Each set of completed CRFs must be reviewed 
and electronically signed and dated by the Investigator. 
16.2. 
Computerized Systems Used for Source Data 
A list of the computerized systems that will be used to create, modify, maintain, archive, retrieve, 
or transmit source data are presented below, pursuant to the Guidance for Industry Computerized 
Systems Used in Clinical Investigations, May 2007. 


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Table 7: 
Computerized Systems Used for Source Data 
Protocol Step  
Computerized System Type or Description 
Obtain informed consent/assent 
NA 
Inclusion/Exclusion criteria 
A 
Dispense study drug 
A, D 
Study drug accountability 
A, E 
Between visit contact 
A 
Medical and Psychiatric History 
A 
Concomitant medication review 
A 
Physical examination 
A 
Neurological examination 
A 
Height (measured by stadiometer)  
A 
Weight (including body mass index) 
A 
Vital signs 
A 
Electrocardiogram (ECG) 
C 
Adverse event monitoring 
A 
Tanner Staging 
A 
Columbia Suicide Severity Rating Scale (C-SSRS) Children’s Assessment  
A 
Clinical Global Impression – Severity (CGI-S) 
A 
ADHD Rating Scale Version IV - Home Version (modified for investigator 
administration) (ADHD-RS-IV HV) 
A 
The Conners 3rd Edition Parent (Conners 3-P) 
A 
Children's Sleep Habits Questionnaire (CSHQ) 
A 
Weiss Functional Impairment Rating Scale – Parent Report (WFIRS-P) 
A 
Physician Withdrawal Checklist (PWC) 
A 
Discontinuation-Emergent Signs and Symptoms (DESS) Scale  
A 
Hematology/Chemistry 
B 
Thyroid panel 
B 
Lipid panel 
B 
Sex hormone tests 
B 
Serum β-hCG (in females) 
B 
Urinalysis 
B 
Urine drug screen 
A 
Urine β-hCG (in females) 
A 
Breath alcohol test 
A 
Statistical Analysis 
SAS®, version 9.1.3 or higher 
 A = EDC (Medidata Rave); B = LIMS; C = Core Lab Over-read; D = IXRS; E = CIMS. 
 Abbreviations: β-hCG = beta- human chorionic gonadotropin; CIMS = Clinical Inventory Management System; 
EDC = electronic data capture (Medidata Rave®); IXRS = interactive recognition system; LIMS = laboratory information 
management system; NA = not applicable. 


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16.3. 
Study Monitoring 
This study will be monitored from initiation to completion by the Sponsor or its representative. 
Monitoring will include personal visits and telephone communication to assure that the 
investigation is conducted according to protocol and in order to comply with International 
Conference on Harmonization (ICH) Good Clinical Practice (GCP). On-site review of CRFs will 
include a review of forms for completeness and clarity, and consistency with source documents 
available for each subject. 
16.4. 
Audits 
The study may be subject to audit by the Sponsor/designee. If such an audit occurs, the 
Investigator must agree to allow access to required subject records. This is dependent on the 
subject/parent/legal guardian granting consent by signing the informed consent form 
(ICF)/informed assent form (IAF). By signing this protocol, the Investigator grants permission to 
personnel from the Sponsor or its representatives for on-site monitoring and auditing of all 
appropriate study documentation, as well as on-site review of the procedures employed in CRF 
generation, where clinically appropriate. 
16.5. 
Study Documentation 
Study records are comprised of source documents, CRFs, and all other administrative 
documents, eg, IRB/IEC correspondence, clinical study materials and supplies shipment 
manifests, monitoring logs, Sponsor and CRO correspondence, etc. A study specific binder will 
be provided with instructions for the maintenance of study records. 
Source document is defined as any hand written or computer generated document that contains 
medical information or test results that have been collected for or are in support of the protocol 
specifications, eg, clinical laboratory reports, clinic notes, drug disbursement log, subject sign in 
sheets, subject completed questionnaires if applicable, telephone logs, ECGs, etc. All draft, 
preliminary and pre-final iterations of a final report are also considered to be source documents, 
eg, faxed laboratory reports and hard copy laboratory reports, faxed initial results and hard copy, 
final report. 
16.6. 
Clinical Laboratory Certification and Normal Values 
A central laboratory will be used for analysis for most of the clinical laboratory tests for this 
study. The central laboratory will provide the Investigator, Sponsor/CRO with laboratory 
certification(s), a dated copy of normal range values for the central clinical laboratory selected to 
analyze clinical specimens. If an exception is granted to use a local laboratory, the Investigator 
must supply the Sponsor/CRO with laboratory certification, lab director’s curricula vitae and a 
current, dated copy of normal range values. 


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17. 
ETHICAL AND REGULATORY OBLIGATIONS 
17.1. 
Study Conduct 
The Investigator agrees that the study will be conducted according to the protocol, ICH GCP, 
ICH guidelines and the ethical principles that have their origin in the Declaration of Helsinki. 
The Investigator will conduct all aspects of the study in accordance with applicable local law(s) 
and regulation(s). 
The Investigator will assure proper implementation and conduct of the study including those 
study-related duties delegated to other appropriately qualified individuals. The Investigator will 
assure that study staff cooperate with monitoring and audits. 
The Investigator must sign and return to Sponsor/CRO the “Investigator Approval" page. 
The Investigator must provide a copy of current curriculum vitae (including a copy of a current 
medical license, current Drug Enforcement Agency (DEA) license, where applicable), and 
financial disclosure information. In countries where medical licensure is not issued, the 
following documentation is acceptable, as applicable: 
• Registration number/stamp with a registration number stated on curriculum vitae. 
• Appropriate diploma number stated on curriculum vitae. 
• Copy of the diploma. 
The Investigator must sign and return a completed Form FDA 1572 "Statement of Investigator" 
to Sponsor/CRO. 
17.2. 
Institutional Review Board/Independent Ethics Committee 
Documented approval for conducting the study from appropriate Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) will be obtained for all participating centers prior to 
initiation of the study, according to ICH GCP, applicable local law(s) and regulation(s). When 
necessary, an extension, amendment or renewal of the IRB/IEC approval must be obtained and 
also forwarded to the Sponsor. The IRB/IEC must supply the Sponsor a list of the IRB/IEC 
membership, and a statement to confirm that the IRB/IEC is organized and operates according to 
ICH GCP, applicable law(s) and regulation(s). 
A copy of written IRB/IEC approval or favorable opinion of the protocol, informed 
consent/assent form and subject recruitment material (if applicable) must be provided to 
Sponsor/CRO prior to start of the study. The approval or favorable opinion letter must be signed 
by the IRB/IEC chairman or designee identify the IRB/IEC name and address, identify the 
clinical protocol by title and/or protocol number, and include the date that approval or favorable 
opinion was granted. The letter must also contain a statement that the IRB/IEC complies with the 
requirements in 21 CFR Part 56 for a study conducted under a US IND or ICH GCP, as 
applicable. 
The Investigator/CRO is responsible for obtaining from the IRB/IEC continued review of the 
clinical research or submitting periodic progress reports, in accordance with applicable 


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regulations, at intervals not to exceed one year or as otherwise specified by the IRB/IEC. The 
Sponsor must be supplied with written documentation of continued review of the clinical 
research. 
The Investigator must promptly inform their IRB/IEC of all SAEs reported by subjects enrolled 
in the study or other safety information reported from Sponsor/CRO in accordance with 
applicable law(s) and regulation(s). 
17.3. 
Informed Consent 
The informed consent and assent forms will be approved by the Sponsor/CRO prior to 
submission to the IRB/IEC. The Sponsor/CRO may provide a template informed consent/assent 
form to be qualified by each research facility to conform to local requirements. All informed 
consent/assent forms must contain the minimum elements as mandated by ICH GCP, applicable 
local law(s) and regulations and will be subject to Sponsor/CRO approval as well as IRB/IEC 
approval. The Sponsor/CRO may submit informed consent/assent forms to a central IRB/IEC for 
review and approval or favorable opinion contingent upon the Investigator’s permission and 
review. 
Before recruitment and enrollment, each prospective subject and at least one parent/legal 
guardian will be given a full explanation of the study, allowed to read the approved informed 
consent/assent forms and be provided ample time and the opportunity to ask any questions that 
may arise. Once all questions have been answered and the Investigator is assured that the 
prospective subject/parent/legal guardian understands the implications of participating in the 
study, the prospective subject and at least one parent/legal guardian will be asked to give 
consent/assent, as appropriate, to participate in the study by signing the informed consent/assent 
form unless otherwise instructed by the IRB. As part of the consent/assent process, each 
prospective subject/parent/legal guardian must consent/assent to direct access to his/her medical 
records for study-related monitoring, auditing, IRB/IEC review, and regulatory inspection. It 
should be clearly explained to each prospective subject/parent/legal guardian that participation in 
each and every clinical visit and assessment is expected. The subject may be discontinued from 
study medication, but that does not necessarily negate the expectation that the subject will 
continue to participate in the study through the final visit/assessment. The Investigator will 
provide a copy of the signed informed consent/assent form to each subject/parent/legal guardian, 
and will record the date of the informed consent on the CRF. 
If an amendment to the protocol changes the subject participation schedule in scope or activity, 
or if important new information becomes available that may be relevant to the 
subject’s/parent’s/legal guardian’s consent/assent, the informed consent/assent form must be 
revised, submitted to the IRB/IEC for review and approval or favorable opinion. The revised 
informed consent/assent form must be used to obtain consent/assent from a subject currently 
enrolled in the study if he or she is affected by the amendment. The revised informed 
consent/assent form must be used to obtain consent/assent from any new subjects who are 
enrolled into the study after the date of the approval or favorable opinion of the protocol 
amendment. 


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17.4. 
Subject Privacy 
The Sponsor (or Sponsor representative) or any designees affirm uphold the subjects 
confidentiality. The subject will be identified by unique code and initials only; full names will be 
masked prior to transmission to the Sponsor. The confidentiality of the subject’s personal data 
shall be protected in accordance with appropriate laws and regulations. 
17.5. 
Protocol Amendments and Emergency Deviations 
All revisions and/or amendments to this protocol must be approved in writing by the Sponsor 
and the appropriate IRB/IEC. The Investigator will not make any changes to the conduct of the 
study or the protocol without first obtaining written approval from the Sponsor and the IRB/IEC, 
except where necessary to eliminate an apparent immediate hazard to a study subject. 
Emergency deviations or modifications may be initiated without Sponsor or IRB/IEC approval or 
favorable opinion, only in cases where the deviation or modification is necessary to eliminate or 
avoid an immediate apparent hazard to subjects. Emergency deviations or modifications must be 
reported to the Sponsor/CRO and the IRB/IEC immediately/within 5 business days of the 
occurrence, or in accordance with applicable regulatory requirements. 
17.6. 
Records Retention 
The Investigator/the site must arrange for retention of study records at the site for at least 
15 years from time of participation in the study or longer in accordance with applicable 
regulations and Sponsor SOPs. The Investigator/site should take measures to prevent accidental 
or premature destruction of these documents. Documents cannot be destroyed without written 
Sponsor authorization. The Sponsor will inform the Investigator/the site when the destruction of 
documents is permitted. 
17.7. 
Inspection of Records 
In the event of an inspection, the Investigator agrees to allow representatives of the Sponsor and 
its representative, the regulatory authorities’ access to all study records. The Investigator will 
promptly notify the Sponsor/CRO of all requests to inspect a Sunovion-sponsored study by 
government agencies and will promptly forward a copy of all such inspection reports. 
17.8. 
Financial Disclosure 
By signing this protocol, the Investigator agrees to provide to the Sponsor prior to start of study 
accurate financial information to allow the Sponsor to submit complete and accurate certification 
and disclosure statements as required by the US FDA regulations (21 CFR Part 54). The 
Investigator further agrees to provide this information on a Financial Disclosure/Certification 
Form that is provided by the Sponsor. The Investigator will update this information if there are 
any relevant changes during the conduct of the study and for one year after completion of the 
study. 
The Investigator also consents to the transmission of this information to the Sponsor for these 
purposes. This may involve the transmission of information to countries that do not have laws 
protecting personal data. 


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17.9. 
Publication Policy 
Any formal presentation or publication of data collected as a direct or indirect result of the study 
will be considered a joint publication by the Investigators and the appropriate personnel of the 
Sponsor. For multicenter studies, it is mandatory that the first publication is based on all data 
obtained from all analyses as stipulated in the protocol. Investigators participating in multicenter 
studies must agree not to present data gathered individually or by a subgroup of centers before 
the full, initial publication, unless this has been agreed to by all other Investigators and by the 
Sponsor. 


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18. 
INVESTIGATOR APPROVAL 
I have read the protocol, SEP360-310, Version 3.00, “An Open-label, Flexibly-dosed, 26-Week 
Extension Safety Study of Dasotraline in Children and Adolescents with Attention Deficit 
Hyperactivity Disorder (ADHD)”, and agree that it contains all necessary details for conducting 
the study and to conduct the study in strict accordance with the specifications outlined herein. 
I agree that no additional procedure(s) will be added during the conduct of the study except 
through protocol amendment by Sunovion Pharmaceuticals Inc. and after documentation of IRB 
approval. 
Investigator Signature: ____________________________________________________ 
Print Investigator Name: __________________________________________________ 
Date: ___________________________________________ 


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19. 
REFERENCES 
Amor LB, Grizenko N, Schwartz G, Lageix P, Baron C, et al. Perinatal complications in children 
with attention-deficit hyperactivity disorder and their unaffected siblings. Rev Psychiatr 
Neurosci 2005;30(2):120-6. 
Arnsten AF, Pliszka SR. Catecholamine influences on prefrontal cortical function: relevance to 
treatment of attention deficit/hyperactivity disorder and related disorders. Pharmacol Biochem 
Behav 2011;99:211-6. 
Aron AR, Poldrack RA. The cognitive neuroscience of response inhibition: relevance for genetic 
research in attention-deficit/hyperactivity disorder. Biol Psychiatry 2005;7:1285-92. 
Boonstra AM, Oosterlaan J, Sergeant JA, Buitelaar JK. Executive functioning in adult ADHD: a 
meta-analytic review. Psychol MEd 2005;35:1097-108. 
Botting N, Powls A, Cooke RWI. Attention deficit hyperactivity disorders and other psychiatric 
outcomes in very low birthweight children at 12 years. J Child Psychol Psychiat 
1997;38(8):931-41. 
Dopheide JA, Pliszka SR. Attention deficit/hyperactivity disorder. In: Dipiro JT, Talbert RL, 
Yee GC, Matzke GR, Wells BG, Posey LM, ed. Pharmacotherapy: a Pathophysiologic 
Approach, Eighth Edition. New York, NY: McGraw-Hill Companies, Inc; 2011: Chapter 72. 
Ferri FF. Attention deficit hyperactivity disorder. Ferri’s Clinical Advisor 2015. St. Louis MO: 
Mosby, an imprint of Elsevier; 2014:160-1. 
Gamo NJ, Arnsten AF. Molecular modulation of prefrontal cortex: rational development of 
treatments for psychiatric disorders. Behav Neurosci 2011;125:282-96. 
Goto Y, Hatakeyama K, Kitama T, Sato Y, Kanemura H, et al. Saccade eye movements as a 
quantitative measure of frontostriatal network in children with ADHD. Brain Dev 
2010;32:347-55. 
Guy W. EDCEU Assessment Manual for Psychopharmacology – Revised. Rockville, MD, US 
Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and 
Mental Health Administration, NIMH Psychopharmacology Research Branch, Division of 
Extramural Research Programs, 1976:534 7. DHEW Publication No ADM 76 338. 
Hannestad J, Gallezot JD, Planeta-Wilson B, Lin SF, Williams WA, van Dyck CH, et al. 
Clinically relevant doses of methylphenidate significantly occupy norepinephrine transporters in 
humans in vivo. Biol Psychiatry 2010;68:854-60. 
Hervey AS, Epstein JN, Curry JF. Neuropsychology of Adults with Attention-
Deficit/Hyperactivity Disorder: A Meta-Analytic Review. Neuropsychology 2004; 18;485-503.  
Luna B, Garver KE, Urban TA, Lazar NA, Sweeney JA. Maturation of cognitive processes from 
late childhood to adulthood. Child Dev 2004;75:1357-72. 
Owens JA, Spirito A, McGuinn M. The Children’s Sleep Habits Questionnaire (CSHQ): 
Psychometric properties of a survey instrument for school-aged children. Sleep 2000;23: 1-9. 


