Clinical trial NCT03231800
Conditions: Attention-Deficit Hyperactivity Disorder (ADHD)
Keywords: Attention-Deficit Hyperactivity Disorder (ADHD)
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2017-07-31; Completion date: 2019-03-15
Enrollment: 95 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A study to evaluate the efficacy and safety of dasotraline in children 6 to 12 years of age with Attention-Deficit Hyperactivity Disorder (ADHD) in a simulated classroom setting.

Detailed description:
This is a randomized, double-blind, placebo-controlled, parallel-group, efficacy and safety study in children with ADHD in a laboratory classroom setting. The study will be comprised of 3 periods: Screening (up to 35 days) including a 3 - 5 day ADHD medication washout prior to Day -1; Double-blind randomized treatment with either dasotraline (2 mg/day) or placebo for 14 days; and a final safety evaluation 7 days after last dose. Prior to the start of treatment (Day 1) and following the conclusion of the double-blind period (Day 15), subjects will undergo a full-day laboratory classroom evaluation in cohorts of up to 18 subjects. Each laboratory classroom day will include seven 30-minute simulated classroom sessions where trained observers will assess subjects using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Scale. In addition during each classroom session, a 10-minute math test (Permanent Product Measure of Performance \[PERMP\]) will be administered to evaluate sustained attention and effort. Seven (± 2) days after the last dose of study drug, subjects will return to the clinic and complete safety assessments.

This study is designed to test the superiority of dasotraline 2 mg/day against placebo based on Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale (SKAMP)-Combined score in pediatric subjects aged 6-12 years with ADHD who weigh ≤ 30 kg

Arms: arm 1: Dasotraline capsule 2mg/day arm 2: Placebo capsule
Interventions: intervention 1: dasotraline intervention 2: Placebo
Intervention descriptions: intervention 1: dasotraline 2mg capsule once daily intervention 2: Placebo capsule once daily

Protocol documents:
Prot_000.pdf: 
Titlpage
Dasotraline (SEP-225289) 
Clinical Study Protocol SEP360-311 
Dasotraline (2mg) in Children Aged 6 to 12 Years with Attention-
Deficit Hyperactivity Disorder (ADHD): A Randomized, 
Multicenter, Double-blind, Placebo-controlled, Parallel-group 
Study of Efficacy and Safety in a Laboratory Classroom Setting
IND No. 071283 
Version 3.00 
Incorporates Amendment 2.00 
19 November 2017 
SUNOVION PHARMACEUTICALS INC. 
84 Waterford Drive 
Marlborough, MA 01752, USA 
(508) 481-6700 


Protocol SEP360-311, Version 3.00 
Dasotraline 
Confidential and Proprietary 
2 
19 November 2017 
RESTRICTED DISTRIBUTION OF PROTOCOLS 
This document contains information confidential and/or of proprietary interest to Sumitomo 
Dainippon Pharma Co. Ltd. and/or Sunovion Pharmaceuticals Inc. (including their 
The information cannot be disclosed to any third party or 
predecessors, subsidiaries or affiliates). 
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 (e.g., 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. This document 
contains information confidential and/or of proprietary interest to Sumitomo Dainippon Pharma 
Co. Ltd. and/or Sunovion Pharmaceuticals Inc. (including their predecessors, subsidiaries or 
The information cannot be disclosed to any third party or used for any purpose other 
affiliates). 
than the purpose for which it is being submitted without the prior written consent of the 
appropriate Sumitomo Dainippon Pharma Company. 


Protocol SEP360-311, Version 3.00 
Dasotraline 
Confidential and Proprietary 
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19 November 2017 
EMERGENCY CONTACTS 
Table 1: Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Responsible Physician 
 
Medical Monitor 
 
SAE/Pregnancy Reporting  
  


Protocol SEP360-311, Version 3.00 
Dasotraline 
Confidential and Proprietary 
4 
19 November 2017 
1.
SYNOPSIS
Name of Sponsor: Sunovion Pharmaceuticals Inc. 
Name of Investigational Product: Dasotraline (SEP-225289) 
Title of Study: Dasotraline (2mg) in Children Aged 6 to 12 Years with Attention-Deficit Hyperactivity 
Disorder (ADHD): A Randomized, Multicenter, Double-blind, Placebo-controlled, Parallel-group 
Study of Efficacy and Safety in a Laboratory Classroom Setting 
Proposed Indication: Attention-Deficit Hyperactivity Disorder (ADHD) 
Study Centers: Approximately 5 centers in North America 
Planned Study Period: 4-6 months 
Study Objectives: 
Primary: To evaluate the efficacy of dasotraline 2 mg/day compared to placebo on attention-deficit 
hyperactivity disorder (ADHD) symptoms in children (6 – 12 years of age), who weigh ≤ 30 kg, in a 
laboratory classroom setting. 
Secondary: 
•
To evaluate the efficacy of dasotraline 2 mg/day compared to placebo on ADHD symptoms
throughout the day (12 to 24 hours post-dose) in children in a laboratory classroom setting.
•
To evaluate the safety and tolerability of dasotraline 2 mg/day using physical examinations,
12-lead electrocardiograms (ECG), vital signs, adverse event (AE) reports, clinical laboratory
results, and the Columbia – Suicide Severity Rating Scale (C-SSRS) Children’s Assessment.
Study Design: This is a randomized, double-blind, placebo-controlled, parallel-group, efficacy and 
safety study in children with ADHD in a laboratory classroom setting. The study will be comprised of 
3 periods: Screening (up to 35 days) including a 3 - 5 day ADHD medication washout prior to Day -1, 
if necessary; Double-blind randomized treatment with either dasotraline (2 mg/day) or placebo for 
14 days; and a final safety evaluation 7 days after last dose. Prior to the start of treatment (Day 1) and 
following the conclusion of the double-blind period (Day 15), subjects will undergo a full-day 
laboratory classroom evaluation in cohorts of up to 18 subjects. Each laboratory classroom day will 
include seven 30-minute simulated classroom sessions where trained observers will assess subjects 
using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Scale. In addition during each 
classroom session, a 10-minute math test (Permanent Product Measure of Performance [PERMP]) will 
be administered to evaluate sustained attention and effort. Seven (± 2) days after the last dose of study 
drug, subjects will return to the clinic and complete safety assessments. 
The primary efficacy endpoint will be the change from baseline to Day 15 in ADHD symptoms as 
measured by the mean SKAMP-Combined score obtained from an average of the 7 SKAMP 
assessments collected across the 12-hour classroom day. The SKAMP is a validated 13-item rating 
scale that assesses manifestations of ADHD in a classroom setting through a combined score and 
2 subscale scores; deportment items (interacting with other children, interacting with adults, remaining 
quiet, staying seated, complying with the teacher’s directions, and following the classroom rules) and 
attention items (getting started, sticking with tasks, attending to an activity, making activity transitions, 
completing assigned tasks, performing work accurately, and being neat and careful while writing or 
drawing). The PERMP is a 5-page math test consisting of 80 problems per page (total of 
400 problems); both attempted problems and correct problems will be assessed. Subjects are to 
complete as many problems as possible in 10 minutes. The appropriate math level for each subject is 
determined based on results of the math pretest administered at screening. 


Protocol SEP360-311, Version 3.00 
 
Dasotraline 
Confidential and Proprietary 
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19 November 2017 
Safety and tolerability will be monitored throughout the study by physical and neurological 
examinations, 12-lead ECG, vital signs, AEs, clinical laboratory evaluations (hematology, chemistry, 
and urinalysis), and the C-SSRS. A Data and Safety Monitoring Board (DSMB) will review safety and 
tolerability data including data on AEs and serious AEs at regular intervals. 
Screening: The screening period will be completed within a maximum of 35 days prior to the first dose 
of study drug and will begin with acquisition of informed assent from the subject and informed consent 
from at least one of the subject’s parents/legal guardians. 
Subjects will be confirmed as meeting DSM-5 criteria for a diagnosis of ADHD. Subjects may be 
either currently untreated or receiving stimulant ADHD medication at Screening. On Day -7 the 
ADHD Rating Scale Version IV - Home Version (modified for investigator administration) 
(ADHD-RS-IV HV) will be completed and subjects will attend a half-day practice laboratory classroom 
session intended to familiarize them with classroom schedules and procedures related to SKAMP 
evaluations, PERMP tests, and other planned activities. Any subjects receiving stimulant medication for 
ADHD will discontinue that ADHD treatment for 3 - 5 days prior to Day -1 in order to ensure that 
there is at least a 72-hour washout before the assessment of ADHD symptoms on Day 1. The day 
before randomization, the subject’s parent/legal guardian will be contacted by study site staff in order 
to confirm the presence of clinically significant ADHD symptoms since discontinuation of stimulant 
medication. Clinically significant is defined as an ADHD-RS-IV HV total score ≥ 26 following a 
minimum 72-hour washout from any prior ADHD treatment. Subjects who do not demonstrate 
clinically significant symptoms (i.e., ADHD-RS-IV ≥ 26) on Day -1 will be considered screen failures 
and will not be eligible for randomization. 
Subjects may be rescreened a maximum of 2 times for out of range clinical laboratory results, 
insufficient medication washout periods, etc. 
Double-blind Period: On Day 1 subjects will return to the clinic in the morning, and those meeting all 
inclusion and no exclusion criteria will be randomized (1:1) to receive 2 mg/day dasotraline, or placebo, 
and will attend classroom sessions in which they will be evaluated for ADHD symptoms using the 
SKAMP assessment. During this baseline classroom assessment (Day 1), subjects will be evaluated at 
regular intervals: approximately 8 AM, 10 AM, 12 PM, 2 PM, 4 PM, 6 PM, and 8 PM. Subjects will 
begin taking study drug on the evening of Day 1 (with or without food) after the final, 8:00 PM baseline 
classroom assessment. Subjects will take one dose each evening before bedtime for a total of 14 days. 
Study drug should be taken at approximately the same time each evening. The first dose of study drug 
may be administered at approximately 8 PM plus or minus 30 minutes, in the clinic after all 
assessments are completed and before the subject leaves, or at home. On the night (Day 14) before the 
second classroom day, study drug must be taken at approximately 8 PM plus or minus 30 minutes. During 
the double-blind period, the clinical site will attempt to contact the subject’s parent/legal guardian daily with a 
reminder to administer study drug. A dosing diary will be provided to the parent/legal guardian to record the 
date and time of each administration of study drug. On Day 15 subjects will return to the clinic in the 
morning at 6:30 AM and classroom sessions will be started at approximately 8 AM, 10 AM, 12 PM, 
2 PM, 4 PM, 6 PM, and 8 PM to coincide with 12, 14, 16, 18, 20, 22, and 24 hours following the 
Day 14 dose.  
End of Study: Seven (±2) days after the last dose of study drug, all subjects will return to the clinic 
and complete assessments. After the EOS visit, all subjects will be referred for continuation of their 
care as determined by the investigator. Additionally, for subjects who complete the study or 
discontinue for tolerability or lack of efficacy reasons, the sponsor will provide support for approved 
ADHD medication costs for up to 3 months after participation in the study, if deemed medically 
appropriate by the subject’s healthcare provider. 
A study schematic is presented in Figure 1. A summary of assessments to be conducted at each 
visit is presented in Table 2, Schedule of Assessments. 