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Passarotti AM, Pavuluri MN. Brain functional domains inform therapeutic interventions in 
attentiondeficit/hyperactivity disorder and pediatric bipolar disorder. Expert Rev Neurother 
2011;11:897-14. 
Perricone G, Morales MR, Anzalone G. Neurodevelopmental outcomes of moderately preterm 
birth: precursors of attention deficit hyperactivity disorder at preschool age. SpringerPlus 
2013;22:221. 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of 
Suicide Assessment (C CASA): classification of suicidal events in the FDA's pediatric suicidal 
risk analysis of antidepressants. Am J Psychiatry 2007;164(7):1035 43. 
Rader R, McCauley L, Callen EC. Current strategies in the diagnosis and treatment of childhood 
attention-deficit/hyperactivity disorder. Am Fam Physician 2009;79(8):657-65. 
Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective Serotonin Reuptake 
Inhibitor Discontinuation Syndrome: A Randomized Clinical Trial. Biol Psychiatry 1998;44:77–
87. 
Volkow ND, Wang GJ, Fowler JS, Gatley SJ, Logan J, et al. Dopamine transporter occupancies 
in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 
1998;155:1325-31. 
Willcutt EG, Doyle AE, Nigg JT, Faraone SV, Pennington BF. Validity of the Executive 
Function Theory of Attention-Deficit/Hyperactivity Disorder: A Meta-Analytic Review. Biol 
Psychiatry 2005:57;1336-46. 


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20. 
APPENDIX I. CARDIAC SAFETY MONITORING (ECG) 
1. Requirements for Testing 
ECG equipment and supplies will be provided by the ECG vendor and should be used for all 
in-clinic protocol ECG assessments. 
• All 12-lead ECGs will be recorded in the same manner. 
• The site personnel must be adequately trained in performing ECGs on the specific 
ECG equipment used in this protocol that is provided by the cardiac safety vendor. 
• To the extent possible, the same ECG machine and personnel should be used to 
acquire a subject’s ECGs throughout the period of their participation in the study. 
• ECGs will be recorded with at least one 10-second single-lead tracing recorded from 
Lead II included. 
2. Subject Restrictions and Instructions 
• Prior to ECG acquisition, the subject will have rested for at least 5 minutes in the 
supine position and will remain so until the ECG is obtained.  
3. Reporting 
• It is the responsibility of the Investigator to perform a safety review of the ECG data 
for changes from previous assessments and/or emergent cardiac dysfunction, and to 
determine subjects’ eligibility or continuance in the study. 
• ECGs will be reviewed, signed and dated by the Investigator listed on the Form FDA 
1572 (MD or DO) after each ECG collection. The same Investigator should review all 
ECG reports for a given subject whenever possible. 
• For all ECGs, a report will be provided by the cardiac safety vendor to the site for 
review and signature. 
• The ECG tracing will be kept with subject’s source documentation and / or CRF 
unless it is specified otherwise. The original ECG and the cardiologist’s over-read 
will be retained at the site. 
4. Data Standardization 
ECG data will be transmitted to a centralized cardiac safety vendor and centrally over-read 
and interpreted using standardized procedures. 


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21. 
APPENDIX II. CLINICALLY RELEVANT CYP2B6 
SUBSTRATES OR INDUCERS OR INHIBITORS 
(GENERIC NAMES) 
The following drugs are prohibited during this study. 
Substrate 
Inhibitor 
Inducer 
artemisinin 
clopidogrel 
artemisinin 
bupropion 
thiotepa 
carbamazepine 
cyclophosphamide 
ticlopidine 
efavirenz 
efavirenz 
voriconazole 
nevirapine 
ifosphamide 
  
phenobarbital 
ketamine 
  
phenytoin 
meperidine 
  
rifampin 
methadone 
  
  
nevirapine 
  
  
propafol 
  
  
selegiline 
  
  
sorafenib 
  
  
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine 
(2007). http://medicine.iupui.edu/clinpharm/ddis/table.aspx. Accessed 21 April 2014. 


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22. 
APPENDIX III. CLINICAL LABORATORY TESTS 
The following clinical laboratory tests are to be performed: 
Clinical Safety Panel 
HEMATOLOGY: 
Hemoglobin, Hematocrit, Platelet Count, RBC Count, WBC - Total Count, WBC Differential 
reported as % and absolute value to include basophils, eosinophils, lymphocytes, monocytes, 
neutrophils 
 
BLOOD CHEMISTRIES: 
Alanine aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate aminotransferase 
(AST), Bicarbonate (HCO3), Bilirubin (Total, Direct, Indirect), Blood Urea Nitrogen (BUN), 
Calcium (Ca), Chloride (Cl), Creatinine, Glucose, Magnesium (Mg), Phosphorus (P), 
Potassium (K), Protein (Total), Sodium (Na), Uric Acid, Albumin 
 
URINALYSIS: 
Blood, Glucose, Ketones, Leukocyte esterase, Microscopic examination, Nitrites, pH, Protein 
 
THYROID PANEL: 
Free T3, Free T4, Thyroid stimulating hormone (TSH) 
 
LIPID PANEL 
LDL-Cholesterol, HDL-Cholesterol, Total Cholesterol, Triglycerides 
 
SEX HORMONES: 
For females: estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). 
For males: testosterone. 
 
URINE DRUG SCREENING: 
Amphetamines, Barbiturates, Benzodiazepines, Cannabinoids, Cocaine, Methamphetamines, 
Methadone, Methylenedioxymethamphetamine (MDMA), Phencyclidine (PCP), Opiates, 
Oxycodone, Tricyclic Antidepressants 
 
OTHER TESTS: 
Breath Alcohol Test, Serum Pregnancy (β-hCG) (in female subjects only), Urine Pregnancy Test 
(in female subjects only) 
 
Laboratory reports will be initialed and dated on all pages by the Investigator listed on the 1572 
(MD or DO). Laboratory test results will be reviewed by the Investigator as they become 
available. The Investigator must determine the clinical significance of all out-of-range lab values 
(except drug screens). Possibly drug-related or clinically relevant abnormal values of uncertain 
causality must be repeated. Any abnormal values that persist should be followed at the discretion 
of the Investigator. 


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23. 
APPENDIX IV. ACCEPTABLE CONTRACEPTIVE 
PROCEDURES DURING THE STUDY 
Female Subjects 
A female subject is eligible to enter and participate in the study if she is of:  
a. Non-childbearing potential (ie, physiologically incapable of becoming pregnant, 
including any female who is premenarchal, surgically sterile, etc).  
b. Child-bearing potential (all females ≥ 8 years of age), has a negative pregnancy test at 
baseline and agrees to satisfy one of the following requirements: 
− Practice true abstinence (consistent with lifestyle) from signing informed 
assent/consent to at least 14 days after the last dose of study drug; or, 
− Use of medically effective method of birth control from signing informed 
assent/consent to at least 14 days after the last dose of study drug, which 
include: prescription hormonal contraceptives (oral, patch, vaginal ring, 
implant, or injection), diaphragm with spermicide, intrauterine device 
(IUD), condom with spermicide, surgical sterilization. 
Male Subjects  
1. Male subject must be willing to remain sexually abstinent (consistent with lifestyle) or 
with female partner(s) of childbearing potential must ensure that their partner(s) uses the 
methods of birth control as outlined for female subjects above. 


Protocol SEP360-310, Version 3.00 
 
Dasotraline 
Confidential and Proprietary 
73 
20 Jan 2016 
24. 
APPENDIX V. TOTAL BLOOD VOLUMES  
An estimated 37.5 mL of blood will be collected for study assessments from each subject during 
the study as shown in Table 8. 
 
Table 8: 
Blood Collection Volumes (mL) 
Visit 
1E 
2E 
3E 
4E 
5E 
6E 
7E 
8E 
9E 
10E 
/ET 
11E 
12E 
13E 
/EOS 
Total 
Week 
Baseline 
1 
2 
4 
6 
10 
14 
18 
22 
26 
27 
28 
29 
Day (±3c) 
0 
7 
14 
28 
42 
70 
98 
126 
154 
182 
189 
196 
203 
(±7) 
Lab test 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology  
CO 
 
 
 
 
 
2 
 
 
2 
 
 
2 
6 
Chemistry 
CO 
 
 
 
 
 
8.5 
 
 
8.5 
 
 
8.5 
25.5 
Thyroid Panelb 
CO 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panelb 
CO 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sex Hormone 
Tests 
CO 
 
 
 
 
 
2 
 
 
2 
 
 
2 
6 
Serum pregnancy
(Females)a,b 
CO 
 
 
 
 
 
 
 
 
 
 
 
 
 
TOTAL 
0 
0 
0 
0 
0 
0 
12.5 
0 
0 
12.5 
 
 
12.5 
37.5 
Abbreviations: CO = Carried over from core study (no additional blood drawn; 0 mL), EOS = End of Study; ET = Early 
Termination = Visit. 
a ≥ 8 years of age. 
b Included in serum chemistry sample. 
c Unless otherwise specified. 

SAP_001.pdf: 
Statistical Analysis Plan (SAP) 
 
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Page 1 of 60 
Sponsor Name:  
Sunovion Pharmaceuticals Inc. 
Protocol Number and Title: 
SEP360-310 
An Open-label, Flexibly-dosed, 26-Week 
Extension Safety Study of Dasotraline in 
Children and Adolescents with Attention Deficit 
Hyperactivity Disorder (ADHD) 
Protocol Version and Date: 
Version 3.0, 20-JAN-2016 
INC Research Project Code: 
1005362 
Author(s): 
Michael L. White, Principal Biostatistician 
SAP Version: 
Draft 1.0  
SAP Version Date:  
09-Mar-2017 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Sunovion 
Pharmaceuticals Inc. Acceptance of this document constitutes agreement by the recipient that 
no information contained herein will be published or disclosed without prior written 
authorization from an official of Sunovion Pharmaceuticals Inc. However, this document may be 
disclosed to appropriate Institutional Review Board and Ethics Committees or duly authorized 
representatives of a national regulatory authority under the condition that they are requested to 
keep it confidential. In the event of an actual or suspected breach of this obligation, INC 
Research should be notified promptly. 


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TABLE OF CONTENTS 
1. 
GLOSSARY OF ABBREVIATIONS ....................................................................... 7 
2. 
PURPOSE ......................................................................................................... 9 
2.1. 
Responsibilities ..................................................................................................................... 9 
3. 
STUDY OBJECTIVES ......................................................................................... 9 
3.1. 
Primary Objective ................................................................................................................ 9 
3.2. 
Secondary Objective(s) ........................................................................................................ 9 
4. 
STUDY DESIGN ............................................................................................... 10 
4.1. 
Brief Description ................................................................................................................. 10 
4.2. 
Determination of Sample Size ........................................................................................... 11 
5. 
STUDY ENDPOINTS ........................................................................................ 11 
5.1. 
Primary Endpoint ................................................................................................................ 11 
5.2. 
Secondary Endpoints .......................................................................................................... 11 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ......................................... 12 
6.1. 
General Methods ................................................................................................................. 12 
6.2. 
Key Definitions.................................................................................................................... 13 
6.2.1. 
Baseline Value ............................................................................................................ 13 
6.2.2. 
Study Day .................................................................................................................... 14 
6.2.3. 
Missing Data and Last Observation Carried Forward (LOCF) .................................... 14 
6.2.4. 
Visit Windows .............................................................................................................. 15 
6.2.5. 
Pooling of Centers ....................................................................................................... 15 
7. 
SUBJECT DISPOSITION .................................................................................. 15 
8. 
ANALYSIS POPULATIONS ............................................................................... 16 
8.1. 
Enrolled Population ............................................................................................................ 16 


 
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8.2. 
Safety Population ............................................................................................................... 16 
8.3. 
Intent-To-Treat (ITT) Population ...................................................................................... 16 
9. 
PROTOCOL DEVIATIONS ................................................................................ 17 
10. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ..................... 17 
10.1. 
Demographics and Other Baseline Characteristics .......................................................... 17 
10.2. 
History ................................................................................................................................. 18 
10.2.1. 
Medical History ............................................................................................................ 18 
10.2.2. 
Psychiatric History ....................................................................................................... 18 
10.3. 
Prior and Concomitant Medications .................................................................................. 18 
10.4. 
Treatment Exposure and Compliance ............................................................................... 19 
11. 
EFFECTIVENESS ANALYSIS ........................................................................ 21 
11.1. 
Change in ADHD-RS-IV ........................................................................................................ 21 
11.1.1. 
Percentage of responders at Post-Baseline Visits ...................................................... 22 
11.2. 
Change in CGI-S ................................................................................................................... 22 
11.3. 
Change from baseline in the ADHD RS-IV HV Inattentiveness and Hyperactivity scores
 