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Protocol SEP360-311, Version 3.00 
 
Dasotraline 
Confidential and Proprietary 
7 
 
19 November 2017 
Subject Exclusion: 
Subjects with any of the following conditions are ineligible for participation in the study:  
1. Subject currently has a diagnosis of asthma that has required daily treatment with 
bronchodilators or nebulizer treatments in the 30 days prior to screening and/or who may 
require daily treatments with these agents over the course of the trial (intermittent use of 
bronchodilators is not exclusionary; subjects who have a history of requiring persistent asthma 
treatment should be discussed with the medical monitor prior to randomization). 
2. Subject has a diagnosis of bipolar I or II disorder, major depressive disorder, conduct disorder, 
obsessive-compulsive disorder, disruptive mood dysregulation disorder (DMDD), intellectual 
disability, any history of psychosis, autism spectrum disorder, Tourette’s Syndrome, or 
confirmed genetic disorder with cognitive and/or behavioral disturbances; generalized anxiety 
disorder or panic disorder that has been the primary focus of treatment at any time during the 
12 months prior to screening; or that required pharmacotherapy any time during the 6 months 
prior to the start of screening. 
3. Subject has failed 2 adequate courses (dose and duration) of stimulant or non-stimulant 
treatment for ADHD. 
4. Subject is considered treatment refractory by the investigator. 
5. Subject shows evidence of any chronic disease of the central nervous system (CNS) such as 
tumors, inflammation, seizure disorder, vascular disorder, potential CNS related disorders that 
might occur in childhood. 
6. Subjects with a history of persistent neurological symptoms attributable to serious head injury; 
history of febrile seizure, drug-induced seizure, or alcohol withdrawal seizure.  
7. Any use of anticonvulsants for seizure control currently or within the past 2 years. 
8. Uncontrolled thyroid disorder indicated by thyroid stimulating hormone (TSH) ≤ 0.8 x the 
lower limit of normal (LLN) or ≥ 1.25 x the upper limit of normal (ULN) for the reference 
laboratory. 
9. Any history of attempted suicide, clinically significant suicidal ideation, or answers “yes” to 
“Suicidal Ideation” item 4 or item 5 for any lifetime history on the C-SSRS Children’s 
Lifetime/Recent assessment at screening. 
10. Subjects having first-degree relatives (biological parent or sibling) with a history of 
schizophrenia, schizoaffective disorder, bipolar I disorder, or bipolar II disorder are also 
ineligible for the study. 
Investigational Product, Dosage and Mode of Administration: Each daily dose will be supplied as 
one 2 mg dasotraline capsule for oral administration. 
Duration of Treatment: 2 weeks 
Reference Therapy, Dosage and Mode of Administration: Each daily dose will be supplied as one 
matching placebo capsule for oral administration. 
Selected Concomitant Medications: Subject must not have taken any of the following medications: 
anticonvulsants for seizure control within 2 years prior to screening; antipsychotic medication within 
6 months prior to screening; herbal and/or complementary treatments, e.g., St. John’s Wort, or 
antidepressant medications (e.g., bupropion, serotonin norepinephrine reuptake inhibitor [SSRI]/ 
selective serotonin reuptake inhibitor [SNRI], tricyclic, etc.) within 6 months prior to Day 1, 
monoamine oxidase (MAO) inhibitors at any time, or non-stimulant product as treatment for ADHD 
within 4 weeks prior to the start of screening. 
Any subjects receiving stimulant medication for ADHD will discontinue that ADHD treatment for 


Protocol SEP360-311, Version 3.00 
 
Dasotraline 
Confidential and Proprietary 
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19 November 2017 
3 - 5 days prior to Day -1 in order to ensure that there is at least a 72-hour washout before the 
assessment of ADHD symptoms on Day -1. Treatment with any ADHD medication is prohibited 
during the washout period. In addition, all subjects are required to refrain from other prohibited 
medications for at least 7 days, unless otherwise specified, prior to the first dose of study drug. 
Use of any of the following medications is not permitted during the study from screening through the 
EOS visit: lithium; alpha-2 adrenergic receptor agonists (including clonidine and guanfacine), 
modafinil, armodafinil, atomoxetine, or any stimulant class agent (methylphenidate- or amphetamine-
based); antidepressant medications (e.g., bupropion, SSRI/SNRI, MAO inhibitor, tricyclic, etc.); 
anticonvulsant medications (e.g., phenytoin, carbamazepine, lamotrigine, valproic acid, etc.); 
antipsychotic medications; pseudoephedrine-containing medications; 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); diphenhydramine 
except topical formulations; herbal and/or complementary treatments, e.g., St. John’s Wort; or 
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. 
Use of any of the following behavioral interventions is not permitted during the study from screening 
through the EOS visit. This includes: ongoing or newly initiated Cognitive Behavioral Therapy (CBT) 
for the treatment of ADHD; behavioral therapies, including school based interventions that were 
initiated less than one month prior to screening; and, behavioral therapy that in the opinion of the 
investigator would interfere with the subject’s ability to participate for the duration of the study. 
School based interventions that have been in place for more than one month prior to screening will be 
allowed. 
Note: 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. Subjects should 
not be enrolled who, in the judgment of the investigator, are expected to start substantially different or 
more intensive course of behavioral therapy over the duration of their participation in the study. 
Study Endpoints:  
Primary Endpoint: Change from baseline at Day 15 in ADHD symptoms as measured by mean 
SKAMP-Combined score obtained from an average of the 7 assessments collected across the 12-hour 
classroom day (12 to 24 hours post-dose). 
Secondary Endpoints:  
• Mean SKAMP-Combined score from the 7 assessments collected across the 12-hour classroom day 
(12 to 24 hours post-dose) on Day 15. 
• SKAMP-Combined score at each of the assessment times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours 
post-dose) during the classroom day on Day 15. 
• Change from baseline at Day 15 in SKAMP-Combined score at each of the assessment times (12-, 
14-, 16-, 18-, 20-, 22-, and 24-hours post-dose) during the classroom day. 
• Change from baseline at Day 15 in mean SKAMP-Attention subscale score obtained from the 
7 assessments collected across the 12-hour classroom day (12 to 24 hours post-dose). 
• SKAMP-Attention subscale score at each of the assessment times (12-, 14-, 16-, 18-, 20-, 22-, and 
24-hours post-dose) during the classroom day on Day 15. 
• Change from baseline at Day 15 in SKAMP-Attention subscale score at each of the assessment 
times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours post-dose) during the classroom day. 
• Change from baseline at Day 15 in mean SKAMP-Deportment subscale score obtained from the 


Protocol SEP360-311, Version 3.00 
 
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19 November 2017 
7 assessments collected across the 12-hour classroom day (12 to 24 hours post-dose). 
• SKAMP-Deportment subscale score at each of the assessment times (12-, 14-, 16-, 18-, 20-, 22-, 
and 24-hours post-dose) during the classroom day on Day 15. 
• Change from baseline at Day 15 in SKAMP-Deportment subscale score at each of the assessment 
times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours post-dose) during the classroom day. 
• Change from baseline at Day 15 in PERMP-Attempted and Correct Problems scores at each of the 
assessment times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours post-dose) during the classroom day. 
• PERMP-Attempted and Correct Problems scores at each of the assessment times (12-, 14-, 16-, 18-, 
20-, 22-, and 24-hours post-dose) during the classroom day on Day 15. 
• Change from baseline at Day 15 in mean PERMP-Attempted score obtained from an average of the 
7 assessments collected across the 12 hour classroom day (12 to 24 hours post-dose). 
• Change from baseline at Day 15 in mean PERMP-Correct score obtained from an average of the 
7 assessments collected across the 12 hour classroom day (12 to 24 hours post-dose). 
• The incidence of overall AEs, serious AEs (SAEs), and AEs (or SAEs) leading to discontinuations. 
• Absolute values and change from baseline in clinical laboratory evaluations (serum chemistry, 
hematology, and urinalysis). 
• Absolute values and changes from baseline in vital signs, body weights, and 12-lead ECGs. 
• Frequency and severity of suicidal ideation and suicidal behavior as assessed by the C-SSRS. 
Statistical Methods:  
Hypotheses: 
Let μ2mg/day, and μPBO represent the changes from baseline at Day 15 in mean SKAMP-Combined score 
for dasotraline 2 mg/day, and placebo arms, respectively. The following hypothesis will be tested to 
compare the mean change value between the dasotraline 2 mg/day group and the placebo group from 
baseline to Day 15: 
1. Dasotraline 2 mg/day versus placebo: 
 
H01: μ2mg/day = μPBO versus H11: μ2mg/day ≠ μPBO 
Efficacy Analysis: 
An analysis of covariance (ANCOVA) will be applied to evaluate the treatment effect for the primary 
efficacy endpoint between the dasotraline 2 mg/day and placebo groups for the intent-to-treat (ITT) 
population. The model will include treatment, mean SKAMP-Combined score at baseline, and site as 
fixed effects. The primary efficacy analysis will be repeated for the per protocol (PP) population. To 
explore the robustness of the primary efficacy analysis of change from baseline at Day 15 in ADHD 
symptoms in mean SKAMP-Combined score, 2 sensitivity analyses will be performed, a placebo-based 
multiple imputation pattern-mixture model (PMM) and a tipping point analysis using the PMM. 
A similar ANCOVA model, as described above, will be used for the secondary efficacy endpoints for 
the ITT population. 
Multiplicity Considerations: There will be no adjustment for multiplicity for the primary efficacy 
analysis, secondary efficacy analyses, or safety analyses. 
Safety Analysis: 
All safety analyses will be performed on the safety population. Overall AEs (or SAEs) and AEs (or 
SAEs) leading to discontinuation will be summarized by system organ class and preferred term by 
presenting the number and percentage of subjects with each AE. Descriptive statistics also will be 
provided by visit for observed values and changes from baseline for the following safety variables: 


Protocol SEP360-311, Version 3.00 
 
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19 November 2017 
laboratory tests, vital signs, and ECG parameters. Frequency and severity of suicidality, as captured by 
the C-SSRS, will be summarized by visit. 
Sample Size:  
A post-hoc ANCOVA-LOCF analysis of data from the SEP360-305 laboratory classroom study was 
conducted to examine the effect of dasotraline 4 mg/day versus placebo in a subset of pediatric patients 
with ADHD aged 6-9 years old. This analysis showed an effect size in this subgroup of 0.95 (LS mean 
difference at Week 2 was 7.2 with a standard error of 2.2). Assuming a smaller effect size for 
dasotraline 2 mg/day vs. placebo than that of dasotraline 4 mg/day vs. placebo, an effect size of 0.7 was 
utilized for the sample size calculation. 
Therefore, assuming an effect size of 0.7 for dasotraline 2 mg/day compared to placebo on the primary 
efficacy endpoint of mean SKAMP-Combined score obtained from the average of 7 assessments 
collected across the 12-hour classroom day, 88 subjects (44 per treatment group) will provide 90% 
power to detect a treatment effect between dasotraline and placebo at the two-sided alpha level of 0.05, 
based on the two-sample t-test with equal variance procedure. 
The study will target approximately 100 subjects (50 per treatment group) randomized to either placebo 
or dasotraline 2 mg/day in an attempt to have 88 subjects complete the trial (assuming a 12% overall 
dropout rate). 
 


Protocol SEP360-311, Version 3.00 
 
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19 November 2017 
Table 2: Schedule of Assessments 
Procedures 
Screening 
Double-blind Period 
End of 
Study 
Clinic Visit 
Practice 
Laboratory 
Classroom 
Session 
Telephone 
Contact 
First 
Laboratory 
Classroom 
Day  
Second 
Laboratory 
Classroom 
Day 
- 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Day -35 
to -8 
Day -7 
Day -1 
Day 1 
Day 15 
Day 21a 
(± 2) 
Obtain informed consent 
X 
 
 
 
 
 
Obtain informed assent 
X 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
X 
X 
X 
 
 
Randomization 
 
 
 
X 
 
 
Dispense study drug 
 
 
 
X 
 
 
Study drug 
accountability 
 
 
 
 
X 
 
Medical History 
X 
 
 
 
 
 
Psychiatric History 
X 
 
 
 
 
 
Family Psychiatric 
History 
X 
 
 
 
 
 
Prior/concomitant 
medication review 
X 
X 
X 
X 
X 
X 
K-SADS-PL 
X 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
X 
Neurological 
examination 
X 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
Weight 
(including body mass 
index) 
X 
 
 
X 
X 
X 
Vital signs 
X 
X 
 
Xb 
Xb 
X 
Electrocardiogram 
(ECG) 
X 
 
 
 
 
X 
Adverse event 
monitoringf 
 
 
 
 
X 
X 
Columbia Suicide 
Severity Rating Scale 
(C-SSRS) 
X 
X 
 
X 
X 
X 


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Table 2: 
Schedule of Assessments (Continued) 
Procedures 
Screening 
Double-blind Period 
End of 
Study 
Clinic Visit 
Practice 
Laboratory 
Classroom 
Session 
Telephone 
Contact 
First 
Laboratory 
Classroom 
Day  
Second 
Laboratory 
Classroom 
Day 
- 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Day -35 
to -8 
Day -7 
Day -1 
Day 1 
Day 15 
Day 21a 
(± 2) 
ADHD-RS-IV HV 
X 
Xg 
X 
 
 
X 
Classroom Practice 
Sessionc 
 
X 
 
 
 
 
SKAMPd 
 
 
 
X 
X 
 
Math pretest for 
determination of math 
level 
X 
 
 
 
 
 
PERMPd 
 
 
 
X 
X 
 
Dosing diary 
distribution/review 
 
 
 
X 
X 
 
Hematology/Chemistry 
X 
 
 
 
 
X 
TSH 
X 
 
 
 
 
 
Serum β-hCG (in 
females ≥ 8 years of 
age)e 
X 
 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
X 
Urine drug screen 
X 
 
 
X 
X 
X 
Urine β-hCG (in females 
≥ 8 years of age)e 
 
 
 
X 
X 
 
Abbreviations: ADHD-RS-IV HV = ADHD Rating Scale Version IV Home Version (modified for investigator 
administration), β-hCG = beta-human chorionic gonadotropin, K-SADS-PL = Schedule for Affective Disorders and 
Schizophrenia for School-Age Children- Present and Lifetime version, PERMP = Permanent Product Measure of 
Performance, SKAMP = Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale, TSH = thyroid stimulating hormone 
a Seven (± 2) days after the last dose of study drug, all subjects will return to the clinic and complete assessments. 
b Heart rate and blood pressure will be measured at approximately the same time on Day 1 and Day 15.  
c Including practice SKAMP assessments, practice PERMP tests, and other planned activities intended to familiarize 
subjects with the classroom setting. 
d Classroom sessions will be started at approximately 8 AM, 10 AM, 12 PM, 2 PM, 4 PM, 6 PM, and 8 PM. 
e Any positive urine β-hCG test should be confirmed by serum β-hCG. 
f Pre-treatment events will be collected from the time of informed consent until the first study drug administration. 
g The ADHD-RS-IV HV may be completed in person or by telephone contact on Day -9, -8, or -7. 
 


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Table 3: 
Sample Laboratory Classroom Day Schedule (Day 15) 
Nominal Time 
Actual Time 
Arrival 
PERMP/SKAMP Meal/snack 
Dismissal 
 
6:30 am 
X 
 
 
 
 
7:30 am 
 
 
X 
 
12 h post-dose 
8:00 am 
 
X 
 
 
 
9:45 am 
 
 
X 
 
14 h post-dose 
10:00 am 
 
X 
 
 
16 h post-dose 
12:00 pm 
 
X 
 
 
 
12:30 pm 
 
 
X 
 
18 h post-dose 
2:00 pm 
 
X 
 
 
 
2:30 pm 
 
 
X 
 
20 h post-dose 
4:00 pm 
 
X 
 
 
22 h post-dose 
6:00 pm 
 
X 
 
 
 
6:30 pm 
 
 
X 
 
24 h post-dose 
8:00 pm 
 
X 
 
 
 
8:45 pm 
 
 
 
X 
Abbreviation: h = hour, PERMP = Permanent Product Measure of Performance, SKAMP = Swanson, Kotkin, 
Agler, M-Flynn, and Pelham Scale 
 
 


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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 ...............14 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................19 
4. 
INTRODUCTION ......................................................................................................23 
4.1. 
Background .................................................................................................................23 
4.2. 
Study Conduct Rationale ............................................................................................24 
4.3. 
Risk-Benefit Assessment ............................................................................................24 
4.4. 
Hypothesis ..................................................................................................................27 
5. 
STUDY OBJECTIVES ..............................................................................................28 
5.1. 
Primary Objectives .....................................................................................................28 
5.2. 
Secondary Objectives .................................................................................................28 
6. 
STUDY ENDPOINTS ................................................................................................29 
6.1. 
Primary Endpoints ......................................................................................................29 
6.2. 
Secondary Endpoints ..................................................................................................29 
7. 
INVESTIGATIONAL PLAN .....................................................................................31 
7.1. 
Overall Study Design ..................................................................................................31 
7.2. 
Treatment Assignment and Blinding ..........................................................................33 
7.2.1. 
Treatment Assignment ................................................................................................33 
7.2.2. 
Blinding ......................................................................................................................33 
7.2.3. 
Emergency Unblinding Procedures ............................................................................33 
7.3. 
Rationale .....................................................................................................................33 
7.3.1. 
Rationale for the Study Design ...................................................................................33 
7.3.2. 
Rationale for the Dosages ...........................................................................................34 
7.3.3. 
Rationale for the Study Population .............................................................................34 
7.3.4. 
Rationale for the Endpoints ........................................................................................34 
7.4. 
Prevention of Missing Data ........................................................................................34 
8. 
SELECTION OF SUBJECTS ....................................................................................35 


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8.1. 
Subject Inclusion Criteria ...........................................................................................35 
8.2. 
Subject Exclusion Criteria ..........................................................................................36 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................40 
9.1. 
Description of Study Drug ..........................................................................................40 
9.2. 
Study Drug Packaging and Labeling ..........................................................................40 
9.2.1. 
Package Description ...................................................................................................40 
9.2.2. 
Labeling Description ..................................................................................................40 
9.3. 
Study Drug Storage .....................................................................................................41 
9.4. 
Dispensing of Study Drug ..........................................................................................41 
9.5. 
Study Drug Accountability .........................................................................................41 
9.6. 
Study Drug Handling and Disposal ............................................................................42 
10. 
TREATMENT OF SUBJECTS ..................................................................................43 
10.1. 
Study Medication ........................................................................................................43 
10.2. 
Treatment Compliance ................................................................................................43 
10.3. 
Concomitant Medications and Therapies ...................................................................43 
10.3.1. 
Prohibited Medications ...............................................................................................44 
10.4. 
Restrictions .................................................................................................................45 
10.5. 
Contraception Requirements ......................................................................................45 
10.6. 
Guidance for Overdose ...............................................................................................45 
10.7. 
Cautions ......................................................................................................................46 
10.8. 
Dietary Guidelines ......................................................................................................46 
11. 
STUDY ASSESSMENTS ..........................................................................................47 
11.1. 
Demographics and Baseline Characteristics ...............................................................47 
11.2. 
Eligibility Assessments ...............................................................................................47 
11.3. 
Efficacy Assessments .................................................................................................48 
11.4. 
Safety Assessments .....................................................................................................48 
11.4.1. 
Adverse Events ...........................................................................................................48 
11.4.2. 
Clinical Laboratory Tests ...........................................................................................48 
11.4.3. 
Vital Signs ..................................................................................................................49 
11.4.4. 
Physical and Neurological Examinations ...................................................................49 
11.4.5. 
Weight and Body Mass Index .....................................................................................49 
11.4.6. 
ECGs ...........................................................................................................................49 
11.4.7. 
Safety Scales ...............................................................................................................49 


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11.5. 
Study Visits and Assessments ....................................................................................50 
11.5.1. 
Screening ....................................................................................................................50 
11.5.1.1. 
Visit 1 (Day -35 to -8) ................................................................................................50 
11.5.1.2. 
Visit 2 (Day -7): Practice Laboratory Classroom Session ..........................................50 
11.5.1.3. 
Visit 3 (Day -1): Telephone Contact ..........................................................................51 
11.5.2. 
Double-blind Period ....................................................................................................51 
11.5.2.1. 
Visit 4 (Day 1): First Laboratory Classroom Day ......................................................51 
11.5.2.2. 
Visit 5 (Day 15): Second Laboratory Classroom Day ................................................52 
11.5.3. 
Visit 6 (Day 21 ± 2): End of Study .............................................................................52 
12. 
SAFETY REPORTING ..............................................................................................53 
12.1. 
Definitions ..................................................................................................................53 
12.1.1. 
Adverse Events ...........................................................................................................53 
12.1.2. 
Serious Adverse Events ..............................................................................................53 
12.2. 
Objective Findings ......................................................................................................54 
12.3. 
Collection and Recording of Adverse Events .............................................................55 
12.4. 
Immediately Reportable Events ..................................................................................56 
12.4.1. 
Serious Adverse Event ................................................................................................56 
12.4.2. 
Pregnancy ...................................................................................................................57 
12.5. 
Data and Safety Monitoring Board .............................................................................57 
13. 
TERMINATION OF SUBJECT FROM STUDY/DISCONTINUATION OF 
STUDY DRUG ...........................................................................................................58 
13.1. 
Criteria for Subject Termination .................................................................................58 
14. 
STUDY TERMINATION ..........................................................................................59 
15. 
STATISTICS ..............................................................................................................60 
15.1. 
Sample Size ................................................................................................................60 
15.2. 
Analysis Populations ..................................................................................................60 
15.3. 
Data Analysis ..............................................................................................................61 
15.3.1. 
Subject Disposition .....................................................................................................61 
15.3.2. 
Drug Exposure and Compliance .................................................................................61 
15.3.3. 
Important Protocol Deviations ....................................................................................61 
15.3.4. 
Demographic and Baseline Characteristics ................................................................61 
15.3.4.1. 
Medical History ..........................................................................................................61 
15.3.4.2. 
Psychiatric History ......................................................................................................62 