23 
11.4. 
Change from baseline in Conners 3-P scale scores ......................................................... 23 
11.5. 
Weiss Functional Impairment Rating Scale – Parent Report (WFIRS-P) ......................... 29 
11.6. 
Subgroup Analysis ............................................................................................................... 30 
12. 
SAFETY....................................................................................................... 30 
12.1. 
Adverse Events (AEs) .......................................................................................................... 30 
12.2. 
Laboratory Evaluations ...................................................................................................... 33 
12.3. 
Breath Alcohol test ............................................................................................................. 39 
12.4. 
Urine Drug Screening ......................................................................................................... 39 
12.5. 
12-lead ECG ......................................................................................................................... 39 


 
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12.6. 
PhysicaL Examination ........................................................................................................ 41 
12.7. 
Neurological Examination .................................................................................................. 41 
12.8. 
Vital Signs ............................................................................................................................ 41 
12.9. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ............................................................ 43 
12.10. 
Children's Sleep Habits Questionnaire (CSHQ) ............................................................ 44 
12.11. 
Tanner Scale ................................................................................................................... 47 
12.12. 
Physician withdrawal checklist (PWC) ......................................................................... 47 
12.13. 
Discontinuation-Emergent Signs and Symptoms (DESS) Scale .................................... 48 
13. 
STATISTICS (TO BE INCORPORATED INTO SECTION 16.1.9 OF CSR) ....... 49 
13.1. 
Statistical methods and analysis outputs ......................................................................... 49 
13.1.1. 
Statistical Methods ...................................................................................................... 49 
14. 
QUALITY CONTROL.................................................................................... 49 
15. 
TABLE AND LISTING SHELLS...................................................................... 49 
15.1. 
Table Shells: See attachment 1 ......................................................................................... 49 
15.2. 
Listing Shells: See attachment 2 ....................................................................................... 49 
15.3. 
Figure Shells: See attachment 3 ....................................................................................... 49 
16. 
REFERENCES .............................................................................................. 50 
17. 
APPENDIX 1 – SCHEDULE OF ASSESSMENTS .................................... 51 
18. 
APPENDIX 2 - PROGRAMMING CONSIDERATIONS ............................. 54 
18.1. 
General Considerations ...................................................................................................... 54 
18.2. 
Table, Listing, and Figure Format .................................................................................... 54 
18.2.1. 
General ........................................................................................................................ 54 
18.2.2. 
Headers ....................................................................................................................... 55 
18.2.3. 
Display Titles ............................................................................................................... 55 
18.2.4. 
Column Headers ......................................................................................................... 55 
18.2.5. 
Body of the Data Display ............................................................................................. 56 


 
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18.2.5.1. 
Table Conventions ............................................................................................................ 56 
18.2.5.2. 
Listing Conventions .......................................................................................................... 57 
18.2.5.3. 
Figure Conventions ........................................................................................................... 57 
18.2.6. 
Footnotes .................................................................................................................... 57 
19. 
APPENDIX 3 – HANDLING PARTIAL/MISSING DATES ......................... 59 
19.1. 
Medication Date .................................................................................................................. 59 
19.2. 
Adverse Event Date ............................................................................................................ 59 
 


 
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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation  
Full Form  
ADHD  
attention deficit hyperactivity disorder  
ADHD RS-IV HV 
ADHD Rating Scale Version IV – Home Version (modified for 
investigator administration)  
AE  
Adverse event  
ALT  
alanine aminotransferase  
AST  
aspartate aminotransferase  
ATC 
Anatomical Therapeutic Chemical Classification 
β-hCG  
beta-human chorionic gonadotropin  
BMI  
Body mass index  
BUN  
Blood urea nitrogen  
CGI-S  
Clinical Global Impression - Severity  
Conners 3-P 
Conners 3rd Edition - Parent 
CSR 
Clinical study report 
CSHQ 
Children’s Sleep Habits Questionnaire  
C-SSRS  
Columbia – Suicide Severity Rating Scale  
DB baseline 
double-blind baseline 
DB treatment 
double-blind treatment (i.e. treatment received during 
SEP360-202) 
DBL 
database lock 
DESS 
Discontinuation-Emergent Signs and Symptoms (DESS) Scale  
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition  
DSM-IV-TR  
Diagnostic and Statistical Manual of Mental Disorders, 
Fourth Edition; Text Revision  
ECG  
electrocardiogram  
eCRF 
electronic case report form 
EOS 
end of study  
ET  
early termination  


 
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Abbreviation  
Full Form  
HR  
heart rate  
ICH  
International Conference on Harmonization  
ITT  
intent-to-treat  
KM 
Kaplan-Meier 
LOCF  
last observation carried forward  
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
n/a 
not applicable 
OL baseline 
open-label baseline 
PR  
time between P wave and QRS in electrocardiograph  
PT 
preferred term 
PWC 
Physician Withdrawal Checklist (PWC)  
QRS  
electrocardiographic wave (complex or interval)  
QT  
electrocardiographic interval from the beginning of the 
QRS complex to the end of the T wave  
QTc  
QT interval corrected for heart rate  
SAE  
serious adverse experience/event  
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
TEAE  
treatment-emergent adverse event  
WBC  
white blood cells  
WHO 
World Health Organization 
WHODRUG 
World Health Organization Drug Dictionary 
WFIRS-P   
Weiss Functional Impairment Rating Scale – Parent Report  
 


 
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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the efficacy and 
safety analyses defined by appropriate data listings, summary tables, and figures, as 
well as statistical methodologies, are outlined in this document and provide valid 
conclusions about the study objectives.   
2.1. 
RESPONSIBILITIES 
INC Research will perform the statistical analyses and is responsible for the production 
and quality control of all tables, figures, and listings. 
The analyses of efficacy, safety for the clinical study report (CSR) are planned to be 
completed after the database lock (DBL).  
3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE 
To evaluate the long-term safety and tolerability of flexibly-dosed dasotraline in 
children and adolescents with ADHD by the incidence of adverse events (AEs; or serious 
AEs [SAEs]), and AEs (or SAEs) leading to discontinuation. 
3.2. 
SECONDARY OBJECTIVE(S) 
The secondary objectives are:  
 
To evaluate the long-term safety and tolerability of flexibly-dosed dasotraline in 
children and adolescents with ADHD by assessing clinical laboratory evaluations, 
vital signs, physical examinations, body height and weight, 12-lead 
electrocardiograms (ECG), Tanner Staging, Children's Sleep Habits Questionnaire 
(CSHQ), and the frequency and severity of suicidal ideation and suicidal behavior 
using the Columbia – Suicide Severity Rating Scale (C-SSRS) Children’s 
Assessment.  
 
To assess the long-term effectiveness of dasotraline in children and adolescents 
with ADHD using the following assessments:  
o the ADHD Rating Scale Version IV - Home Version (modified for 
investigator administration) (ADHD-RS-IV HV)  


 
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o the Clinical Global Impression – Severity (CGI-S)  
o the Conners 3rd Edition Parent (Conners 3-P)  
 
To evaluate health-related quality of life and functional impairment in children 
and adolescents with ADHD using the Weiss Functional Impairment Rating Scale – 
Parent Report (WFIRS-P).  
 
To assess potential withdrawal symptoms following discontinuation of 
dasotraline treatment using the following assessments (administered during the 
withdrawal period):  
o Discontinuation-Emergent Signs and Symptoms (DESS) Scale  
o Physician Withdrawal Checklist (PWC)  
 
4. 
STUDY DESIGN 
4.1. 
BRIEF DESCRIPTION 
This is an open-label, flexibly-dosed, 26-week extension study in children and 
adolescents with ADHD who have completed 6 weeks of double-blind treatment in the 
core study (SEP360-202). Subjects who meet all eligibility criteria will transition directly 
from the core study and will not need to complete the End of Study (EOS) visit in the 
core study. Subjects will take the first dose of open-label study drug in this extension 
study on Day 1, the morning following the open-label (OL) Baseline visit. Subjects will 
continue to take study drug for 26 weeks, at approximately the same time each morning 
including on the days when clinic visits occur. Dasotraline will be dosed at 2 mg/day for 
the first week of the study (Days 1 - 7). Subjects will then be flexibly dosed (2, 4, or 6 
mg/day) thereafter beginning on Day 8 based on the investigator’s assessment of 
effectiveness and tolerability. After the OL Baseline visit, subjects will return to the 
clinic weekly for the first 2 weeks, once every 2 weeks for the next 4 weeks, then once 
every 4 weeks for the remainder of the treatment period for clinical evaluation, and 
once at the end of the withdrawal period (Visit 13E). At the approximate midpoint 
between the scheduled monthly visits (i.e., 14 ± 2 days after a visit) during the 
treatment period, the site staff will contact the subject’s parent/legal guardian via 
telephone, text, or email in order to evaluate the safety of the subjects as well as to 
remind subject/parent/legal guardian about adherence to study drug administration 
and upcoming visits, following which, if necessary, an unscheduled visit can be arranged. 


 
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All assessments will be performed as per the schedule of assessment in Appendix 1. 
4.2. 
DETERMINATION OF SAMPLE SIZE 
This study is projected to enroll up to 330 subjects based on the number of subjects 
who complete the core study. 
5. 
STUDY ENDPOINTS 
5.1. 
PRIMARY ENDPOINT  
The primary endpoint is:  
 
The incidence of overall AEs (or SAEs), and AEs (or SAEs) leading to 
discontinuation. 
5.2. 
SECONDARY ENDPOINTS  
The secondary endpoints are:  
 
Clinical laboratory evaluations (serum chemistry, hematology, lipid panel, 
thyroid function panel, urinalysis, sex hormones).  
 
Clinical evaluations (vital signs, physical examination, body height and weight, 
Tanner Staging, and 12-lead ECG).  
 
Frequency and severity of suicidal ideation and suicidal behavior using the 
C-SSRS.  
 
Change in CGI-S score. 
 
Change in ADHD-RS-IV HV total score.  
 
Change in the inattentiveness and hyperactivity subscales of the ADHD-RS-IV HV. 
 
Change in Conners 3-P total score and subscale scores (Oppositional, Cognitive 
problems, Hyperactivity, and ADHD Index).  


 
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 
Change in CSHQ total score and 8 subscale scores (bedtime resistance, sleep 
onset delay, sleep duration, sleep anxiety, night wakings, parasomnias, sleep 
disordered breathing, and daytime sleepiness).  
 
Change in WFIRS-P total score and 6 domain scores (family, school learning 
behavior, life skills, child's self-concept, social activities, and risky activities).  
 
Symptoms of withdrawal using:  
o PWC score  
o DESS score  
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
 
All analyses and summaries will be produced using SAS® version 9.3 (or higher) for 
windows.  
 
All statistical summaries will be presented based on the treatment received in the 
double-blind core study (SEP360-202), called DB treatment.  Because the treatment 
received in SEP360-310 is flexible, the treatment groups for summary in SEP360-310 
will be labeled as:  
o placebo / dasotraline flexible,  
o dasotraline 2 mg/day / dasotraline flexible,  
o dasotraline 4 mg/day / dasotraline flexible,  
o dasotraline combined / dasotraline flexible, and 
o total.   
 
The dasotraline combined group will include those subjects who were treated in 
SEP360-202 with dasotraline 2 mg/day and dasotraline 4 mg/day.  
 
Summaries will also be presented by visits (Double-Blind Baseline, Open-Label 
Baseline, Weeks 1, 2, 4, 6, 10, 14, 18, 22, 26, Week 26 or Treatment Period LOCF, 


 
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and EOS).  See the details for the DESS and PWC for discussion of the display of visits 
for those summaries.   
 
Unless otherwise specified, continuous variables will be summarized with descriptive 
statistics including: n, arithmetic mean, standard deviation (SD), 95% confidence 
interval for the mean, median, minimum, and maximum values. All 
categorical/qualitative data will be presented using frequency counts and 
percentages. Shift tables will be produced for some assessments and will contain 
counts and percentages of subjects in each cross-classification level of baseline 
versus post-baseline assessment. Only subjects with a non-missing value for both 
baseline and post-baseline, at a given visit, will be included in these tables.  
 
The listings will be provided using the enrolled  population (defined in Section 8.1). 
For listings related to analyses conducted using the intent-to-treat population, a flag 
will be shown in the subject column identifying subjects who were excluded from 
the intent-to-treat population. In general, the subject listings will be sorted by the 
treatment group, subject number and assessment date (and time, if applicable). 
 
Data for unscheduled assessments will be included when selecting worst result for 
shift analyses, and for summary of normal/abnormal values. The summary of 
observed value and change from DB baseline and change from OL baseline data will 
be performed by nominal visits (scheduled visits).  Unscheduled assessments will be 
included in Week 26 or Treatment Period LOCF, as long as that unscheduled 
assessment was not completed more than 3 days after the last dose of study 
medication. 
6.2. 
KEY DEFINITIONS 
6.2.1. 
Baseline Value  
Two different baseline values are defined for this study.  
The first baseline value, called the DB baseline, is the baseline value from the double-
blind core study, SEP360-202.  This value is the last non-missing assessment value up to 
and including the day of first dose of study drug in SEP360-202.  
The second baseline value, called the OL baseline, is defined as Week 6 (LOCF) from the 
core study, SEP360-202, which is also the assessment at the start of SEP-360-310. For 


 
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the questionnaire based endpoints, domain scores for the Week 6 (LOCF) may come 
from different assessment dates.  This occurs when an incomplete questionnaire was 
completed at the Week 6 assessment of SEP360-202. 
For assessments completed at the EOS assessment, a third baseline value is defined as 
the last assessment on treatment.  This baseline will be the SEP360-310 LOCF value. 
6.2.2. 
Study Day 
Study day is defined as the number of days from the date of first dose in the SEP360-310 
study to the event/visit date. It is calculated as follows:  
If event date falls on or after the date of first dose then  
 
Study Day = Event or Visit Date – First Dose Date + 1  
If event date falls before the date of first dose then 
 
Study Day = Event or Visit Date – First Dose Date 
Hence, the date of first dose is referred to as Day 1. The previous day is Day -1.  
6.2.3. 
Missing Data and Last Observation Carried Forward (LOCF) 
Methods for handling missing item responses on the questionnaire instruments (i.e. 
ADHD-RS-IV HV, Conners 3-P, and WFIRS-P) are described in different sections later on.  
 
If a subject discontinues the study prematurely, the last available data (excluding early 
termination visit assessments if done more than 3 days after the last dose of study 
medication, unscheduled assessments after the early termination assessment if done 
more than 3 days after the last dose of study medication, and Withdrawal Period 
assessments) will be carried forward to the study endpoint (i.e. the LOCF approach) at 
Week 26.  Visits earlier than the early termination date for subjects who discontinued 
the study prematurely will be included in the LOCF process, even if they are more than 
3 days after the last dose of study medication. 
The AE and concomitant medication start/end dates will be imputed based on the rules 
described in Appendix 3. 