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15.3.4.3. 
Family Psychiatric History .........................................................................................62 
15.3.5. 
Efficacy Analyses .......................................................................................................62 
15.3.5.1. 
Primary Efficacy Endpoint Analysis ..........................................................................62 
15.3.5.2. 
Secondary Efficacy Endpoint Analysis ......................................................................62 
15.3.5.3. 
Adjustment for Multiplicity ........................................................................................63 
15.3.5.4. 
Subgroup Analysis ......................................................................................................63 
15.3.6. 
Safety Analyses ..........................................................................................................63 
15.3.6.1. 
Adverse Events ...........................................................................................................64 
15.3.6.2. 
Clinical Laboratory Assessments ...............................................................................65 
15.3.6.3. 
ECGs ...........................................................................................................................65 
15.3.6.4. 
Vital Signs ..................................................................................................................65 
15.3.6.5. 
Neurological Examination ..........................................................................................65 
15.3.6.6. 
Concomitant Medications ...........................................................................................65 
15.3.6.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................65 
15.3.6.8. 
Subgroup Analysis ......................................................................................................65 
15.3.7. 
Treatment of Missing Data .........................................................................................65 
15.3.8. 
Sensitivity Analyses ....................................................................................................66 
16. 
PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL /DATA 
COLLECTION, MANAGEMENT, AND QUALITY ASSURANCE ......................67 
16.1. 
Data Collection/Electronic Data Capture (EDC) ........................................................67 
16.2. 
Computerized Systems Used for Source Data ............................................................67 
16.3. 
Study Monitoring ........................................................................................................68 
16.4. 
Audits ..........................................................................................................................68 
16.5. 
Study Documentation .................................................................................................69 
16.6. 
Clinical Laboratory Certification and Normal Values ................................................69 
17. 
ETHICAL AND REGULATORY OBLIGATIONS..................................................70 
17.1. 
Study Conduct ............................................................................................................70 
17.2. 
Institutional Review Board .........................................................................................70 
17.3. 
Informed Consent .......................................................................................................71 
17.4. 
Subject Privacy ...........................................................................................................71 
17.5. 
Protocol Amendments and Emergency Deviations ....................................................72 
17.6. 
Records Retention .......................................................................................................72 
17.7. 
Inspection of Records .................................................................................................72 


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17.8. 
Financial Disclosure ...................................................................................................72 
17.9. 
Publication Policy .......................................................................................................72 
18. 
REFERENCES ...........................................................................................................74 
19. 
INVESTIGATOR APPROVAL .................................................................................76 
20. 
APPENDIX I. CARDIAC SAFETY MONITORING (ECG) ....................................77 
21. 
APPENDIX II. BODY MASS INDEX DETERMINATION ....................................78 
22. 
APPENDIX III. CLINICAL LABORATORY TESTS ..............................................79 
23. 
APPENDIX IV. CLINICALLY RELEVANT CYP2B6 SUBSTRATES OR 
INDUCERS OR INHIBITORS (GENERIC NAMES) ..............................................80 
24. 
APPENDIX V. GROWTH CHART (MALE). ...........................................................81 
25. 
APPENDIX VI. GROWTH CHART (FEMALE)......................................................82 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Assessments ............................................................................................11 
Table 3: 
Sample Laboratory Classroom Day Schedule (Day 15) .............................................13 
Table 4: 
List of Abbreviations ..................................................................................................19 
Table 5: 
Definition of Key Study Terms ..................................................................................22 
Table 6: 
Investigational Product ...............................................................................................40 
Table 7: 
Computerized Systems Used for Source Data ............................................................67 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................32 
 


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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 4 and Table 5. 
Table 4: List of Abbreviations 
Abbreviation 
Full Form 
ADHD 
Attention deficit hyperactivity disorder 
ADHD-RS-IV  
ADHD Rating Scale Version IV  
ADHD-RS-IV HV ADHD Rating Scale Version IV - Home Version (modified for 
investigator administration) 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical therapeutic chemical (class) 
BMI 
Body mass index  
CAP 
College of American Pathologists 
CBT 
Cognitive Behavioral Therapy 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression–Severity of Illness 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
Central nervous system 
CRF 
Case report form 
CRO 
Contract research organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTM 
Clinical trial material 
DAT 
Dopamine transporter 
DBL 
Database lock 
DEA 
Drug Enforcement Agency 
DHPG 
3, 4-dihydroxyphenylglycol 
DMDD 
Disruptive mood dysregulation disorder 
DMP 
Data Management Plan 
DNRI 
Dopamine and norepinephrine, reuptake inhibitor 
DSM-IV-TR 
Diagnostic and Statistical Manual for Mental Disorders Fourth 
Edition; Text Revision 


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Table 4: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
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 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus  
HR 
Heart rate  
IAF 
Informed assent form 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISI 
Insomnia Severity Index 
ITT 
Intention-to-Treat 
IUD 
Intrauterine device 
IXRS 
Interactive response system 
K-SADS-PL 
Schedule for Affective Disorders and Schizophrenia for School-
Age Children Present and Lifetime Version 
LLN 
Lower limit of normal 
MAO 
Monoamine oxidase (inhibitor) 
MDD 
Major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
NET 
Norepinephrine transporter 
ODD 
Oppositional defiant disorder 
PD 
Protocol deviations 
PERMP 
Permanent Product Measure of Performance 
PMM 
Pattern-mixture model 
POC 
Point of care 
PP 
Per-Protocol 


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Table 4: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
PR 
Time between P wave and QRS in electrocardiography 
PT 
Preferred term 
PVG 
Pharmacovigilance 
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 
QTcB 
QTc with Bazett correction 
QTcF 
QTc with Fridericia correction 
RR 
Electrocardiographic interval between 2 consecutive R waves  
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SKAMP 
Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale 
SNRI 
Serotonin norepinephrine reuptake inhibitor 
SSRI 
Selective serotonin reuptake inhibitor 
SOC 
System organ class 
TSH 
Thyroid stimulating hormone 
UDS 
Urine drug screen 
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 
WHO-DD 
World Health Organization drug dictionary 
 


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Table 5: 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. 
Screened Subject 
Any subject who signed the study specific informed consent and 
completed at least one study related procedure. 
Screen Failure 
Any subject who signed the study specific informed consent but 
either failed to meet study requirements during screening or met 
study requirements at screening but was not enrolled/randomized. 
Study Drug (or 
Study medication) 
Term to cover investigational drug, placebo, and/or active 
control. 
Treatment Period 
The period of the study in which the study drug is administered. 
Randomized Subject 
Any subject who was randomized into the treatment period of the 
study and was assigned a randomization number. 
Completed Subject 
Any subject who participated throughout the duration of the 
study, up to and including both visits 5 and 6. 
Early Termination 
Subject 
Any subject who was successfully screened and randomized into 
the treatment period of the study, but did not complete the study. 
End of Treatment 
The day that the subject received the 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, although 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 are proposed to have a critical 
role in the development of ADHD and thus receptors associated with these are key drug targets 
(Rader-2009).  
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 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 allows plasma concentrations to 
remain in a therapeutic range over the 24-hour dosing interval at steady state. 


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As there is a considerable unmet medical need for ADHD medications in children and 
adolescents that optimize onset and duration of action, 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 
Dasotraline has been evaluated for the treatment of ADHD in 4 completed placebo controlled 
studies, 2 in adults and 2 in children 6 -12 years of age. Moreover, an open label de novo study 
in adults and an open label extension study in children have also been completed. Additional 
studies on the pharmacokinetics and abuse liability of the compound have also shown the drug to 
have a tolerable profile. 
This will be the third study to assess the efficacy and safety of dasotraline in pediatric subjects 
with ADHD. The prior 2 studies demonstrated efficacy at 4 mg in comparison to placebo. This 
study will utilize a simulated classroom setting, identical to the one used in SEP360-305, to 
evaluate the efficacy and safety of dasotraline 2 mg/day in pediatric subjects with ADHD. In this 
setting subjects encounter activities and interaction normally found in a typical school day. The 
laboratory school protocol (Wigal-2006) is a particularly useful method for evaluation of 
efficacy in subjects with ADHD because it represents a controlled study setting for evaluation 
and comparison of study treatments. 
The present study seeks to evaluate the efficacy and safety of dasotraline 2 mg/day. Data 
supporting the safety and efficacy of both a 2 mg and a 4 mg dose would afford a range of 
potential doses (2-4 mg/day) for children, allowing clinicians the flexibility to achieve the 
optimal benefit/risk for each patient. 
Further information on nonclinical and other clinical studies is provided in the Investigator’s 
Brochure. 
4.3. 
Risk-Benefit Assessment 
There are two recently completed studies in children with ADHD that report on the efficacy and 
tolerability of dasotraline (SEP360-202 and SEP360-305), both of which demonstrated 
statistically significant improvement compared to placebo at the 4 mg/day dose. A third study, 
SEP360-310, has been completed but the analyses are not yet finalized. 
 
SEP360-202 
SEP360-202 evaluated the efficacy and safety of 2 doses of dasotraline (2 mg/day and 4 mg/day) 
in pediatric subjects with ADHD. In this 6-week double-blind, placebo controlled trial, 
dasotraline (4 mg/day) was superior to placebo, and well tolerated. 
In SEP360-202, overall, 54.1% of subjects experienced at least 1 Treatment Emergent Adverse 
Event (TEAE) during the study, 38.6% experienced a TEAE that was considered by the 
Investigator to be related to study drug, and 6.7% experienced a TEAE that led to 
discontinuation of study drug. Subjects in the dasotraline 4 mg/day group experienced more 


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TEAEs, more related TEAEs, and more TEAEs that led to a discontinuation than the dasotraline 
2 mg/day group and the placebo group, and the placebo group experienced the least in each of 
these categories. No subjects experienced an SAE and there were no deaths during the study. 
 
SEP360-305 
SEP360-305 evaluated the efficacy and safety of dasotraline (4 mg/day) to placebo, in pediatrics 
with ADHD in a classroom laboratory setting over 2 weeks. The dasotraline (4 mg/day) dose 
demonstrated statistically superior efficacy when compared to placebo, and was well tolerated. 
In SEP360-305, TEAEs were more common in patients taking dasotraline compared with those 
taking placebo (data from the discontinued 6 mg arm of this trial are included here for safety 
consideration). TEAEs were generally mild or moderate in severity. Four patients receiving 
dasotraline experienced severe TEAEs: 4 mg/day: 1 case of insomnia and 1 case of decreased 
appetite; 6 mg/day: 2 cases of insomnia. No serious AEs occurred in patients treated with 
dasotraline. TEAEs associated with discontinuation were hallucinations (2 cases in the 6 mg/day 
group, 1 case in the 4 mg/day group), insomnia (1 case in the 4 mg/day group), decreased 
appetite (1 case in the 6 mg/day group), and rash (1 case in the 4 mg/day group). 
 
Moreover, there have been three studies of dasotraline efficacy and tolerability in adults with 
ADHD including one long term de novo trial for safety; SEP360-201, SEP360-301, and 
SEP360-304 respectively. 
 
SEP360-201 
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 Rating 
Scale Version IV (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 Clinical Global Impression–Severity of Illness (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. Adverse events (AEs) were 
consistent with dasotraline pharmacology, ie, insomnia, decreased appetite, dry mouth, and 
headache. Worsening of insomnia associated with dasotraline was characterized by AEs, and 
shifts in Insomnia Severity Index (ISI) total score, particularly with dasotraline 8 mg/day. AEs, 
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 
 


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SEP360-301 
The second adult study (SEP360-301) evaluated the efficacy and safety of dasotraline (4 mg/day 
and 6 mg/day) and although the doses were found safe, and the 6 mg arm showed numerically 
greater improvement over placebo, neither dose was statistically significantly different than 
placebo. 
 
SEP360-304 
The third study (SEP360-304) showed that dasotraline, flexibly dosed from 4 mg/day to 
8 mg/day, appeared to be safe, well tolerated, and effective in adults for the long term treatment 
of ADHD. Given the long half-life of dasotraline, dosing increments at a frequency of no more 
than every 2 weeks may improve overall tolerability. 
 
The pharmacokinetics and abuse potential for dasotraline have been assessed in several studies. 
One study was completed that evaluated the safety, tolerability, pharmacokinetic, and 
pharmacodynamic properties of dasotraline in pediatric (6 – 12 years) and adolescent 
(13 - 17 years) subjects with ADHD. In this multicenter, open-label study 105 subjects were 
assigned to single oral doses of dasotraline 1 - 16 mg in a dose-escalating manner. Dasotraline 
was characterized by slow absorption (median tmax was 9.6 to 12 hours) and elimination (median 
t½ was 56 to 84 hours) in both pediatric and adolescent subjects. The change in Cmax with dose 
was slightly greater than dose proportional. Increase in overall exposure (AUC) with dose was 
greater than dose proportional. Apparent oral clearance was highest in the lowest dose group 
relative to the higher dose groups. No deaths, serious adverse events (SAE), or discontinuations 
because of an adverse event (AE) were reported in this study. The most frequently reported AE 
by investigators were tachycardia (25 subjects; 23.8%) and electrocardiogram QT prolonged 
(5 subjects; 4.8%), nearly all of which were considered related to study drug and mild in 
severity. Tachycardia AEs were reported in both age groups and in every dose cohort. Most 
events of tachycardia were reported on the day of study drug administration. No subjects 
experienced QT prolongations > 500 msec. Based on the centrally read electrocardiogram 
(ECGs) in the study, no clinically significant trends were identified within the ECG results. 
Blood pressure increased, blood pressure systolic increased, blood pressure orthostatic abnormal, 
and orthostatic hypotension AEs were reported in 1 subject each. Overall, after dosing, 
90 subjects (85.7%) met predefined criteria for orthostatic tachycardia and 40 (38.1%) met 
predefined criteria for orthostatic hypotension. 
Two studies have been completed to support dasotraline as a compound 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. 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 evaluated dasotraline’s abuse 
liability and was conducted in recreational stimulant users; results indicated that dasotraline has 


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low abuse liability (Koblan-2016). 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 another 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) also 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. 
4.4. 
Hypothesis 
This study is designed to test the superiority of dasotraline 2 mg/day against placebo based on 
Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale (SKAMP)-Combined score in pediatric 
subjects aged 6-12 years with ADHD who weigh ≤ 30 kg. 


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5. 
STUDY OBJECTIVES 
5.1. 
Primary Objectives 
The primary objective is to evaluate the efficacy of dasotraline 2 mg/day compared to placebo on 
attention-deficit hyperactivity disorder (ADHD) symptoms in children (6 - 12 years of age) in a 
laboratory classroom setting as measured by the change form baseline at Day 15 in SKAMP 
Combined Score. 
5.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the efficacy of dasotraline compared to placebo on ADHD symptoms 
throughout the day (12 to 24 hours postdose) in children in a laboratory classroom setting 
as measured by sub scores of the SKAMP and PERMP. 
• To evaluate the safety and tolerability of dasotraline using physical examinations, 12-lead 
electrocardiograms (ECG), vital signs, adverse event (AE) reports, clinical laboratory 
results, and Columbia – Suicide Severity Rating Scale (C-SSRS) Children’s Assessment. 


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6. 
STUDY ENDPOINTS 
6.1. 
Primary Endpoints 
The primary endpoint is change from baseline at Day 15 in ADHD symptoms as measured by 
mean SKAMP-Combined score obtained from an average of the 7 assessments collected across 
the 12-hour classroom day (12 to 24 hours postdose). 
6.2. 
Secondary Endpoints 
The secondary endpoints are: 
• Mean SKAMP-Combined score from the 7 assessments collected across the 12-hour 
classroom day (12 to 24 hours postdose) on Day 15 
• SKAMP-Combined score at each of the assessment times (12-, 14-, 16-, 18-, 20-, 22-, 
and 24-hours postdose) during the classroom day on Day 15 
• Change from baseline at Day 15 in SKAMP-Combined score at each of the 
assessment times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours postdose) during the 
classroom day 
• Change from baseline at Day 15 in mean SKAMP-Attention subscale score obtained 
from the 7 assessments collected across the 12-hour classroom day (12 to 24 hours 
postdose) 
• SKAMP-Attention subscale score at each of the assessment times (12-, 14-, 16-, 18-, 
20-, 22-, and 24-hours postdose) during the classroom day on Day 15 
• Change from baseline at Day 15 in SKAMP-Attention subscale score at each of the 
assessment times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours postdose) during the 
classroom day 
• Change from baseline at Day 15 in mean SKAMP-Deportment subscale score 
obtained from the 7 assessments collected across the 12-hour classroom day 
(12 to 24 hours postdose) 
• SKAMP-Deportment subscale score at each of the assessment times (12-, 14-, 16-, 
18-, 20-, 22-, and 24-hours postdose) during the classroom day on Day 15 
• Change from baseline at Day 15 in SKAMP-Deportment subscale score at each of the 
assessment times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours postdose) during the 
classroom day 
• Change from baseline at Day 15 in Permanent Product Measure of Performance 
(PERMP)-Attempted and Correct Problems scores at each of the assessment times 
(12-, 14-, 16-, 18-, 20-, 22-, and 24-hours postdose) during the classroom day 
• PERMP-Attempted and Correct Problems scores at each of the assessment times (12-, 
14-, 16-, 18-, 20-, 22-, and 24-hours postdose) during the classroom day on Day 15 


Protocol SEP360-311, Version 3.00 
 
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• Change from baseline at Day 15 in mean PERMP-Attempted score obtained from an 
average of the 7 assessments collected across the 12-hour classroom day (12 to 
24 hours postdose). 
• Change from baseline at Day 15 in mean PERMP-Correct score obtained from an 
average of the 7 assessments collected across the 12-hour classroom day (12 to 
24 hours postdose). 
• The incidence of overall AEs, serious AEs (SAEs), and AEs (or SAEs) leading to 
discontinuations 
• Absolute values and change from baseline in clinical laboratory evaluations (serum 
chemistry, hematology, and urinalysis) 
• Absolute values and changes from baseline in vital signs, body weights, and 12-lead 
ECGs 
• Frequency and severity of suicidal ideation and suicidal behavior as assessed by the 
C-SSRS 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, double-blind, placebo-controlled, parallel-group, efficacy and safety study, 
in pediatric subjects with ADHD in a laboratory classroom setting. The study will target 
100 subjects (50 per treatment group) to complete the study. The study will be comprised of 
3 periods: Period 1: screening (up to 35 days) including a 3 - 5 day ADHD medication washout, 
if necessary, prior to Day -1; Period 2: double-blind randomized treatment with either dasotraline 
(2 mg/day) or placebo for 14 days; and Period 3: End of Study (EOS) visit (7 days after last 
dose). Prior to the start of treatment (Day 1) and following the conclusion of the 14-day double-
blind period (Day 15), subjects will undergo a full-day laboratory classroom evaluation during 
which up to 18 subjects will be assessed. Each laboratory classroom day will include seven 
30-minute simulated classroom sessions where trained observers will assess subjects using the 
SKAMP Scale. In addition during each classroom session, a 10-minute math test (Permanent 
Product Measure of Performance [PERMP]) will be administered to evaluate sustained attention 
and effort. The appropriate math level for each subject is determined based on results of the math 
pretest administered at screening. 
The primary efficacy endpoint will be baseline to endpoint change in the SKAMP-Combined 
score. 
Safety and tolerability will be monitored throughout the study by physical and neurological 
examinations, 12-lead ECG, vital signs, AEs, clinical laboratories (hematology, chemistry, and 
urinalysis), and C-SSRS. A Data and Safety Monitoring Board (DSMB) will review safety and 
clinical outcome data including data on AEs and serious AEs at regular intervals. 
Screening: The screening period will be completed within a maximum of 35 days prior to the 
first dose of study drug and will begin with acquisition of informed assent from the subject and 
informed consent from at least one of the subject’s parents/legal guardians. 
Subjects will be confirmed as meeting DSM-5 criteria for a diagnosis of ADHD. Subjects may 
be currently untreated for ADHD or receiving a treatment regimen of stimulant medication for 
ADHD at Screening. On Day -7 the ADHD Rating Scale Version IV - Home Version (modified 
for investigator administration) (ADHD-RS-IV HV) will be completed and subjects will attend a 
half-day practice laboratory classroom session intended to familiarize them with classroom schedules 
and procedures related to SKAMP evaluations, PERMP tests, and other planned activities. Any 
subjects receiving stimulant medication for ADHD will discontinue that ADHD treatment for 
3 - 5 days prior to Day -1 in order to ensure that there is at least a 72-hour washout before the 
assessment of ADHD symptoms on Day -1. The day before randomization, the subject’s 
parent/legal guardian will be contacted by study site staff in order to confirm the presence of 
clinically significant ADHD symptoms. Clinically significant is defined as an ADHD-RS-IV HV 
total score ≥ 26. Subjects who do not demonstrate clinically significant symptoms on Day -1 will 
be considered screen failures and will not be eligible for randomization. 
Subjects may be rescreened a maximum of 2 times for out of range clinical laboratory results, 
insufficient medication washout periods, etc. 