 
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6.2.4. 
Visit Windows 
All data will be organized and analyzed according to the scheduled times as outlined in 
the protocol and by the visit denoted on the electronic case report form (eCRF) except 
for early termination (ET) visits during the treatment period.  
If a subject terminates early and within the 26-week treatment period, the ET visit will 
be remapped based on the study day of the visit as follows.  
ET Day Criteria 
Visit 
1 ≤ study day ≤ 10 
Week 1 
11 ≤ study day ≤ 17 
Week 2 
18 ≤ study day ≤ 31 
Week 4 
32 ≤ study day ≤ 45 
Week 6 
46 ≤ study day ≤ 73 
Week 10 
74 ≤ study day ≤ 101 
Week 14 
102 ≤ study day ≤ 129 
Week 18 
130 ≤ study day ≤ 157 
Week 22 
158 ≤ study day, but not more than 3 days after 
treatment termination 
Week 26 
 
If a subject already has a scheduled visit at the mapped visit time, then the ET visit will 
be assigned as unscheduled at that mapped study week. If more than 1 observation is 
collected at a scheduled visit after baseline, the earliest value (based on collection or 
visit date) will be used at the visit, and other value(s) will be set as unscheduled.  If the 
early termination visit date is more than 3 days after the date of last dose, then the 
visit will be assigned as unscheduled if EOS is available, or the visit will be assigned as 
EOS if EOS is missing.  
These ET visit remapping rules will apply to all data points. All tables and figures will be 
presented by the remapped visit. All data listings will be reported using the visit as 
denoted on the eCRF. 
6.2.5. 
Pooling of Centers  
There will be no statistical analyses of endpoints by pooled centers in this study. 
 
7. 
SUBJECT DISPOSITION  
Subject disposition will be summarized for the enrolled population. Subjects who took 
at least one dose of study medication will be summarized by DB treatment and overall. 


 
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Subjects who completed the study and discontinued early from the study will be 
summarized by DB treatment and overall. The summary of subject disposition by 
discontinuation reason will be presented. If there are multiple reasons for 
discontinuation, the primary reason (determined by the investigator) will be used for 
the summary. All percentages will be based on the number of enrolled subjects within 
each DB treatment group and overall. 
Using the safety population (defined in Section 8.2), the number of days until treatment 
discontinuation will be analyzed using Kaplan-Meier (KM) methodology.  Subjects who 
complete the study treatment period will be censored on the study day of the last dose.  
Median, 25th percentile, and 75th percentile for days until discontinuation will be 
presented for each DB treatment and overall. A Kaplan-Meier plot will be used to 
display these results.  
A listing of study completion will be provided for all enrolled subjects, with flags 
provided to identify subjects in the safety and ITT populations. 
8. 
ANALYSIS POPULATIONS 
8.1. ENROLLED POPULATION 
The Enrolled population includes all subjects with an informed consent. All disposition 
summaries will be performed in the enrolled population. 
8.2. SAFETY POPULATION  
The Safety population includes all subjects who enter this study and receive at least one 
dose of study drug. All safety analyses will be performed in the Safety population. 
8.3. INTENT-TO-TREAT (ITT) POPULATION  
The ITT population is defined as all subjects who enter this study and receive at least 
one dose of study drug, and have a baseline effectiveness measure and at least one post 
baseline effectiveness measure in ADHD-RS-IV HV. The ITT population will be used for 
the effectiveness and quality of life analyses. 
For the definition of ITT, the baseline effectiveness measure for determination of 
inclusion in the population is the OL baseline value. 


 
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9. 
PROTOCOL DEVIATIONS 
Protocol deviations will be collected during monitoring visits.  These deviations will be 
placed into the following categories: concomitant medications, dosing, enrolment 
criteria, laboratory, non-compliance, visit schedule, visit/procedure requirement, and 
other. 
A summary table will be provided as the number and percentage of subjects with at 
least one important protocol deviation and the number of subjects in each category. A 
listing will be provided containing all protocol deviations.  
10. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS  
10.1. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographics (collected at enrollment into the SEP360-202 study) (sex, race, ethnicity, 
age [years], age group [6-9 and 10-12 years], weight [kg], height [cm], body mass index 
[BMI, kg/m2], and World Health Organization (WHO) z-scores and percentiles for height 
and BMI) will be summarized by DB treatment and overall for the safety and ITT 
populations.  These values will be referred to as DB baseline values. 
The age, age group [6-9 and 10-13 years], weight, height, BMI, and WHO percentiles for 
height and BMI at the time of enrollment into the SEP360-310 study will be summarized 
by DB treatment and overall for the safety and ITT populations.  These values will be 
referred to as OL baseline values. Note that some subjects who were 12 years old at 
entry into SEP360-202 had turned 13 years old at the time of entry into SEP360-310. 
Sex, race, age group, and ethnicity will be summarized by using summary statistics for 
categorical variables (frequencies and percentages).  Percentages for sex, race, age 
group, and ethnicity will be based on the number of subjects within a DB treatment 
group. The DB baseline and OL baseline values for Age, height, height percentile, 
weight, BMI, and BMI percentile will be summarized by using summary statistics for 
continuous variables (number of subjects, arithmetic mean, standard deviation, 95% 
confidence interval for mean, median, minimum and maximum values). 
Age will be calculated as the number of years between date of birth and date of 
enrollment into the SEP360-202 and SEP360-310 studies.  
BMI (kg/m2) = Weight(kg)/(Height(m))2 


 
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Normal age and sex-based percentiles for weight, height, and BMI will be determined 
using the WHO growth charts.  
BMI category: Underweight (< 5 percentile), Normal (≥ 5 - < 85 percentile), Overweight 
(≥ 85 - < 95 percentile), Obese (≥ 95 percentile). 
A listing of demographic data will be provided for the enrolled population. 
10.2. 
HISTORY  
10.2.1. 
Medical History  
In SEP360-202, medical history was coded using the Medical Dictionary for Regulatory 
Activities (MedDRA version 18.0).  For subjects who enrolled in SEP360-310, the medical 
history data collected during the SEP360-202 study will be carried over into the 
SEP360-310 study database.  The count and percentage of subjects under each history 
term, coded by system organ class (SOC) and preferred term (PT), will be summarized 
by DB treatment and overall. Percentages will be based on number of safety subjects 
within DB treatment group. Additionally, if a subject had 1 or more history events under 
any given SOC or PT, the subject will be counted only once under that SOC or PT.   
A listing of medical history will be provided for the enrolled population. 
10.2.2. 
Psychiatric History  
Psychiatric history will be summarized by DSM-5. The psychiatric history data collected 
during the SEP360-202 study will be carried over into the SEP360-310 study database. 
The count and percentage of subjects under each DSM-5 code will be summarized by DB 
treatment and overall. All percentages will be based on the number of safety subjects 
within a DB treatment group. If a subject had 1 or more history events more than once, 
the subject will be counted only once under any given DSM-5 code. 
A listing of psychiatric history will be provided for the enrolled population.  
10.3. PRIOR AND CONCOMITANT MEDICATIONS 
All medications will be coded using the World Health Organization drug dictionary 
(WHODRUG) version Quarter 1 2016 (March 1st, 2016).  Medications ongoing at the time 
of completion of the SEP360-202 study will be carried over into the SEP360-310 study 
database.  


 
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The prior medications will include medications started prior to the first dose date of 
open-label study drug. The concomitant medications will include medications used on or 
after the first dose date of open-label study drug. Concomitant medications will include 
prior medications that continued use on or after the first dose of open-label study drug.  
Concomitant medications will be separated into the following subsets: 
 
Medications used during the treatment period excluding medications that 
started on or after the last dose of open-label study drug 
 
Medications with start date on or after the first dose date of open-label study 
drug; this subset may include medications that had a change in dosage or 
frequency of use that had been used prior to open-label treatment. 
 
Medications started on or after the last dose of open-label study drug  
For the summary tables, the count and percentage of subjects under each anatomical 
therapeutic chemical (ATC) class level 2 and PT will be summarized by DB treatment 
and overall. If a subject has taken 1 or more prior or concomitant medications more 
than once, the subject will be counted only once under any given drug class. 
A listing of prior and concomitant medications will be provided for the enrolled 
population. Flags will be included in the listing to distinguish prior versus concomitant 
medications and to identify medications started on or after the last dose of open-label 
study drug. 
10.4. 
TREATMENT EXPOSURE AND COMPLIANCE  
Each subject will be dispensed one to three 10-day blister card(s) per scheduled visit 
based on his or her next expected visit date. Subjects will take 1 capsule of study 
medication per day at approximately the same time each morning. The number of 
capsules dispensed, the number of capsules returned, along with corresponding dates 
will be captured on the CRF and used to calculate exposure and compliance to study 
medication in terms of the number of doses taken. 
First dose date in the SEP360-310 study will be based on the date of intake on the 
Dosing Accountability record. If the date of intake is missing on this record, it will be 
assumed the subject initiated one day after the first dispensation of SEP360-310 
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The last dose date will be based on the investigator’s provided date on the disposition 
page. If the last dose date on the disposition page is missing, then last dose date will be 
based on the last date of intake from the Dosing Accountability log form that 
corresponds to the last dispensation of study drug. 
Duration of Exposure (days) = Last dose date – first dose date + 1. 
If a subject has only the first dose date and missing last dose date, the duration of 
exposure will be counted as 1 day. 
If the subject has drug dispensed, but the first dose date is missing and the last dose 
date is missing, the duration of exposure will be counted as 1 day. 
The duration of exposure to SEP360-310 study drug (number and percentage of subjects 
with exposure to study drug ≥ 1 day, ≥ 7 days, ≥ 14 days, ≥ 21 days, ≥ 28 days, ≥ 42 
days, ≥ 56 days, ≥= 70 days, ≥ 84 days, ≥ 98 days, ≥ 112 days, ≥ 154 days, ≥ 168 days, ≥  
182 days) will be summarized by DB treatment and overall. 
Cumulative exposure to dasotraline across the SEP360-202 and SEP360-310 studies will 
be summarized by DB treatment and overall.  Cumulative exposure to dasotraline for a 
subject who received double-blind Placebo in the SEP360-202 study will be limited to 
the duration of treatment in the SEP360-310 study.  Duration of treatment will be 
categorized as (≥ 1 day, ≥ 7 days, ≥ 14 days, ≥ 21 days , ≥ 28 days, ≥ 42 days,  ≥ 56 days, 
≥ 70 days, ≥ 84 days, ≥ 98 days, ≥ 112 days, ≥ 126 days, ≥ 140 days, ≥ 154 days, ≥ 168 
days, ≥ 182 days, ≥ 196 days, ≥ 210 days, and ≥ 224 days). 
Duration of SEP360-310 dose will also be provided by DB treatment group and overall. 
The number of days each dose was taken will be summarized. 
The summary will also include the average daily dose (mg) for all subjects, the average 
daily dose (mg) for subjects who complete the study, the modal daily dose (mg) for all 
subjects, and the modal daily dose (mg) for subjects who complete the study. The 
modal daily dose will also be reported for each visit. The average daily dose is 
calculated as [(2*number of days 2 mg was taken) + (4*number of days 4 mg was taken) 
+ (6*number of days 6 mg was taken)] / (date of last dose – date of first dose + 1). For 
each subject the modal daily dose is defined as the dose taken most frequently. 
Unscheduled visits will also be considered in the calculations when reporting data at 
each visit. If 2 or more different doses were taken an equal number of days, then modal 


 
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dose will equal the dose that the subject last takes. The number of days each dose was 
used will be summarized. Also, the total person-years during SEP360-310 will be 
summarized. The total person-years is defined as the sum of the duration of dosing in 
days for all subjects divided by 365.25.   
A bar chart will summarize the percentage of subjects taking 2 mg, 4 mg, and 6 mg at 
each visit.  
A summary will also be provided for the changes in dose from the previous visit. 
Categories that will be summarized include: maintained dose at 2 mg, down-titrated to 
2 mg, up-titrated to 4 mg, maintained dose at 4 mg, down-titrated to 4 mg, up-titrated 
to 6 mg, maintained dose at 6 mg. Data from unscheduled visits will also be considered 
when assigning categories. The category will represent the change from the most recent 
visit. If the dose was changed during an unscheduled visit, then the category will 
represent the change from the most recent unscheduled visit. 
Treatment compliance will be determined for each subject at each visit and over all 
visits. A descriptive summary will be provided.  
Compliance = (Capsules Dispensed – Capsules Returned)*100/Capsules Expected. 
Subjects are expected to take 1 capsule per day. Only visits with both capsules 
dispensed and capsules returned will be included. For overall compliance if the number 
of capsules returned is missing for one or more visits for a subject, then overall 
compliance will be considered missing for that subject. 
Subjects who take less than 75% of scheduled doses or who take more than 125% of 
scheduled doses will be considered noncompliant. 
 
11. 
EFFECTIVENESS ANALYSIS 
11.1. CHANGE IN ADHD-RS-IV 
The first effectiveness endpoint is the change from DB baseline and change from OL 
baseline in Attention Deficit Hyperactivity Disorder Rating Scale-fourth edition (ADHD 
RS-IV) HV total score. The primary study population is the ITT population. 


 
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The ADHD RS-IV HV includes 18 questions about frequency of recent symptoms of ADHD. 
ADHD RS-IV HV score is collected at each visit. Each question is scored on a 4-point 
scale ranging from 0 (no symptoms) to 3 (severe symptoms) with total score ranging 
from 0 to 54. The 9 odd-numbered items (i.e. 1, 3, 5, 7, 9, 11, 13, 15, and 17) assess 
inattentive symptoms, and the 9 even-numbered items (i.e. 2, 4, 6, 8, 10, 12, 14, 16, 
and 18) assess hyperactive-impulsive symptoms. Hence, for inattention subscale, the 
score is obtained by adding the responses to the scores of the 9 odd-numbered items, 
and for the hyperactivity-impulsivity subscale, the score is obtained by adding the 
scores of the 9 even-numbered items. The total score is obtained by adding the 
inattention and hyperactivity-impulsivity subscale scores. 
The observed value, change from DB baseline, and change from OL baseline for the 
ADHD RS-IV total score will be summarized descriptively by DB treatment and overall, 
and by visit (Week 1, Week 2, Week 4, Week 6, Week 10, Week 14, Week 18, Week 22, 
Week 26, and Week 26 (LOCF)).  
The line-plot of Mean (±SE) change from DB baseline in ADHD RS-IV HV total score will 
be provided by DB treatment and overall, and visit using the ITT population. At 
baseline, the change from baseline will be displayed as 0.  A similar line-plot will be 
produced showing the change from OL baseline.  
11.1.1. 
Percentage of responders at Post-Baseline Visits  
A subject is defined as a responder if they have a ≥ 30% (and ≥ 50%) improvement in 
ADHD RS-IV HV total score compared with the DB baseline.   
A similar definition for responder will be defined if the subject has a >= 30% (and >= 
50%) improvement in ADHD RS-IV HV total score compared with the OL baseline. 
The number of subjects with such responses compared to DB baseline and OL baseline 
will be summarized by DB treatment and overall, and by visit for the ITT population.  
11.2. CHANGE IN CGI-S  
The CGI-S modified assessment asks the clinician one question: “Considering your total 
clinical experience with this population, how mentally ill is the subject at this time?” 
The clinician’s answer is rated on the following 7-point scale: 1 = normal, not at all ill; 
2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = 
severely ill; 7 = among the most extremely ill subjects.  