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7.2. 
Treatment Assignment and Blinding 
7.2.1. 
Treatment Assignment 
After successfully meeting study entry criteria, subjects will be randomly assigned in a 1:1 ratio 
to 1 of the following treatments: 
• 2 mg/day dasotraline (N = 50 subjects) 
• Placebo (N = 50 subjects) 
An Interactive Response System (IXRS) will be used to manage randomization on Day 1 and, if 
necessary, for emergency unblinding (see Section 7.2.3) of treatment assignment during the 
study. The IXRS is an integrated web based subject and drug management system. 
Study medication will be assigned by an IXRS based on the randomization schedule. The IXRS 
will generate instructions on which medication number to assign to a subject. 
7.2.2. 
Blinding 
This is a double-blind study. All study drug capsules (both dasotraline and placebo) are identical 
in color, shape, size, and packaging in order to maintain the blind. 
Subjects, Sponsor personnel, Investigator staff, persons performing the assessments, clinical 
operations personnel, data analysts, and personnel at central laboratories will remain blind to the 
identity of the treatment from the time of randomization until database lock and unblinding, 
using the following methods; (1) randomization data are kept strictly confidential until the time 
of unblinding, and will not be accessible by anyone else involved in the study with the exception 
of Data and Safety Monitoring Board (DSMB) members involved in regular review of safety 
data, and Clinical Trial Materials Management personnel, (2) the identity of the treatments will 
be concealed by the use of study drugs that are all identical in packaging, labeling, schedule of 
administration, and appearance. 
7.2.3. 
Emergency Unblinding Procedures 
The IXRS will be used, if necessary, for emergency unblinding of treatment assignment during 
the study. The blinded dose information is to be broken only in an emergency when knowledge 
of such treatment may have an impact on further treatment decisions or aid in the emergency 
treatment of the subject. Any subject for whom the blind is broken is to be discontinued from 
receiving any additional study drug and should undergo early termination procedures as 
described in Section 14. 
7.3. 
Rationale 
7.3.1. 
Rationale for the Study Design 
The current study is a randomized, double-blind, placebo-controlled, parallel-group, laboratory 
classroom study in pediatric subjects with ADHD weighing ≤ 30 kg. This study was designed to 
evaluate the efficacy and duration of effect of dasotraline (2 mg/day) compared with placebo 
over an entire day in a simulated classroom setting. The laboratory school protocol is a 
particularly useful method for evaluation of efficacy in subjects with ADHD because it 


Protocol SEP360-311, Version 3.00 
 
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represents a controlled study setting for evaluation and comparison of study treatments and is 
designed to mimic a typical school day. 
7.3.2. 
Rationale for the Dosages 
The dosage of 2 mg/day of dasotraline was selected to evaluate dasotraline safety, tolerability, 
and efficacy within the dose range being evaluated in the ongoing studies in pediatric subjects 
with ADHD. 
A dasotraline 2 mg/day dose is expected to produce mg/kg exposures in pediatric subjects 
weighing ≤ 30 kg similar to those demonstrated to be effective in both children and adults with 
ADHD. In prior studies it was noted that AEs appear to be dose related. Therefore, 2 mg in 
smaller children may be efficacious and better tolerated. 
7.3.3. 
Rationale for the Study Population 
The subject population includes males and females ranging from 6 to 12 years of age, 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 ADHD (inattentive, 
hyperactive, or combined presentation); diagnosis will be confirmed using the Schedule for 
Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime Version 
(K-SADS-PL). Subjects are required to weigh ≤ 30 kg since a 2 mg/day dose in such a group is 
expected to have mg/kg exposures similar to those demonstrated to be effective in children and 
adults. 
7.3.4. 
Rationale for the Endpoints 
The primary efficacy measure (mean SKAMP-Combined Score) is a widely accepted efficacy 
endpoint intended to assess functional impairment related to ADHD and has been used in many 
laboratory classroom studies in children (Childress-2015, Wigal-2014). 
7.4. 
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) use of clinical 
sites with a good track record of having performed this type of study, (ii) training provided to the 
clinical sites on the importance of the informed consent/assent process and ensuring subjects and 
their parent/guardian understand the commitment they are making, including the intent to 
complete the trial, and (iii) monitoring data collection for adherence during the study. 


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8. 
SELECTION OF SUBJECTS 
Subjects may be rescreened a maximum of 2 times for out of range clinical laboratory results, 
insufficient medication washout periods, etc. 
8.1. 
Subject Inclusion Criteria 
The subjects who fulfill the following criteria will be included in the study. 
1. Subject is 6 - 12 years old, inclusive at screening and randomization. 
2. Subject weighs ≤ 30 kg at the time of screening. 
3. 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 provide 
informed assent prior to study participation. 
4. Subject meets Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
(DSM-5) criteria for a primary diagnosis of ADHD (inattentive, hyperactive, or 
combined presentation) at screening established by a comprehensive psychiatric 
evaluation that reviews DSM-5 criteria and confirmed using the Schedule for Affective 
Disorders and Schizophrenia for School-Age Children-Present and Lifetime version 
(K-SADS-PL) at screening. 
5. Subject is currently either untreated for ADHD or receiving a treatment regimen of a 
stimulant medication prescribed as monotherapy (i.e., methylphenidate, mixed 
amphetamine salts, lisdexamphetamine, or dextroamphetamine) within the approved 
labeled dose range for ADHD. 
6. In the opinion of the investigator, the subject is not treatment refractory. 
7. Any subject not receiving ADHD medication at screening must display clinically 
significant ADHD symptoms, as measured by an ADHD-RS-IV score ≥ 26 at screening 
and Day -7. 
8. For any subject receiving monotherapy stimulant treatment for ADHD, that treatment 
must be well tolerated and clinically effective based on clinical assessment and informant 
interview, as well as, review of available medical records. Note: The ADHD Rating Scale 
Version IV - Home Version (modified for investigator administration) (ADHD-RS-IV 
HV) will be administered at Screening by the investigator to inform clinical evaluation. 
9. Subject is male or a non-pregnant, non-lactating female. 
10. Subject, if female, must not be pregnant or breastfeeding, and if ≥ 8 years of age must 
have a negative serum pregnancy test at screening. 
11. Female subjects of childbearing potential and male subjects with female partners of 
childbearing potential must practice true abstinence (consistent with lifestyle) and must 
agree to remain abstinent or agree to use an effective and medically acceptable form of 
birth control, from the time of informed consent/assent to at least 14 days after the last 
dose of the study drug has been taken. See Section 10.5 for information on acceptable 
methods of birth control. 


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12. Subject must be in general good health (defined as the absence of any clinically relevant 
abnormalities as determined by the investigator) based on screening physical and 
neurological examinations, medical history, and clinical laboratory values (hematology, 
chemistry, and urinalysis). Note: If any of the hematology, chemistry, or urinalysis results 
are not within the laboratory’s reference range, then the subject can be included only if 
the investigator determines the deviations to be not clinically relevant. 
13. Subject is within the 3rd to 97th percentile for gender specific weight-for-age from the 
Centers for Disease Control and Prevention (CDC) growth charts. See Sections 24, 
and 25, Appendix V and VI for growth charts. 
14. Subject must report a history of being able to swallow capsules. 
15. Subject and subject’s parent/legal guardian must be able to fully comprehend the 
informed consent/assent forms, understand and be willing and able to comply with all 
study procedures and visit schedule, and be able to communicate satisfactorily with the 
investigator and study coordinator. 
16. Subject, on Day -1, has evidence of clinically significant ADHD symptoms as measured 
by an ADHD-RS-IV HV total score ≥ 26. If subject has been receiving stimulant 
pharmacotherapy for ADHD the ADHD-RS-IV should be administered following a 
minimum 72-hour washout from prior ADHD medication treatment. 
8.2. 
Subject Exclusion Criteria 
The subjects who meet any of the following criteria will be excluded from the study 
1. Subject or parent/legal guardian has commitments during the study that would interfere 
with attending study visits. 
2. Subject is currently being treated for ADHD with a non-stimulant product, or has been 
treated with a non-stimulant product in the 4 weeks prior to the start of screening. 
3. Subject has failed 2 adequate courses (dose and duration) of stimulant or non-stimulant 
treatment for ADHD. 
4. Subject is considered treatment refractory, as judged by the investigator. 
5. Subject currently has a diagnosis of asthma that has required daily treatment with 
bronchodilators or nebulizer treatments in the 30 days prior to screening and/or who may 
require daily treatments with these agents over the course of the trial. Intermittent use of 
bronchodilators is not exclusionary. Subjects who have a history of requiring persistent 
asthma treatment should be discussed with the medical monitor prior to randomization. 
6. Subject has any clinically significant unstable medical abnormality, chronic disease, or a 
history of a clinically significant abnormality of the cardiovascular, gastrointestinal, 
respiratory, hepatic, or renal systems, or a disorder or history of a condition (eg, 
malabsorption, gastrointestinal surgery) that may interfere with drug absorption, 
distribution, metabolism, or excretion. Note: Active medical conditions that are minor or 
well-controlled are not exclusionary if they do not affect risk to the subject or the study 
results. In cases in which the impact of the condition upon risk to the subject or study 
results is unclear, the medical monitor should be consulted. Any subject with a known 


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cardiovascular disease or condition (even if controlled) must be discussed with the 
medical monitor during screening. 
7. Subject has a history or presence of abnormal ECGs, which in the investigator’s opinion 
is clinically significant. Screening site ECGs will be centrally over-read, and eligibility 
will be determined by the investigator based on the results of the over-read report. 
8. Subject has any diagnosis of bipolar I or II disorder, major depressive disorder, conduct 
disorder, obsessive-compulsive disorder, any history of psychosis, autism spectrum 
disorder, disruptive mood dysregulation disorder (DMDD), intellectual disability, 
Tourette’s Syndrome, confirmed genetic disorder with cognitive and/or behavioral 
disturbances. Note: Subjects with oppositional defiant disorder (ODD) are permitted to 
enroll in the study as long as ODD is not the primary focus of treatment. 
9. Subject has a first-degree relative (biological parent or sibling) with a history of 
schizophrenia, schizoaffective disorder, bipolar I disorder, or bipolar II disorder. 
10. Subject has generalized anxiety disorder or panic disorder that has been the primary focus 
of treatment at any time during the 12 months prior to screening or that has required 
pharmacotherapy any time during the 6 months prior to screening. 
11. Subject has evidence of any chronic disease of the central nervous system (CNS) such as 
tumors, inflammation, seizure disorder, vascular disorder, potential CNS related disorders 
that might occur in childhood (eg, Duchenne Muscular dystrophy, myasthenia gravis, or 
other neurologic or serious neuromuscular disorders). 
12. Subjects with a history of persistent neurological symptoms attributable to serious head 
injury. 
13. History of febrile seizure, drug-induced seizure, or alcohol withdrawal seizure is 
exclusionary. 
14. Subjects taking anticonvulsants for seizure control currently or within the past 2 years are 
not eligible for study participation. 
15. Subject has uncontrolled thyroid disorder as evidenced by thyroid stimulating hormone 
(TSH) ≤ 0.8 x the lower limit of normal (LLN) or ≥ 1.25 x the upper limit of normal 
(ULN) for the reference laboratory. 
16. 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 Lifetime/Recent 
assessment at screening. 
17. Subject has any history of attempted suicide or clinically significant suicidal ideation, in 
the opinion of the investigator. 
18. Subject has a history of severe allergies to more than 1 class of medication or multiple 
adverse drug reactions or has a history of allergic reaction or has a known or suspected 
sensitivity to any substance that is contained in the study drug formulations. 
19. Subject has history of intolerance (safety) or lack of efficacy to stimulants. 
20. Subject has taken any antipsychotic medication within 6 months prior to screening. 


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21. Subject has taken any herbal and/or complementary treatments, eg, St. John’s Wort, 
within 6 months prior to Day 1. 
22. Subject has taken any antidepressant medication (eg, bupropion, selective serotonin 
reuptake inhibitor [SSRI]/ serotonin norepinephrine reuptake inhibitor [SNRI], tricyclic, 
etc) within 6 months prior to Day 1. 
23. Subject has ever taken any monoamine oxidase [MAO] inhibitor at any time. 
24. Subject is currently undergoing ongoing or newly initiated Cognitive Behavioral Therapy 
(CBT) for the treatment of ADHD; behavioral therapies, including school based 
interventions that were initiated less than one month prior to screening; or, behavioral 
therapy that in the opinion of the investigator would interfere with the subject’s ability to 
participate for the duration of the study. School based interventions that have been in 
place for more than one month prior to screening will be allowed. Note: 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. 
Subjects should not be enrolled who, in the judgment of the investigator, are expected to 
start substantially different or more intensive course of behavioral therapy over the 
duration of their participation in the study. 
25. Subject or subject’s family anticipates a move outside the geographic range of 
investigative site during the study period, or plans extended travel inconsistent with the 
recommended visit interval during study duration. 
26. Subject has history of, or current, malignancy other than non-melanomatous skin cancer. 
27. Subject has history of positive test for Hepatitis B surface antigen or Hepatitis C 
antibody. 
28. Subject is known to have tested positive for human immunodeficiency virus (HIV). 
29. Subject has participated in a classroom study within 6 months prior to the start of 
screening or has participated in any other clinical study with an investigational 
drug/product within 90 days prior to the start of screening or is currently participating in 
another clinical trial. 
30. Subject shows evidence of substance or alcohol use or is currently using tobacco or other 
nicotine-containing products, or has a positive urine drug screen (UDS) at screening. 
Note: Subjects with a positive UDS may be allowed to continue in the study, provided 
that the investigator determines that the positive test is as a result of taking medications 
as prescribed after consultation with the medical monitor. 
31. Subject is taking any disallowed medications for chronic treatment. 
32. Subject has previously been enrolled in a clinical trial of dasotraline (SEP-225289). 
33. Subject’s parent/legal guardian is an investigational site staff member or the relative of an 
investigational site staff member. 
34. Subject is, in the opinion of the investigator, unsuitable in any other way to participate in 
this study. 


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35. Subject’s sibling or family member living in the same household is participating in the 
same laboratory classroom cohort for this study. 
36. Subject is unable to perform at the basic level of the standardized math test as defined in 
the laboratory classroom manual. 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Description of Study Drug 
The study medication is described in Table 6. 
Table 6: 
Investigational Product 
Attribute 
Investigational Product 
Product name 
Dasotraline 2 mg 
Matching Placebo 
Dosage form 
Capsules 
Capsules 
Unit dose 
One capsule 
One capsule 
Route of administration 
Oral 
Oral 
Physical description 
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. 
The matching placebo capsule is identical to dasotraline in color, shape, size, and packaging and 
contains all ingredients, except the active dasotraline. 
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 or 
placebo capsules (7 days + 3 extra days). 
9.2.2. 
Labeling Description  
All packaging for the study drug 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 identifiers 
• Batch number 
• Unique medication number 


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9.3. 
Study Drug Storage 
All study medication should be stored at 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(s)/legal 
guardian(s) will be instructed to store the study medication at room temperature. 
In addition, the subject’s parent(s)/legal guardian(s) 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 other ADHD treatments from the subject’s access. 
9.4. 
Dispensing of Study Drug 
An Interactive Response System (IXRS) will be used to manage subject screening and 
enrollment. The IXRS is an integrated web-based subject and drug management system. Specific 
User Manuals will be supplied. 
Study medication blister cards will be assigned by the IXRS based on the treatment schedule. 
The IXRS will generate instructions on which medication number to assign to a subject. 
Appropriate guidelines should be followed in proper dispensation to the study participant. Each 
subject will be dispensed two 1-week blister cards on Day 1. Proper accountability records must 
be maintained and accurately document all drug dispensing activities. 
Under supervision from the subject’s parent/legal guardian, subjects will self-administer the 
study drug on an outpatient basis (see Section 10.1). The daily dosage (one capsule) will be 
clearly labeled on the study drug blister card. 
9.5. 
Study Drug Accountability 
The Investigator or designee is responsible for storing the drug in a secure location and for 
maintaining adequate records of 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 drug will be 
returned to the Sponsor, unless other instructions are provided in writing by Sponsor/ clinical 
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 Investigator, or designee, agrees to collect and document all used and unused study 
medication from study subjects/parents/legal guardians at appropriate study visits. 
Study drug will not be dispensed to any person who is not a study subject under this protocol. 
On Day 1 a dosing diary will be provided to the parent/legal guardian to record the date and time 
of each administration of study drug. On Day 15 the parent/legal guardian will bring the dosing 
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9.6. 
Study Drug Handling and Disposal 
A drug inventory record will be supplied by the Sponsor/CRO. The Investigator or designee on 
an ongoing basis must maintain a drug inventory record of supplied, received, dispensed, and 
returned study drug. The Investigator or designee is required to return all unused supplies of 
study drug as well as empty packaging from used study drug to the Sponsor or designee as 
instructed. The Investigator or designee is required to maintain copies of medication shipping 
receipts, drug accountability records, and records of return or final disposal of the study drug in 
accordance with local regulatory requirements. 


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10. 
TREATMENT OF SUBJECTS 
10.1. 
Study Medication  
As described in Section 7.2.1, subjects will be randomized to 1 of 2 treatments (2 mg/day 
dasotraline or placebo). 
Under supervision from the subject’s parent/legal guardian, subjects will self-administer the 
study drug on an outpatient basis for 14 days beginning the evening of Day 1. Study drug should 
be taken at approximately the same time each evening. The first dose of study drug may be 
administered in the clinic, at approximately 8 PM plus or minus 30 minutes, after all assessments 
are completed, before the subject leaves, or at home. On Day 14, the night before the second 
classroom day, study drug must be taken at approximately 8 PM plus or minus 30 minutes. All 
study medication doses will consist of 1 capsule per day taken by mouth. 
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. 
Treatment Compliance 
During the double-blind period, the clinical site will attempt to contact the subject’s parent/legal 
guardian daily with a reminder to administer study drug. 
The Investigator will record the dose of the study drug and the dates of the initial and final 
administration for each dose. 
Compliance with study drug will be monitored closely and determined at each visit. Subjects and 
their parent(s)/legal guardian(s) will be instructed to bring all unused study drug with them to the 
Day 15 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 subjects and their parent(s)/legal guardian(s), and at the investigator’s 
discretion may result in termination of the subject from the study. All subjects and their 
parent(s)/legal guardian(s) 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. 
10.3. 
Concomitant Medications and Therapies 
The following information on all medication administered between signed consent/assent and the 
EOS visit or at discontinuation will be recorded on the CRF: Medication name, dose, frequency, 
route, start date, stop date, and indication. 
All medications will be coded using World Health Organization drug dictionary (WHO-DD). 
Information on the format and version of the coding dictionary will be provided in the Data 
Management Plan (DMP). 


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Collection of prior medications is described in Section 11.1. 
10.3.1. 
Prohibited Medications 
Subject must not have taken any of the following medications within the timeframe listed: 
• Anticonvulsants for seizure control within 2 years prior to screening 
• Antipsychotic medication within 6 months prior to screening 
• Herbal or complementary treatments, eg, St. John’s Wort, within 6 months prior to 
Day 1 
• Any antidepressant medication (eg, bupropion, SSRI/ SNRI, tricyclic, etc) within 
6 months prior to Day 1 
• MAO inhibitor at any time 
• Non-stimulant product as treatment for ADHD within 4 weeks prior to the start of 
screening. 
Any subjects receiving stimulant medication for ADHD will discontinue that ADHD treatment 
for 3 - 5 days prior to Day -1 in order to ensure that there is at least a 72-hour washout before the 
assessment of ADHD symptoms on Day -1. Treatment with any ADHD medication is prohibited 
during the washout period. In addition, all subjects are required to refrain from other prohibited 
medications for at least 7 days, unless otherwise specified, prior to the first dose of study drug. 
Use of any of the following medications is not permitted during the study from screening 
through the EOS visit: 
• Lithium (any lithium preparation or formulation) 
• Alpha-2 adrenergic receptor agonists (including clonidine and guanfacine), modafinil, 
armodafinil, atomoxetine, or any non-stimulant class agent 
• Antidepressant medications (eg, bupropion, SSRI/SNRI, MAO inhibitor, tricyclic, 
etc) 
• Anticonvulsant medications (eg, phenytoin, carbamazepine, lamotrigine, valproic 
acid, etc) and antipsychotic medications 
• Pseudoephedrine-containing medications  
• 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 
• Diphenhydramine except topical formulations 
• Herbal or complementary treatments, eg, St. John’s Wort  
• CYP2B6 substrates or inhibitors or inducers of CYP2B6 (see Section 23, 
Appendix IV). 


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10.4. 
Restrictions 
Subject is currently undergoing ongoing or newly initiated Cognitive Behavioral Therapy (CBT) 
for the treatment of ADHD; behavioral therapies, including school based interventions that were 
initiated less than one month prior to screening; or, behavioral therapy that in the opinion of the 
investigator would interfere with the subject’s ability to participate for the duration of the study. 
School based interventions that have been in place for more than one month prior to screening 
will be allowed. 
Note: 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. 
Subjects should not be enrolled who, in the judgment of the investigator, are expected to start 
substantially different or more intensive course of behavioral therapy over the duration of their 
participation in the study. 
10.5. 
Contraception Requirements 
Female Subjects 
A female subject is eligible to enter and participate in the study if she is of:  
a. Non-childbearing potential (i.e., 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 
screening and agrees to satisfy one of the following requirements: 
− Practice true abstinence (consistent with lifestyle) from signing informed 
consent/assent to at least 14 days after the last dose of study drug; or, 
− Use of medically effective method of birth control from signing informed 
consent/assent 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  
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. 
10.6. 
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. 
Activated charcoal may be of value if administered very soon after a dasotraline overdose (i.e., 
during the absorption process). 


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10.7. 
Cautions 
Dasotraline is an ocular irritant. Therefore appropriate precautions should be taken to avoid 
ocular exposure to the contents of the dasotraline capsules. 
10.8. 
Dietary Guidelines 
Study drug may be taken without regard for food. 
During the practice laboratory classroom session and the laboratory classroom days, meals and 
snacks will be provided as described in the Laboratory Classroom Manual. 