 
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The analysis will be performed using the same methodology described above for the 
ADHD RS-IV endpoint, using the ITT population.  
The line-plot of Mean (±SE) change from DB baseline and OL baseline in CGI-S score will 
be provided by DB treatment and overall, and by visit. 
11.3. CHANGE FROM BASELINE IN THE ADHD RS-IV HV INATTENTIVENESS AND 
HYPERACTIVITY SCORES  
For the hyperactivity-impulsivity and inattentiveness subscales of the ADHD RS-IV HV, 
the same methodology used for the ADHD RS-IV HV Total score described in section 11.1 
will be used.  
11.4. CHANGE FROM BASELINE IN CONNERS 3-P SCALE SCORES  
The Conners 3rd Edition - Parent (Conners 3–P) assesses behaviors and other concerns in 
children between the ages of 6 and 18, inclusive. The full-length version of the Conners 
3–P will be used.  Assessments of Conners 3-P are completed at each clinic assessment 
visit as well as assessment of the child’s behavior over the past week prior to the 
parent’s assessment. The full-length version provides a thorough assessment of ADHD 
and addresses comorbid disorders such as Oppositional defiant disorder (ODD) and 
conduct disorder. Responses to the Conners 3-P will be used to calculate the scale 
scores.  
The item numbers associated with each scale are noted below.  
Conners 3-P Content Scales  
Inattention (10 items) 
12. Has trouble staying focused on one thing at a time.  
23. Has a short attention span.  
28. Avoids or dislikes things that take a lot of effort and are not fun.  
44. Has trouble concentrating.  
47. Doesn’t pay attention to details; makes careless mistakes.  
49. Has trouble changing from one activity to another.  
67. Inattentive, easily distracted.  
77. Gets bored.  
88. Gives up easily on difficult tasks. 
95. Has trouble keeping his/her mind on work or play for long.  
 
Hyperactivity/Impulsivity (14 items) 
 


 
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19. Fidgeting.  
43. Blurts out answers before the question has been completed.  
45. Is constantly moving.  
50. Excitable, impulsive.  
52. Gets over-stimulated.  
54. Acts as if driven by a motor.  
55. Blurts out the first thing that comes to mind. 
61. Has difficulty waiting for his/her turn. 
69. Runs or climbs when he/she is not supposed to.  
71. Is noisy and loud when playing or using free time.  
93. Leaves seat when he/she should stay seated.  
98. Fidgets or squirms in seat.  
99. Restless or overactive.  
104. Interrupts others (for example, butts into conversations or games).  
 
Learning Problems (9 items) 
 
5. Spelling is poor.  
7. Does not understand what he/she reads.  
9. Is good at memorizing facts. (R) 
15. Forgets things already learned.  
36. Has trouble with reading.  
51. Needs extra explanation of instructions.  
53. Learns information as separate facts; does not “get the big picture.”  
60. Reads slowly and with a lot of effort.  
87. Cannot grasp arithmetic.  
 
Executive Functioning (9 items) 
 
34. Fails to finish things he/she starts. 
37. Has trouble getting started on tasks or projects.  
63. Completes projects at the last minute.  
72. Is good at planning ahead. (R) 
75. Forgets to turn in completed work.  
79. Fails to complete schoolwork, chores, or tasks (even when he/she understands and 
is trying to cooperate).  
84. Has trouble organizing tasks or activities.  
90. Is messy or disorganized.  
97. Loses things (for example, schoolwork, pencils, books, tools, or toys).  
 
Defiance/Aggression (14 Items)  
 
16. Bullies, threatens, or scares others.  
22. Is cold-hearted and cruel.  
27. Uses a weapon (for example, a bat, brick, broken bottle, knife, or gun).  


 
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30. Starts fights with others on purpose. 
39. Physically hurts people.  
46. Tells lies to hurt other people.  
48. Is angry and resentful.  
57. Tries to get even with people.  
58. Steals secretly (for example, shoplifting or forgery).  
65. Intentionally damages or destroys things that belong to others.  
83. Threatens to hurt others.  
86. Swears or uses bad language.  
94. Actively refuses to do what adults tell him/her to do.  
102. Argues with adults.  
 
Peer Relations (6 Items)  
 
10. Does not get invited to play or go out with others. 
13. Has no friends. 
24. Has trouble keeping friends. 
62. Is one of the last to be picked for teams or games. 
64. Interacts well with other children. (R) 
92. Does not know how to make friends.  
 
DSM-IV-TR Symptom Scales  
ADHD Inattentive (10 Items)  
 
2. Is forgetful in daily activities.  
28. Avoids or dislikes things that take a lot of effort and are not fun.  
35. Does not seem to listen to what is being said to him/her.  
47. Doesn’t pay attention to details; makes careless mistakes.  
68. Does not follow through on instructions (even when he/she understands and is trying 
to cooperate).  
79. Fails to complete schoolwork, chores, or tasks (even when he/she understands and 
is trying to cooperate).  
84. Has trouble organizing tasks or activities.  
95. Has trouble keeping his/her mind on work or play for long.  
97. Loses things (for example, schoolwork, pencils, books, tools, or toys).  
101. Is easily distracted by sights or sounds.  
 
ADHD Hyperactive-Impulsive (11 items)  
 
3. Talks too much.  
45. Is constantly moving.  
54. Acts as if driven by a motor.  
69. Runs or climbs when he/she is not supposed to.  
43. Blurts out answers before the question has been completed.  
61. Has difficulty waiting for his/her turn. 


 
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71. Is noisy and loud when playing or using free time.  
93. Leaves seat when he/she should stay seated.  
98. Fidgets or squirms in seat.  
99. Restless or overactive.  
104. Interrupts others (for example, butts into conversations or games).  
 
Conduct Disorder (15 items) 
 
6. Skips classes.  
11. Has forced someone into sexual activity.  
16. Bullies, threatens, or scares others.  
27. Uses a weapon (for example, a bat, brick, broken bottle, knife, or gun).  
30. Starts fights with others on purpose. 
39. Physically hurts people.  
41. Is cruel to animals.  
56. Lies to avoid having to do something or to get things.  
58. Steals secretly (for example, shoplifting or forgery).  
65. Intentionally damages or destroys things that belong to others.  
76. Runs away from home for at least one night.  
78. Has intentionally set fires for the purpose of causing damage.  
89. Has broken into someone else’s house, building, or car.  
91. Goes out at night even though it breaks the rules.  
96. Steals while confronting a person (for example, mugging, purse snatching, or armed 
robbery).  
 
Oppositional Defiant Disorder (8 items) 
 
14. Loses temper.  
21. Blames others for his/her mistakes or misbehavior.  
48. Is angry and resentful.  
57. Tries to get even with people.  
59. Annoys other people on purpose.  
73. Is irritable and easily annoyed by others.  
94. Actively refuses to do what adults tell him/her to do.  
102. Argues with adults.  
 
Indices  
 
Conners 3-P ADHD Index (10 Items)  
 
19. Fidgeting.  
35. Does not seem to listen to what is being said to him/her.  
47. Doesn’t pay attention to details; makes careless mistakes.  
67. Inattentive, easily distracted.  
84. Has trouble organizing tasks or activities.  


 
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88. Gives up easily on difficult tasks. 
98. Fidgets or squirms in seat.  
99. Restless or overactive.  
101. Is easily distracted by sights or sounds.  
104. Interrupts others (for example, butts into conversations or games).  
 
Conners 3-P Global Index (10 Items)  
 
19. Fidgeting.  
25. Cries often and easily.  
29. Mood changes quickly and drastically.  
34. Fails to finish things he/she starts. 
40. Demands must be met immediately—easily frustrated.  
50. Excitable, impulsive.  
67. Inattentive, easily distracted.  
81. Temper outbursts.  
85. Disturbs other children.  
99. Restless or overactive.  
 
Each item has responses provided as 0 = Not true at all (Never, Seldom), 1 = Just a little 
true (Occasionally), 2 = Pretty much true (Often, Quite a bit), 3 = Very much true (Very 
often, Very frequently). 
 
Items marked with a (R) are reverse scored.  The responses will be scored as (4 – item 
score) when contributing to a raw score.  
 
For each scale except the ADHD Index, raw scores for each scale are calculated as the 
sum of the item responses (taking into account any reverse scored items).   
 
For the ADHD Index, the item responses are transposed prior to calculating the sum.   
For item numbers 19, 47, 67, 84, 99, 101, and 104, the following transposition is made.   
If the item response is 0 or 1, then the transposed score = 0. 
If the item response is 2 then the transposed score = 1. 
If the item response is 3 then the transposed score = 2. 
 
For the item numbers 35, 88, and 98, the following transposition is made.   
If the item response is 0 or 1, then the transposed score = 0. 
If the item response is 2 or 3, then the transposed score = 2. 
 
In the event of a missing item response, Conners gives the following guidance as to the 
maximum number of allowable item omissions.   
Scale  
Total Items 
Maximum Allowable 
Item Omissions 
Inattention 
10 
1 
Hyperactivity/Impulsivity 
14 
2 


 
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Scale  
Total Items 
Maximum Allowable 
Item Omissions 
Learning Problems  
9 
1 
Executive Functioning 
9 
1 
Defiance/Aggression 
14 
2 
Peer Relations 
6 
1 
DSM-IV-TR ADHD Inattentive 
10 
1 
DSM-IV-TR ADHD Hyperactive-
Impulsive 
11 
2 
DSM IV-TR Conduct Disorder  
15 
2 
DSM IV-TR Oppositional Defiant 
Disorder  
8 
1 
Conners 3 ADHD Index  
10 
1 
Conners 3 Global Index 
10 
1 
 
If there are omitted item responses and the number of omitted item response does not 
exceed the maximum allowable item omissions, then the raw score will be prorated as:  
 
Prorated Score = (Obtained raw score for scale / Total number of items in scale with a 
response) * (Total number of Items in the scale). As an example, if the 
Hyperactivity/Impulsivity has responses for 12 of the 14 items in the scale, then the 
number of missing responses is less than or equal to the maximum allowable number of 
omissions.  Suppose the sum of the responses provided is 15. Then the prorated score 
will equal (15/12) * 14 = 17.5. 
 
 If the number of omitted item responses exceeds the maximum allowable number 
noted, the raw scale score will not be calculated.  
 
For all scale scores except the ADHD Index, the raw scores will be converted to age/sex 
adjusted T-scores according to the scoring manual (Conner, 2008). The T-scores will be 
used in the statistical analyses.  
 
For the ADHD Index score, the total of the transposed scores (or prorated transposed 
score, if 1 item response is missing) is given a probability index score according to the 
following table. The probability score is the probability of a classification of ADHD 
based on the total transposed score.  
 
Total Transposed Score  
Probability (%)  
0 
11 
1 
29 
2 
41 
3 
51 
4 
56 
5 
64 


 
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Total Transposed Score  
Probability (%)  
6 
71 
7 
77 
8 
82 
9 
87 
10 
91 
11 
94 
12 
97 
13 
98 
14 
99 
15 
99 
16 
99 
17 
99 
18 
99 
19 
99 
20 
99 
 
The probability score for the ADHD Index will be used in the statistical analysis.  
 
For the Conners 3-P scale scores, the same methodology, described for the ADHD RS-IV 
Total in section 11.1, will be used for this analysis.  The analysis will be performed 
using the ITT population. 
11.5. WEISS FUNCTIONAL IMPAIRMENT RATING SCALE – PARENT REPORT 
(WFIRS-P)  
The WFIRS-P is an ADHD-specific instrument completed by the parent/legal guardian to 
evaluate domains of daily functioning that are likely to be impaired in ADHD. The 
WFIRS-P comprises 50 items used to provide measures of impairment in 6 domains 
(family, learning and school, life skills, child’s self-concept, social activities and risky 
activities) and overall (total score). The items relate to the period since the last visit 
and are scored using a 4-point Likert scale: 0 (never or not at all); 1 (sometimes or 
somewhat); 2 (often or much); or 3 (very often or very much). The instrument is 
completed at Week 0, Week 14, and Week 26 or ET.   
The WFIRS-P domain scores for each patient were the mean of the items in each 
domain, or of all the items for total score, omitting items with a missing or ‘not 
applicable’ score. WFIRS-P domain or total scores were considered invalid if more than 
30 % of the item scores used for calculation were missing or ‘not applicable’ (with the 
exception of one question relating to siblings, for which a score of ‘not applicable’ 
could contribute to the minimum number of items).  


 
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For the WFIRS-P total score and domain scores, the same methodology used for the 
ADHD RS-IV HV Total score described in section 11.1 will be used for this analysis. 
Frequency summaries of the count of items with a response of 2 or 3 will also be done 
by DB treatment group (and overall), and visit.   
11.6. SUBGROUP ANALYSIS 
Subgroup analyses of the ADHD RS-IV HV total score will be conducted using the 
following subsets of the ITT population: 
 
Gender: Male and Female  
 
Race Group: White, Black or African American, Asian, and Other 
 
DB Study Age Group (6-9 years, 10-12 years) 
 
DB Baseline Study BMI category: Underweight (< 5 percentile), Normal (≥ 5 - < 85 
percentile), Overweight (≥ 85 - < 95 percentile), Obese (≥ 95 percentile) 
12. 
SAFETY 
The safety will be assessed on the basis of study agent exposure, adverse events, 
clinical laboratory data, ECG parameters, vital signs, physical examinations, 
neurological examinations, Tanner Staging, Children’s Sleep Habit’s Questionnaire 
(CSHQ), and Columbia – Suicide Severity Rating Scale (C-SSRS) Children’s Assessment.  
All safety data listings will be presented by subject and visit for all enrolled subjects. 
The safety data summarizations will be performed in the safety population. 
12.1. 
ADVERSE EVENTS (AEs) 
The summary of AEs (or SAEs) will be limited to TEAEs. A TEAE is any AE (or SAE) 
occurring on or after the date of the first dose of study drug in the SEP360-310 study. 
All AEs will be coded using MedDRA version 19.0.  
TEAEs will be further divided into: 


 
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1.)  Those events with onset between the date of the first dose of study drug in the 
SEP360-310 study and 3 days after the last dose of study medication in SEP360-
310, inclusive.  These will be called on treatment events. 
2.) Those events with onset more than 3 days after the last dose of study 
medication in SEP360-310. These will be called post-treatment events. 
AEs with preferred terms of “Insomnia”, “Initial insomnia”, “Middle insomnia”, or 
“Terminal insomnia”, or AEs with Higher Level Term of “Disturbances in initiating and 
maintaining sleep” will be presented on AE tables in a combined term called “Combined 
insomnia” with the individual preferred terms within the combined term directly 
underneath. 
All TEAEs will be summarized by SOC and PT. Though only TEAEs will be included in the 
summary tables, all AEs will be included on the listings (non-TEAEs will be flagged). 
An overall summary table of TEAEs by DB treatment will be produced for the following 
categories: 


 
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 
Number and percentage of  subjects with a TEAE 
 
Number and percentage of subjects with a treatment-related TEAE 
 
Number and percentage of subjects with a TEAE leading to discontinuation  
 
Number and percentage of subjects with a Treatment-related TEAE leading to 
discontinuation  
 
Number and percentage of subjects with a serious TEAE 
 
Number and percentage of subjects with a serious TEAE leading to 
discontinuation  
 
Number and percentage of subjects with a treatment-related serious TEAE 
 
Number and percentage of subjects with a Treatment-related serious TEAE 
leading to discontinuation  
 
Number and percentage of subjects with a TEAE leading to death 
This overall summary will be repeated for each onset period. For the post-treatment 
events, the denominators will be the number of subjects in each DB treatment group 
whose end of study visit was more than 3 days after the last dose date.  
Subgroup analyses of the above noted TEAE categories will be produced for the 
following subgroups (sex, race (categorized as White, Black or African American, Asian, 
and Other), DB baseline age group (6-9 vs. 10-12 years)).  
Adverse events will be summarized by DB treatment and overall for subjects in the 
safety population. The following summaries of AEs will be provided: 
 
TEAEs by SOC and PT 
 
TEAEs by PT  
 
TEAEs by PT (≥ 3% in any DB treatment group)  
 
Serious TEAEs by SOC and PT 
 
TEAEs leading to discontinuation by SOC and PT 
 
TEAEs by SOC and PT and maximum severity. Missing severity, if any, will be 
assumed as ‘severe’. 


 
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 
TEAE by relationship to study treatment (related or not related) by SOC and PT. 
Missing relationships, if any, will be assumed to be ‘related’. 
 
Treatment related SAEs by SOC and PT 
The prevalence of Insomnia by study day in the study will be presented graphically by 
DB treatment and overall.  Combined insomnia events will be used for this analysis.  On 
any study day, the numerator will be the number of subjects who were experiencing 
insomnia (noting that subjects may have experienced multiple episodes during the 
study), and the denominator will be the number of subjects remaining on open-label 
study drug treatment.  
The following listings of AEs will be provided: 
 
All AEs 
 
Adverse events leading to discontinuation of study drug 
 
Serious adverse events 
In the summary tables subjects may be counted under multiple SOCs and PTs, but for 
each SOC and PT, subjects are only counted once. If a subject has the same AE on 
multiple occasions, the highest severity (severe, moderate, mild) recorded for the event 
will be presented and the highest drug relationship (1 = ‘Unrelated’, 2 = ‘Unlikely to be 
Related’, 3 = ‘Possibly Related’, 4 = ‘Probably Related’, 5 = ‘Related’), reclassified into 
Related (‘Possibly Related’, ‘Probably Related’, ‘Related’) or Not Related (‘Unrelated’ 
and ‘Unlikely to be Related’), will be presented on the respective tables. Percentages 
are based on the number of subjects in the safety population. 
12.2. 
LABORATORY EVALUATIONS 
The following laboratory tests are planned to be performed: 
HEMATOLOGY: (Differential reported as % and absolute value)  
Hemoglobin, Hematocrit, Platelet Count, red blood cell (RBC) count, white blood cell 
(WBC) - total count, WBC differential reported as % and absolute values to include 
basophils, eosinophils, lymphocytes, monocytes, neutrophils. 
BLOOD CHEMISTRIES:  
Alanine aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate 
aminotransferase (AST), Bicarbonate (HCO3), Bilirubin (Total, Direct, Indirect), Blood 
Urea Nitrogen (BUN), Calcium (Ca), Chloride (Cl), Creatinine, Glucose, Magnesium 


 
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(Mg), Phosphorus (P), Potassium (K), Protein (Total), Sodium (Na), Uric Acid, Albumin  
URINALYSIS:  
Blood, Glucose, Ketones, Leukocyte Esterase, Microscopic Examination, Nitrites, pH, 
Protein 
THYROID PANEL: 
Free T3, Free T4, Thyroid stimulating hormone (TSH)  
LIPID PANEL: 
LDL-Cholesterol, HDL-Cholesterol, Total Cholesterol, Triglycerides 
SEX HORMONES: 
For females: estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone 
(LH).  
For males: testosterone. 
URINE DRUG SCREENING: 
Amphetamines, Barbiturates, Benzodiazepines, Cannabinoids, Cocaine, 
Methamphetamines, Methadone, Methylenedioxymethamphetamine (MDMA), 
Phencyclidine (PCP), Opiates, Oxycodone, Tricyclic Antidepressants 
OTHER TESTS:  
Breath Alcohol Test, Serum Pregnancy (β-hCG) (in female subjects only), Urine 
Pregnancy Test (in female subjects only) 
 
 
Hematology, chemistry, urinalysis, thyroid panel, lipid panel, and sex hormones are 
collected at Open-label baseline, Week 14, Week 26 or ET, and the EOS Visit. 
The laboratory results collected in conventional units will be converted to SI units, and 
the SI units will be used for all of the summaries and listings. Clinical laboratory test 
results (hematology, chemistry, urinalysis, thyroid panel, lipid panel, and sex hormones) 
and their changes from DB baseline and OL baseline will be summarized by DB 
treatment and overall, and by visits including the endpoint (Week 26 LOCF), using 
descriptive statistics. For hematology, chemistry lipid panel, thyroid panel, and sex 
hormone tests, result will also be categorized as “Normal”, “Low”, or “High” based on 
their normal ranges. For urinalysis results, tests will be classified as “Normal” or 
“Abnormal”. Shift tables comparing laboratory test results from baseline to Week 26 


 
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LOCF will be presented. Percentages are based on the number of the safety subjects in 
a high, low or normal category with non-missing values for both baseline and post-
baseline at the given visit. 
In addition, the markedly abnormal post-baseline laboratory results will be summarized 
for certain laboratory tests. 
Summaries will be presented separately for hematology and chemistry for subjects with 
at least one markedly abnormal value during the open-label treatment period. A listing 
of all markedly abnormal results will be provided. 
The criteria for markedly abnormal values are defined below. 
Parameter 
(Unit) 
 Markedly Abnormal 
Range (Conventional 
Unit) 
Conversion 
Factor 
(Conventional to 
SI) / SI unit 
SI Unit Markedly 
Abnormal Range  
Hematology 
 
 
 
Hemoglobin 
(g/dL)  
Female: ≤ 9.5, 
Male: ≤ 11.5 
≥ 17.2 
10 / g/L 
Female: ≤ 95 g/L, 
Male: ≤ 115 g/L, 
≥ 172 g/L 
Hematocrit 
(fraction, %) 
≤ 30, ≥ 50 
0.01 / (fraction of 
1) 
≤ 0.30, ≥ 0.50 (1) 
WBC (10 3/μL) 
≤ 2.8, ≥ 16 
1 / x10 9/L (PPD 
Conv unit K/cu 
mm) 
≤ 2.8, ≥ 16 
RBC (10 6/μL)  
≤ 3.0, ≥ 6.0 
1 / x10 12/L (PPD 
Conv unit x10 6/cu 
mm)  
≤ 3.0, ≥ 6.0 
Platelet Count 
(10 3/μL) 
≤ 100, ≥ 500 
1 / x10 9/L (PPD 
Conv unit K/cu 
mm)  
≤ 100, ≥ 500 
Eosinophils (%) 
≥ 10 
1 / % 
≥ 10 


 
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Parameter 
(Unit) 
 Markedly Abnormal 
Range (Conventional 
Unit) 
Conversion 
Factor 
(Conventional to 
SI) / SI unit 
SI Unit Markedly 
Abnormal Range  
Neutrophils (%)  ≤ 15 
1 / % 
≤ 15 
Clinical 
Chemistry 
 
 
 
ALP (U/L) 
≥ 3 x ULN 
1 / U/L 
≥ 3 x ULN 
ALT (U/L)  
≥ 2 x ULN 
1 / U/L 
≥ 2 x ULN 
AST (U/L)  
≥ 2 x ULN 
1 / U/L 
≥ 2 x ULN 
Total Bilirubin 
(mg/dL)  
≥ 2.0 
17.1 / mcmol/L 
≥ 34.2 
Albumin (g/dL)  
< 50% LLN 
10 / g/L 
< 50% LLN 
Creatinine 
(mg/dL)  
≥ 2.0 
88.4 / mcmol/L 
≥ 176 
Creatine 
Phosphokinase 
(CPK) (U/L) 
≥ 450 
1 / U/L 
≥ 450 
LDH (U/L)  
≥ 3 x ULN 
1 / U/L 
≥ 3 x ULN 
GGT (U/L)  
≥ 150 
1 / U/L 
≥ 150 
Sodium 
(mEq/L)  
≤ 130, ≥ 150 
1 / mmol/L 
≤ 130, ≥ 150 
Potassium 
(mEq/L)  
≤ 3, ≥ 5.5 
1 / mmol/L 
≤ 3, ≥ 5.5 
Bicarbonate 
(mEq/L) 
< 18, > 30 
1 / mmol/L 
< 18, > 30 
Calcium 
(mg/dL)  
< 8.4, or > 11.5 
0.25 / mmol/L 
< 2.1, or > 2.8 


 
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Parameter 
(Unit) 
 Markedly Abnormal 
Range (Conventional 
Unit) 
Conversion 
Factor 
(Conventional to 
SI) / SI unit 
SI Unit Markedly 
Abnormal Range  
Chloride 
(mEq/L)  
< 90, > 115 
1 / mmol/L 
< 90, > 115 
Blood Urea 
Nitrogen 
(mg/dL) 
≥ 30 
0.357 / mmol/L 
> 10.7 
Glucose 
(fasting) 
(mg/dL) 
≤ 45, ≥ 126 
0.05551 / mmol/L 
≤ 2.5, ≥11.1 
Glucose 
(random) 
(mg/dL) 
≤ 45, > 200 
0.05551 / mmol/L 
≤ 2.5, ≥11.1 
Lipid Panel 
(Fasting) 
 
 
 
Total 
Cholesterol 
(mg/dL) 
≥ 240 
0.0259 / mmol/L 
≥ 6.2 
Triglycerides 
(mg/dL)  
Female: ≥ 170, 
Male: ≥ 200 
0.0113 / mmol/L 
Female: ≥ 1.92,  
Male: ≥ 2.26 
HDL-C (mg/dL)  
≤ 30 
0.0259 / mmol/L 
≤ 0.77 
LDL-C (mg/dL)  
≥ 160 
0.0259 / mmol/L 
≥ 4.14 
Urinalysis 
 
 
 
RBC (hpf)  
> 15 
N/A 
> 15 
WBC (hpf)  
> 15 
N/A 
> 15 
Sex Hormones 
 
 
 


 
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Parameter 
(Unit) 
 Markedly Abnormal 
Range (Conventional 
Unit) 
Conversion 
Factor 
(Conventional to 
SI) / SI unit 
SI Unit Markedly 
Abnormal Range  
FSH  (mIU/mL) 
 
1 / IU/L 
> 4.2, for Females 
with Tanner Stage = 
1 
FSH  (mIU/mL) 
 
1 / IU/L 
> 10.8, for Females 
with Tanner Stage = 
2 
FSH  (mIU/mL) 
 
1 / IU/L 
> 12.8, for Females 
with Tanner Stage = 
3 
FSH  (mIU/mL) 
 
1 / IU/L 
> 11.7, for Females 
with Tanner Stage = 
4 
FSH  (mIU/mL) 
 
1 / IU/L 
> 9.2, for Females 
with Tanner Stage = 
5 
LH (mIU/mL) 
 
1 / IU/L 
> 0.18, for Females 
with Tanner Stage = 
1 
LH (mIU/mL) 
 
1 / IU/L 
> 4.7, for Females 
with Tanner Stage = 
2 
LH (mIU/mL) 
 
1 / IU/L 
> 12.0, for Females 
with Tanner Stage = 
3 
LH (mIU/mL) 
 
1 / IU/L 
> 11.7, for Females 
with Tanner Stage = 
4 
LH (mIU/mL) 
 
1 / IU/L 
> 11.7, for Females 
with Tanner Stage = 
5 


 
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Listings will be provided for pregnancy tests.  No other summarizations of pregnancy 
tests will be provided. 
12.3. 
BREATH ALCOHOL TEST 
Breath alcohol examination will be monitored at Open-Label Baseline, Week 14, and the 
EOS Visit. The breath alcohol examination data will be presented in a data listing.  
12.4. 
URINE DRUG SCREENING  
Urine drug screening tests are collected at Open-Label Baseline, Week 2, Week 6, Week 
10, Week 14, Week 18, Week 22, Week 26, and at the EOS. The urine drug screening 
data will be presented in a data listing. 
12.5. 
12-LEAD ECG  
Assessment of Standard 12-lead ECG are obtained at each clinic assessment during the 
study.  A central ECG Standard 12-lead ECG will record heart rate (HR), PR interval, RR 
interval, QT interval, Bazett’s corrected QT (QTcB), Fridericia’s corrected QT interval 
(QTcF), and QRS duration. The overall ECG assessment will be centrally reported as 
“Normal”, “Abnormal, Not Clinically Significant”, or “Abnormal, Clinically Significant” 
with respect to relevant abnormalities. 
Observed results of each ECG parameter, change from DB baseline, and change from OL 
baseline will be summarized by DB treatment and overall, and by visit using descriptive 
statistics. 
The QTcF and QTcB results will be adjusted as follows:  
QTcF = QT/ 3√ RR 
QTcB = QT/2√ RR 
Bazett’s and Fridericia’s corrected QTc values will be classified as having QTc 
prolongation according to the following conditions. 
 
QTc Prolongation 
QTc >460 msec  


 
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QTc Prolongation 
Increase from double-blind baseline QTc ≥ 60 msec 
Increase from double-blind baseline QTc ≥ 30 msec 
Increase from open-label baseline QTc ≥ 60 msec 
Increase from open-label baseline QTc ≥ 30 msec 
 
The number and percentage of subjects with QTc prolongation using either of the two 
correction methods (Bazett’s, Fridericia’s) will be summarized by DB treatment and 
overall, and by visit.  
A shift table comparing the overall ECG assessment from baseline to Week 26 or ET, and 
from baseline to EOS will be presented.  
In addition, the markedly abnormal post-baseline ECG results will also be summarized 
for subjects with at least one markedly abnormal value during the treatment period. 
The summary will be completed by DB treatment and overall, and age groups (6 - < 8 
years, 8 - < 12 years, 12 - < 16 years, and > 16 years), and overall using the age at the 
time of the individual assessment.  
A listing of markedly abnormal values will be provided. 
Criteria for markedly abnormal values, used in the SEP360-202 study, are presented in 
the table below.  They will also be used for the SEP360-310 study summary. 
ECG parameter 
(unit) 
Age (years old) 
Abnormally Low Abnormally 
High 
HR (bpm) 
6 to <8 
< 65 
> 115 
8 to <12 
< 55 
> 110 
12 to <16 
< 50 
> 105 
≥16 
< 50 
> 100 
PR interval (msec) 
6 to <8 
-- 
> 160 
8 to <12 
-- 
> 175 
12 to <16 
-- 
> 180 
≥16 
-- 
> 200 
QRS interval (msec) 6 to <8 
-- 
> 100 
8 to <12 
-- 
> 105 


 
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ECG parameter 
(unit) 
Age (years old) 
Abnormally Low Abnormally 
High 
12 to <16 
-- 
> 110 
≥16 
-- 
> 120 
 
12.6. PHYSICAL EXAMINATION  
Physical examinations are performed at Open-Label Baseline, Week 14, Week 26 or ET, 
and End of Study. Any clinically significant abnormalities at screening will be recorded 
on the medical history form. Any new or worsening clinically significant abnormality at 
all other visits will be recorded as an AE. 
12.7. NEUROLOGICAL EXAMINATION  
Neurological examinations will be performed at Open-Label Baseline, Week 14, Week 26 
or ET, and End of Study. 
Each assessment (i.e. Cranial Nerves, Motor System, Sensory System, Reflexes, 
Coordination, Gait and Rhomberg’s test) will be summarized using summary statistics 
for categorical variables (normal/abnormal) at each visit by treatment and overall. All 
percentages will be based on the number of safety subjects in each DB treatment group. 
Shift table for baseline condition vs. the worst result during the treatment period 
(Abnormal > Normal) will be produced by DB treatment and overall.  Percentages will be 
based on the number of subjects in the safety population.  The number of subjects 
without an assessment at the visit will be noted on the shift table. 
12.8. VITAL SIGNS  
Vital signs (blood pressure, pulse rate, height, height WHO z-score, weight, BMI, BMI z-
score, respiratory rate, and oral temperature) will be monitored at every clinic visit. 
Respiratory rate and oral temperature will be measured following 5 minutes of supine 
rest. 
At any clinic assessment, orthostatic hypotension (determined by blood pressure 
measurements only) is defined as having either a ≥ 20 mmHg reduction from supine to 
standing position in systolic blood pressure (SBP) or ≥ 10 mmHg reduction from supine to 
standing position in diastolic blood pressure (DBP) or both. Orthostatic tachycardia is 
defined as heart rate increase ≥ 20 bpm from supine to standing position. 


 
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Observed values, change from DB baseline, percent change from DB baseline, change 
from OL baseline, percent change from OL baseline for each vital sign parameter.  will 
be summarized at each visit by DB treatment and overall. 
In addition, the markedly abnormal post-baseline vital signs results will also be 
summarized for subjects with at least one markedly abnormal value during the 
treatment period. A listing will be provided for all markedly abnormal vital signs. A shift 
table will be presented comparing shifts from the baseline visit to Week 26 LOCF. 
Percentages will be based on the number of safety subjects with a non-missing value for 
both the baseline and post-baseline visit for the given vital sign. A shift table for BMI 
classification will also be presented comparing shifts from the baseline visit to Week 26 
LOCF.  
Parameter 
(unit) 
Age 
(years old) 
Markedly Low 
Markedly High 
SBP (supine, 
standing) 
(mmHg) 
6-12 
Value ≤ 70 and≥ 20 
decrease from baseline 
Value ≥ 120 and 
≥ 20 increase from 
baseline 
13-18 
Value ≤ 90 and 
≥ 20 decrease from 
baseline 
Value ≥ 135 and 
≥ 20 increase from 
baseline 
DBP (supine, 
standing) 
(mmHg) 
6-12 
Value ≤ 40 and 
≥ 15 decrease from 
baseline 
Value ≥ 80 and 
≥ 15 increase from 
baseline 
13-18 
Value ≤ 50 and 
≥ 15 decrease from 
baseline 
Value ≥ 90 and 
≥ 15 increase from 
baseline 
Pulse rate 
(supine, 
standing) (bpm) 
6-10 
Value ≤ 60 and 
≥ 15 decrease from 
baseline 
Value ≥ 135 and 
≥ 15 increase from 
baseline 
11-18 
Value ≤ 50 and 
≥ 15 decrease from 
baseline 
Value ≥ 120 and 
≥ 15 increase from 
baseline 
SBP orthostatic 
criteria (mmHg) 
~ 
≥ 20 decrease from 
supine to standing 
position 
NA 
DBP orthostatic 
criteria (mmHg) 
~ 
≥ 10 decrease from 
supine to standing 
position 
NA 
Pulse rate 
orthostatic 
criteria (bpm) 
~ 
NA 
≥ 20 increase from 
supine to standing 
position 


 
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Temperature 
(˚C) 
~ 
NA 
Value ≥ 38.3°C and 
≥0.8°C increase from 
baseline 
Note: ~ means that the abnormal range is applicable for all subjects within age 
group: 6 to 17 years old. 
 
Vital signs data will be provided in a data listing.  
 
12.9. Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire used for suicide 
assessment that evaluates suicidal ideation and behavior.  
This study will utilize the “Since Last Visit” version of the C-SSRS at each visit. 
Subjects will be placed into categories for suicidal ideation and for suicidal behavior 
based on their responses to various questions. 
The Suicidal Ideation categories will be determined as follows by examining the 
response to the 5 questions under Suicidal Ideation.  
 
Type 
Section 
Suicidal Ideation 
(0) None – if response is No to Questions 1 and 2  
 
(1) Wish to be Dead – if response to Question 1 is Yes and 
responses to Questions 2-5 are No.  
 
(2) Non-Specific Active Suicidal Thoughts – if response to 
Question 2 is Yes and response to Questions 3-5 are No. 
 
(3) Active Suicidal Ideation with Any Methods (Not Plan) 
without Intent to Act – if response to question 3 is Yes 
and response to questions 4 and 5 are No.  
 
(4) Active Suicidal Ideation with Some Intent to Act, 
without Specific Plan – if response to Question 4 is Yes 
and response to Question 5 is No.  
 
(5) Active Suicidal Ideation with Specific Plan and Intent 
– if response to Question 5 is Yes. 
 


 
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For suicidal behavior, the following categories will be used. The categories will be 
determined based on the response to the questions under Suicidal Behavior.  
 
 
Type 
Section 
Suicidal Behavior 
 
Preparatory Acts or Behavior – if response to 
Preparatory Acts and Behavior is Yes and responses to 
Actual Attempt, Interrupted Attempt, and Aborted 
Attempt are No 
 
Aborted Attempt – if response to Aborted Attempt is 
Yes and responses to Actual Attempt and Interrupted 
Attempt are No. 
 
Interrupted Attempt – if response to Interrupted 
Attempt is Yes and response to Actual Attempt is No. 
 
Actual Attempt – if response to Actual Attempt is Yes. 
 
None – if responses to all the above 4 questions are 
No.  
 
The frequency and percentage by DB treatment and overall, and visit will be 
summarized for all C-SSRS responses.  
Frequency and severity of suicidality using the C-SSRS will be summarized, using a shift 
table to examine changes in C-SSRS Scores from baseline compared to the worst 
(highest) category during the treatment period and visit, by DB treatment and overall.  
 
12.10. CHILDREN'S SLEEP HABITS QUESTIONNAIRE (CSHQ) 
The CSHQ is a retrospective, 45-item parent questionnaire that is used to examine sleep 
behavior in young children. The questionnaire is completed at each clinical assessment 
by the subject’s parent or guardian. Each scored question is rated on a 3-point scale as 
occurring “usually” (i.e., 5–7 times within the past week), “sometimes” (i.e., 2–4 times 
within the past week), or “rarely” (i.e., never or 1 time within the past week). A 
number of items on the questionnaire are reverse-scored, so that higher scores 


 
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consistently indicate problem behaviors. Ratings are combined to form eight subscales: 
Bedtime Resistance, Sleep Onset Delay, Sleep Duration, Sleep Anxiety, Night Wakings, 
Parasomnias, Sleep Disordered Breathing, and Daytime Sleepiness. 
The CSHQ will be completed at Open-Label Baseline, and at each scheduled visit 
through Week 26 or ET. 
 
The questions associated with each subscales are as follows:  
 
Subscale   
Question (Item Number) 
Reverse 
Scored  
Bedtime Resistance  
Child goes to bed at the same time at night (R) 
(1) 
Yes  
 
Child falls asleep alone in own bed (R) (3) 
Yes 
 
Child falls asleep in parent’s or sibling’s bed 
(4) 
No  
 
Child needs parent in the room to fall asleep 
(5) 
No 
 
Child struggles at bedtime (cries, refuses to 
stay in bed, etc.) (6) 
No  
 
Child is afraid of sleep alone (8) 
No  
 
 
 
Sleep Onset Delay  
Child falls asleep within 20 minutes after going 
to bed (R) (2) 
Yes 
Sleep duration 
Child sleeps too little (9) 
No 
 
Child sleeps the right amount (R) (10) 
Yes 
 
Child sleeps about the same amount each day 
(R) (11) 
Yes 
 
 
 
Sleep Anxiety 
Child needs parent in the room to fall asleep 
(5) 
No  
 
Child is afraid of sleeping in the dark (7) 
No  
 
Child is afraid of sleep alone (8) 
No  
 
Child has trouble sleeping away from home 
(visiting relatives, vacation, etc.) (21) 
No  
 
 
 


 
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Subscale   
Question (Item Number) 
Reverse 
Scored  
Night Wakings  
Child moves to someone else’s bed during the 
night (parent, brother, sister, etc.) (16) 
No  
 
Child awakes once during the night (24) 
No  
 
Child awakes more than once during the night 
(25) 
No  
 
 
 
Parasomnias 
Child wets the bed at night (12) 
No  
 
Child talks during sleep (13) 
No  
 
Child is restless and moves a lot during sleep 
(14) 
No  
 
Child sleepwalks during the night (15) 
No  
 
Child grinds teeth during sleep (your dentist 
may have told you this) (17) 
No  
 
Child awakens during night screaming, 
sweating, and inconsolable (22) 
No  
 
Child awakens alarmed by a frightening dream 
(23) 
No  
 
 
 
Sleep Disordered Breathing 
Child snores loudly (18) 
No  
 
Child seems to stop breathing during sleep (19) 
No  
 
Child snorts and/or gasps during sleep (20) 
No  
 
 
 
Daytime Sleepiness 
Child wakes up by him/herself (26) (R) 
Yes 
 
Child wakes up in negative mood (27) 
No  
 
Adults or siblings wake up child (28) 
No  
 
Child has difficulty getting out of bed in the 
morning (29) 
No 
 
Child takes a long time to become alert in the 
morning (30) 
No  
 
Child seems tired (31) 
No  
 
Appeared very sleepy or fallen asleep 
Watching TV (32) 
No  
 
Appeared very sleepy or fallen asleep Riding 
No  


 
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Subscale   
Question (Item Number) 
Reverse 
Scored  
Car (33)  
 
A Total Sleep Disturbances score is calculated as the sum of all 33 CSHQ scored 
questions, and can range from 33 to 99. (Two scored items are counted twice in the 
calculation of two different subscales).  
At any assessment, a missing response to an item associated with a subscale will result 
in that subscale set to missing.  Any missing response to the 33 CSHQ questions will 
result in a missing Total Sleep Disturbances score.  
 
Summaries of observed values and changes from DB baseline and OL baseline in 
observed values will be done by DB treatment and overall for each visit using 
descriptive statistics. 
12.11. TANNER SCALE  
The Tanner scale is a scale of physical development in children, adolescents, and 
adults. The scale defines physical measurements of development based on external 
primary and secondary sex characteristics, such as the size of the breasts, genitalia, 
testicular volume, and development of pubic and axillary hair.  
The Tanner stage is collected for each subject at OL Baseline, and at the Week 26 or 
Early Termination visit.  
A shift table comparing the baseline stage with the stage at Week 26 or Early 
Termination will be done by gender, DB treatment and overall.  Percentages will be 
calculated using the number of subjects with an assessment completed at both baseline 
and EOS.  
12.12. PHYSICIAN WITHDRAWAL CHECKLIST (PWC)  
The Physician Withdrawal Checklist (PWC) is used to evaluate symptoms of withdrawal 
after discontinuation of study drug. Symptoms are assessed as present or absent and if 
present then intensity is assessed as mild, moderate, or severe.   
This checklist will be assessed at the end of treatment visit (Week 26) or treatment 
termination and at the Week 29 or EOS Visit.  


 
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The scale includes 20 symptoms. Each symptom is assessed on a 4-point scale using the 
following: 
 
0=Not Present 
 
1=Mild 
 
2=Moderate 
 
3=Severe 
 
The score for each question is summed to compute a total score ranging from 0 to 60. If 
the response to any question is missing, then the total score will be missing. The PWC 
will be summarized using descriptive statistics by visit for the total score. The number 
and percentage of subjects with a Present response (mild, moderate, or severe) will be 
provided for each of the 20 PWC items. In addition, responses of moderate or severe 
will be summarized separately at each visit.  
Analyses of the PWC will be repeated by gender subgroups. 
12.13. DISCONTINUATION-EMERGENT SIGNS AND SYMPTOMS (DESS) SCALE  
The DESS Scale (Rosenbaum-1998) is a clinician-rated instrument of 43 items used to 
evaluate signs and symptoms associated with discontinuation or interruption of 
monoamine reuptake inhibitor treatment. 
 
On non-clinic days, the DESS Scale will be completed by site staff during a call to the 
subject/parent/legal guardian. 
The DESS will be assessed at the Week 26 or Early Termination Visit, and then 
reassessed at Week 27, Week 28, and Week 29 or End of Study.  
Each of the 43 signs and symptoms is assessed and placed in one of the following 
categories: new symptom, old symptom but worse, old symptom but improved, old 
symptom but unchanged, and symptom not present. Each sign and symptom that is 
placed in the category new symptom or in the category old symptom but worse receives 
1 point. All other categories receive 0 points. The total DESS score is the sum of the 
number of points, which corresponds to the number of symptoms rated as either a new 
symptom or as an old symptom but worse. The score ranges from 0 to 43, where higher 
scores indicate more discontinuation-emergent signs and symptoms. The total score and 
change from Week 26 will be summarized descriptively separately by visit. For each 


 
Sunovion Pharmaceuticals Inc. 
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Version 1.0 
 
 
  INC Research © LLC 
Page 49 of 60 
symptom, the number and percentage of subjects reporting the symptom as new or 
worsened will be provided. 
Analyses of the DESS will be repeated by gender subgroups. 
 
13. 
STATISTICS (TO BE INCORPORATED INTO SECTION 16.1.9 
OF CSR)  
13.1. 
STATISTICAL METHODS AND ANALYSIS OUTPUTS  
13.1.1. 
Statistical Methods 
Statistical Analysis System (SAS) version 9.3 will be used to perform all the statistical 
analyses in the CSR. 
14. 
QUALITY CONTROL 
SAS programs are developed to produce clinical trial output such as analysis data sets, 
summary tables, data listings and figures. INC Research SOPs 03.010.02 and 03.013.02 
provide an overview of the development of such SAS programs. 
INC Research SOP 03.009.04 describes the quality control procedures that are 
performed for all SAS programs and output. Quality control is defined here as the 
operational techniques and activities undertaken to verify that the SAS programs 
produce the proper clinical trial output by checking for their logic, efficiency, and 
commenting, and by review of the produced output.  
 
15. 
TABLE AND LISTING SHELLS 
15.1. 
TABLE SHELLS: SEE ATTACHMENT 1 
15.2. 
LISTING SHELLS: SEE ATTACHMENT 2 
15.3. 
FIGURE SHELLS: SEE ATTACHMENT 3 
 
 


 
Sunovion Pharmaceuticals Inc. 
SEP360-310 
Version 1.0 
 
 
  INC Research © LLC 
Page 50 of 60 
16. 
REFERENCES 
Conners, C.K. Conners' Rating Scales 3rd Edition 2008 - Conners 3 (2014). 
Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective Serotonin Reuptake 
Inhibitor Discontinuation Syndrome: A Randomized Clinical Trial. Biol Psychiatry 
1998;44:77–87. 
 


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Page 51 of 60 
17. 
APPENDIX 1 – SCHEDULE OF ASSESSMENTS 
All assessments will be performed as per the “Schedule of Assessments” copied from the protocol. 
 
OL 
Baseline a 
Treatment Period 
Withdrawal Period 
Visit  
1E 
2E 
3E 
4E 
5E 
6E 
7E 
8E 
9E 
10E/ET 
11E 
Call 
12 E 
Call 
13E/EOS 
Week 
 
Week 1 
Week 2 
Week 4 
Week 6 
Week 10 
Week 14 
Week 
18 
Week 
22 
Week 
26 b 
Week 
27 b 
Week 
28 b 
Week 
29 b 
Day 
Day 0 
Day 7 ± 
3 
Day 14 ± 
3 
Day 28 
± 3 
Day 42 ± 
3 
Day 70 ± 
3 
Day 98 ± 
3 
Day 
126 ± 
3 
Day 
154 ± 3 
Day 
182 ± 3 
Day 
189 ± 
3 
Day 
196 ± 
3 
Day 203 
± 3 
Obtain informed 
consent/assent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense study drugc  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Study drug accountability  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Between visit contactd  
 
 
 
 
 
At the approximate midpoint between Visits 5E and 
6E, Visits 6E and 7E, Visits 7E and 8E, Visits 8E and 9E, 
and Visits 9E and 10E.  
 
 
 
Medical and Psychiatric 
History  
X (carried 
over) 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
review  
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Physical Examination 
X (carried 
over) 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Neurological Examination 
X (carried 
over) 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Height (measured by 
stadiometer) 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Weight (including body 
mass index) 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Vital Signs 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Electrocardiogram (ECG) 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Adverse Event Monitoring 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 


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OL 
Baseline a 
Treatment Period 
Withdrawal Period 
Visit  
1E 
2E 
3E 
4E 
5E 
6E 
7E 
8E 
9E 
10E/ET 
11E 
Call 
12 E 
Call 
13E/EOS 
Week 
 
Week 1 
Week 2 
Week 4 
Week 6 
Week 10 
Week 14 
Week 
18 
Week 
22 
Week 
26 b 
Week 
27 b 
Week 
28 b 
Week 
29 b 
Day 
Day 0 
Day 7 ± 
3 
Day 14 ± 
3 
Day 28 
± 3 
Day 42 ± 
3 
Day 70 ± 
3 
Day 98 ± 
3 
Day 
126 ± 
3 
Day 
154 ± 3 
Day 
182 ± 3 
Day 
189 ± 
3 
Day 
196 ± 
3 
Day 203 
± 3 
Tanner Staging 
X (carried 
over) 
 
 
 
 
 
 
 
 
X 
 
 
 
Columbia Suicide Severity 
Rating Scale (C‐SSRS) 
Children’s Assessmente  
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Clinical Global Impression 
– Severity (CGI‐S)  
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ADHD Rating Scale Version 
IV ‐ Home Version 
(modified for investigator 
administration) (ADHD‐RS‐
IV HV)  
 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Conners 3rd Edition 
Parent (Conners 3‐P)  
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Children's Sleep Habits 
Questionnaire (CSHQ)  
 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Weiss Functional 
Impairment Rating Scale – 
Parent Report (WFIRS‐P)  
X (carried 
over) 
 
 
 
 
 
X 
 
 
X 
 
 
 
Physician Withdrawal 
Checklist (PWC)j  
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Discontinuation‐Emergent 
Signs and Symptoms 
(DESS) Scale j  
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Hematology/Chemistry  
 
X (carried 
over) 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Thyroid panel f  
X (carried 
over) 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Lipid panelg  
X (carried 
over) 
 
 
 
 
 
X 
 
 
X 
 
 
X 


Protocol SEP360-310, Version 0.1 
 
Dasotraline 
 
  INC Research © LLC 
Page 53 of 60 
 
OL 
Baseline a 
Treatment Period 
Withdrawal Period 
Visit  
1E 
2E 
3E 
4E 
5E 
6E 
7E 
8E 
9E 
10E/ET 
11E 
Call 
12 E 
Call 
13E/EOS 
Week 
 
Week 1 
Week 2 
Week 4 
Week 6 
Week 10 
Week 14 
Week 
18 
Week 
22 
Week 
26 b 
Week 
27 b 
Week 
28 b 
Week 
29 b 
Day 
Day 0 
Day 7 ± 
3 
Day 14 ± 
3 
Day 28 
± 3 
Day 42 ± 
3 
Day 70 ± 
3 
Day 98 ± 
3 
Day 
126 ± 
3 
Day 
154 ± 3 
Day 
182 ± 3 
Day 
189 ± 
3 
Day 
196 ± 
3 
Day 203 
± 3 
Sex hormone testsh  
X (carried 
over) 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Serum β‐hCG (in females)i  
X (carried 
over) 
 
 
 
 
 
 
 
 
 
 
 
X 
Urinalysis  
X (carried 
over) 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Urine drug screen  
X (carried 
over) 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
Urine β‐hCG (in females)i  
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
Breath alcohol test  
X (carried 
over) 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 


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Page 54 of 60 
18. 
APPENDIX 2 - PROGRAMMING CONSIDERATIONS 
All tables, data listings, figures (TLFs), and statistical analyses will be generated using 
SAS®, Release 9.3 or higher (SAS® Institute Inc., Cary, NC, USA). Computer-generated 
table, listing and figure output will adhere to the following specifications.   
18.1. 
GENERAL CONSIDERATIONS 
 
One SAS program can create several outputs.  
 
One output file can contain several outputs.  
 
Output files will be delivered in Rich Text Format (RTF) for draft and in PDF format 
for final. 
18.2. 
TABLE, LISTING, AND FIGURE FORMAT 
18.2.1. 
General 
 
All TLFs will be produced in landscape format, unless otherwise specified. 
 
All TLFs will be produced using the Courier New font, size 8  
 
The data displays for all TLFs will have a 1.5-inch binding margin on top of a 
landscape oriented page and a minimum 1-inch margin on the other 3 sides. 
 
Headers and footers for figures will be in Courier New font, size 8. 
 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
 
Tables and listings will be in black and white (no color), unless otherwise specified. 
Figures will be provided in color. 
 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used (see below). 
 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters will be used, where possible, if they 
are appropriate to help display math symbols (e.g., μ). Certain subscripts and 
superscripts (e.g., cm2) will be employed on a case-by-case basis. 
 
Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate. 


Protocol SEP360-310, Version 0.1 
 
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Page 55 of 60 
18.2.2. 
Headers 
 
All output should have the following header at the top left of each page: 
Sunovion Pharmaceuticals, Inc. 
Protocol SEP360-310  
          
 
All output should have Page n of N at the top or bottom right corner of each page. 
TLFs should be internally paginated in relation to the total length (i.e., the page 
number should appear sequentially as page n of N, where N is the total number of 
pages in the table). 
 
18.2.3. 
Display Titles 
 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
International Conference on Harmonization (ICH) E3 numbering is strongly 
recommended but sponsor preferences should be obtained prior to final 
determination. A decimal system (x.y and x.y.z) should be used to identify TLFs with 
related contents. The title is centered. The analysis population should be identified 
on the line immediately following the title. The title and table designation are 
single spaced. A solid line spanning the margins will separate the display titles from 
the column headers. There will be 1 blank line between the last title and the solid 
line. 
Table x.y.z 
First Line of Title  
(<Population Name>) 
 
18.2.4. 
 Column Headers 
 
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters.  
 
In the case of efficacy tables, the variable (or characteristic) column will be on the 
far left followed by the DB treatment group columns and total column (if 
applicable). P-values may be presented under the total column or in separate p-
value column (if applicable). Within-treatment comparisons may have p-values 
presented in a row beneath the summary statistics for that treatment. 
 
For numeric variables, include “unit” in column or row heading when appropriate. 


Protocol SEP360-310, Version 0.1 
 
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Page 56 of 60 
 
Analysis set sizes will be presented for each DB treatment group in the column 
heading as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ 
used for the descriptive statistics representing the number of subjects in the 
analysis set. 
 
The order of treatments in the tables and listings will be Placebo first in the case of 
placebo controlled studies and Active comparators first in the case of active 
comparator trials, followed by a ‘All’ or ‘Total’ column (if applicable). 
18.2.5. 
Body of the Data Display 
18.2.5.1. Table Conventions 
 
Units will be included where available.  
 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the table, even if n=0 for 
all treatment groups in a given category that is between the minimum and maximum 
level for that parameter. For example, the frequency distribution for symptom 
severity would appear as: 
Severity Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
 
An Unknown or Missing category may be added to any parameter for which 
information is not available for 1 or more subjects.  
 
Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to 1 more significant digit than the original values, and 
standard deviations should be printed out to 2 more significant digits than the 
original values. The minimum and maximum should report the same significant digits 
as the original values. For example, for systolic blood pressure: 
n 
 XX 
Mean 
XXX.X 
Std Dev 
X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
 
Tabular display of data for medical history, prior / concomitant medications, and all 
tabular displays of adverse event data should be presented by the body system, 


Protocol SEP360-310, Version 0.1 
 
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Page 57 of 60 
treatment class, or SOC with the highest occurrence in the active treatment group 
in decreasing order, assuming all terms are coded. Within the body system, drug 
class and SOC, medical history (by PT), drugs (by ATC code), and adverse events (by 
preferred term) should be displayed in decreasing order. If incidence for more than 
1 term is identical, those terms should then be sorted alphabetically.  
 
Missing descriptive statistics or p-values which cannot be estimated should be 
reported as “-” with a corresponding footnote (“- = unknown or not evaluated”), or 
as “N/A”, with the footnote “N/A = not applicable”, whichever is appropriate. 
 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis set 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number of 
subjects exposed.  
 
Where a category with a subheading (such as SOC) has to be split over more than 
one page, output the subheading followed by “(cont)” at the top of each subsequent 
page.  The overall summary statistics for the subheading should only be output on 
the first relevant page. 
18.2.5.2. Listing Conventions 
 
Listings will be sorted for presentation in order of double-blind treatment groups as 
noted in section 6.1, subject number, visit/collection day, and visit/collection time. 
 
Dates will be printed as recorded on CRF.  
 
All observed time values must be presented as recorded on CRF. 
 
Units will be included where available. 
18.2.5.3. Figure Conventions 
 
Unless otherwise specified, for all figures, time will be displayed on the X-axis and 
endpoint (e.g., overall survival) values will be displayed on the Y-axis. 
18.2.6. 
Footnotes 
 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
 
Footnotes should begin with “Note:” if an informational footnote, or 1, 2, 3, or a, b, 
c etc. if a reference footnote. Each new footnote should start on a new line where 
possible. 


Protocol SEP360-310, Version 0.1 
 
  INC Research © LLC 
Page 58 of 60 
 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing.  
 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, the listing source (only for 
table outputs) and the date the output was produced.   
 
Cross-reference: Listing xx.x 
 
Program: Txxxxxx.sas                                                                                              <date> 


Protocol SEP360-310, Version 0.1 
 
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Page 59 of 60 
19. 
APPENDIX 3 – HANDLING PARTIAL/MISSING DATES 
19.1. 
MEDICATION DATE 
For prior and concomitant medications with incomplete dates, the following rules will 
be used to impute start and/or stop dates for the purposes of determining if a 
medication is prior or concomitant only. 
 
For start dates, if day is missing the first of the month will be used. If month is 
missing January will be used. If the start date is completely missing, the date of 
first dose will be used. If the stop date is complete and the imputed start date is 
after the actual stop date, then the start date will be imputed as the stop date. 
 
For stop dates, if the day is missing then the last day of the month will be used. 
If the month is missing then December will be used. If the stop date is 
completely missing then the date of last dose will be used. If the start date is 
complete and the imputed stop date is earlier than the actual start date, the 
stop date will be imputed as the start date. 
Both prior and concomitant medications are collected on the same CRF page, the 
following rules will be used to distinguish prior versus concomitant medication: 
 
Medications with a start date prior to the first date of study drug will be 
considered prior medications.  
 
Medications with a start date on or after the first date of study drug will be 
considered concomitant medications.  
 
Medications that are ongoing are considered concomitant medications. 
19.2. 
ADVERSE EVENT DATE 
If the adverse event start date is partially or completely missing, then the following 
rules will be used to impute the start date for the purposes of determining the 
treatment emergence of adverse events. .   
 
If the start day is missing then the first day of the month will be used. 
 
If the start month is missing then January will be used.  
 
If the start date is completely missing then the date of first dose will be used. 


Protocol SEP360-310, Version 0.1 
 
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Page 60 of 60 
 
If the end date is complete and the imputed start date is after the end date, 
then the start date will be imputed as the end date.