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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, Schedule of Assessments. 
Training, as appropriate, will be provided for study site staff administering each of the 
effectiveness and safety assessments. 
11.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics include date of birth, sex, ethnicity, race, and medical 
history. For medical, psychiatric, and family psychiatric histories, only relevant/significant 
history and recurrence of any condition will be collected. All medications taken during the 
30 days before signed consent/assent will be recorded; data collected will be the same as for 
concomitant medications (see Section 10.3). Weight, height, and BMI collection are described in 
Section 11.4.5. Physical and neurological examinations are described in Section 11.4.4. 
11.2. 
Eligibility Assessments 
Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and 
Lifetime version (K-SADS-PL) 
The K-SADS-PL will be used at screening to confirm the diagnosis of ADHD.  
The K-SADS-PL is a semi-structured diagnostic interview designed to assess current and past 
episodes of psychopathology in children and adolescents according to Diagnostic and Statistical 
Manual for Mental Disorders Fourth Edition; Text Revision (DSM-IV-TR) criteria. The 
K-SADS-PL covers a broad spectrum of most child psychiatric diagnoses, with the exception of 
pervasive development disorders and personality disorders. The K-SADS-PL includes questions 
about school performance and other issues relevant to children and adolescents. There is a base 
instrument (82 items) and 5 required diagnostic supplements which are completed depending on 
the results of the base screening: (1) Affective Disorders; (2) Psychotic Disorders; (3) Anxiety 
Disorders; (4) Behavioral Disorders; (5) Substance Abuse and Other Disorders. 
The K-SADS-PL takes about 45-90 minutes to administer. 
ADHD Rating Scale Version IV - Home Version (modified for investigator administration) 
(ADHD-RS-IV HV) 
The ADHD-RS-IV HV will be used to assess the presence of clinically significant ADHD 
symptoms on Day -1. 
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 


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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. 
11.3. 
Efficacy Assessments 
Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Scale  
The SKAMP is a validated 13-item rating scale that assesses manifestations of ADHD in a 
classroom setting through a combined score and 2 subscale scores; deportment items (interacting 
with other children, interacting with adults, remaining quiet, staying seated, complying with the 
teacher’s directions, and following the classroom rules) and attention items (getting started, 
sticking with tasks, attending to an activity, making activity transitions, completing assigned 
tasks, performing work accurately, and being neat and careful while writing or drawing). 
Permanent Product Measure of Performance (PERMP) 
The PERMP is a 5-page math test consisting of 80 problems per page (total of 400 problems). 
Both attempted problems and correct problems will be assessed. Subjects are to complete as 
many problems as possible in 10 minutes. 
The appropriate math level for each subject is determined based on results of a math pretest 
administered at screening. 
11.4. 
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 either at 
Screening or subsequently during study conduct. 
11.4.1. 
Adverse Events 
Adverse events will be collected for each subject. Parents/guardians should be queried in a non-
leading manner, without specific prompting (if the child has complained about changes in health 
and how the child has been feeling). Subjects should also be queried in a non-leading manner, 
without specific prompting (e.g., “How have you been feeling? Have you felt different?). See 
Section 12, Safety Reporting 
AEs and SAEs will be monitored throughout the study at all visits starting after the first dose of 
study drug. 
Untoward medical occurrences that occur prior to the first dose of study drug will be collected as 
pre-treatment events. 
11.4.2. 
Clinical Laboratory Tests 
The clinical laboratory tests required by protocol are listed in Section 22, Appendix III. 
Blood and urine samples will be collected for clinical laboratory tests. All clinical laboratory 
tests will be performed centrally. For detailed instructions regarding clinical laboratory 
procedures, sampling, and shipping guidelines refer to the Central Laboratory Instructions 
Manual. Samples will be processed at a central laboratory to ensure consistency. All clinical 


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laboratories will be College of American Pathologists (CAP) and Clinical Laboratory 
Improvement Amendments (CLIA) (or equivalent) certified. 
Any POC (point of care) kits that are performed on site by study personnel rather than in a lab- 
must be CLIA waived and the study center must possess a CLIA certificate of Waiver. 
11.4.3. 
Vital Signs 
Respiratory rate and oral body 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. 
11.4.4. 
Physical and Neurological Examinations 
Clinically significant physical examination findings, as judged by the investigator, at screening 
will be recorded as medical history and after screening will be recorded as AEs or pre-treatment 
events depending on the timing in relationship to the first dose of study drug. 
Neurological examination parameters will be assessed by the investigator as normal or abnormal. 
11.4.5. 
Weight and Body Mass Index 
Body weight while wearing street clothes and without shoes will be recorded in kilograms (kg). 
Height without shoes will be recorded in centimeters (cm). Body mass index will be calculated 
by the electronic data capture (EDC) system using height measured at screening and weight from 
the appropriate visit. 
11.4.6. 
ECGs 
Centrally-read ECG: 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 
lab according to established quality assurance procedures for inter/intra reader variability. Refer 
to Section 20, Appendix I for additional information. 
Standard 12 lead ECG will record heart rate (HR), PR interval, RR interval, QT interval, QTc 
with Bazett correction (QTcB) and QTc with Fridericia correction (QTcF) intervals, and QRS 
duration. 
11.4.7. 
Safety Scales 
Columbia Suicide Severity Rating Scale (C-SSRS) Children’s Assessment 


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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. 
This study will utilize 2 versions of the C-SSRS. At the screening visit, the lifetime/recent 
version will be completed; for all subsequent 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. 
11.5. 
Study Visits and Assessments 
11.5.1. 
Screening 
Subjects may be rescreened a maximum of 2 times for out of range clinical laboratory results, 
insufficient medication washout periods, etc. 
11.5.1.1. Visit 1 (Day -35 to -8) 
Subjects will be evaluated at this visit to determine their eligibility to enroll in the study. The 
following study-related procedures will be performed: 
• Obtain informed consent/assent 
• Review inclusion/exclusion criteria 
• Collect medical, psychiatric, and family psychiatric histories 
• Record prior and concomitant medications 
• Perform physical and neurological examinations 
• Measure height and weight, record BMI 
• Collect vital signs 
• Perform ECG 
• Administer K-SADS-PL, C-SSRS lifetime/recent version, ADHD-RS-IV HV, math 
pretest for placement level 
• Collect samples for clinical laboratories (hematology, serum chemistry, TSH, 
urinalysis), UDS, serum pregnancy test for females ≥ 8 years of age 
11.5.1.2. Visit 2 (Day -7): Practice Laboratory Classroom Session 
At this visit the following study-related procedures will be performed: 
• Review inclusion/exclusion criteria  
• ADHD-RS-IV HV. Note: The ADHD-RS-IV HV may be completed in person or by 
telephone contact on Day -9, -8, or -7. 


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• Record prior and concomitant medications 
• Collect vital signs 
• Administer C-SSRS since last visit version 
• Conduct Laboratory Practice Classroom Session. Details are provided in the 
Laboratory Classroom Manual. 
11.5.1.3. Visit 3 (Day -1): Telephone Contact 
The parent/legal guardian of the subject will be contacted by telephone to determine the subject’s 
continued eligibility for the study. The following study-related procedures will be performed: 
• Review inclusion/exclusion criteria  
• Record prior and concomitant medications 
• Administer ADHD-RS-IV HV 
If a subject does not demonstrate an ADHD-RS-IV HV total score ≥ 26 then he or she is not 
eligible to continue in the study. 
11.5.2. 
Double-blind Period 
11.5.2.1. Visit 4 (Day 1): First Laboratory Classroom Day 
At this visit the subject should arrive at the clinic by 6:30 AM and the following study-related 
procedures will be performed: 
• Record prior and concomitant medications 
• Review inclusion/exclusion criteria 
• Measure weight, record BMI 
• Collect vital signs once. 
• Administer C-SSRS since last visit version 
• Collect samples for UDS, urine pregnancy test for females ≥ 8 years of age 
• Randomize to treatment  
• Dispense study drug 
• Provide dosing diary 
• Conduct 7 classroom sessions according to a Laboratory Classroom Manual common 
to all investigational sites.  
Subjects will begin taking double-blind study drug on the evening of Day 1 at approximately 8 
PM plus or minus 30 minutes. The first dose of study drug may be administered in the clinic, 
after all assessments are completed, or at home. 
During the double-blind period, the clinical site will attempt to contact the subject’s parent/legal 
guardian daily with a reminder to administer study drug. 


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11.5.2.2. Visit 5 (Day 15): Second Laboratory Classroom Day 
At this visit the subject should arrive at the clinic by 6:30 AM and the following study-related 
procedures will be performed: 
• Perform study drug accountability 
• Collect dosing diary 
• Record prior and concomitant medications 
• Record AEs 
• Measure weight, record BMI 
• Collect vital signs once. For each subject the time should be the same as on Day 1. 
• Administer C-SSRS since last visit version 
• Collect samples for UDS, urine pregnancy test for females ≥ 8 years of age 
• Conduct 7 classroom sessions according to the Laboratory Classroom Manual. 
11.5.3. 
Visit 6 (Day 21 ± 2): End of Study 
Final safety assessments will be completed at this visit. The following study-related procedures 
will be performed: 
• Record prior and concomitant medications 
• Perform physical and neurological examinations 
• Measure weight, record BMI 
• Collect vital signs 
• Perform ECG 
• Record AEs 
• Administer C-SSRS since last visit version, ADHD-RS-IV HV 
• Collect samples for clinical laboratories (hematology, serum chemistry, urinalysis), 
UDS, serum pregnancy test for females ≥ 8 years of age 
All subjects including those who discontinue study drug prior to completion will be asked to 
return 7 (± 2) days after the last dose of study drug and complete the EOS visit. 
After the EOS visit, all subjects will be referred for continuation of their care as determined by 
the investigator. Additionally, for subjects who complete the study or discontinue for tolerability 
or lack of efficacy reasons, the sponsor will provide support for approved ADHD medication 
costs for up to 3 months after participation in the study, if deemed medically appropriate by the 
subject’s healthcare provider. 


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12. 
SAFETY REPORTING 
12.1. 
Definitions 
12.1.1. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
Untoward medical occurrences that occur between the time of informed consent/assent and first 
study drug administration are pre-treatment events. Those that occur after first administration of 
study drug are considered AEs. 
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 after first administration of study drug 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. 
• 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 (e.g., elective surgery) that was 
scheduled before the study entry, i.e., 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. 
SAE criteria information will be captured on the CRF. 
12.2. 
Objective Findings 
Clinically significant abnormal objective findings (e.g., 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 (e.g., viral hepatitis will be recorded 
as the AE, not transaminase elevation). If a definite diagnosis is not available, then record the 
sign (e.g., clinically significant elevation of transaminase levels) or symptom (e.g., 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 study center. 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 
Screening is indicated as clinically significant and is not covered by the inclusion or exclusion 
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 EOS 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 of Adverse Events 
All pre-treatment events and AEs must be recorded in the subject’s study records/source 
documents in accordance with the Investigator’s normal clinical practice. All pre-treatment 
events and AEs/all AEs must be recorded on the CRF. 
All AEs will be followed 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 Not Changed 
• Not Applicable. 
• Unknown 
The outcome of the AE: 
• Recovered/Resolved 
• Recovering/Resolving 
• Not Recovered/Not Resolved 
• Recovered/Resolved with Sequelae 
• Fatal 


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• 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 center staff becomes aware of a SAE that occurs in a study subject 
after first administration of study drug 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 must be recorded on the CRF and the data recorded should 
agree with 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. 
SAEs will be followed until resolution, loss to follow-up, stabilization of condition, or the event 
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In addition to the initial 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 center staff becoming aware of the event. The SAE form must be signed by 
the Investigator or appropriate designee. PPD-PVG provides the SAE form used to report SAEs. 
The Sponsor or designee will promptly notify all study centers 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) by the Principal Investigator or the appropriate person at the study center if required per 
IRB guidelines. 
12.4.2. 
Pregnancy 
Pregnancies that occur from the time of informed consent/assent 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 commence discontinuation of 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 study center and undergo a 
serum pregnancy test, as confirmation of pregnancy. If positive, the female pregnant 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 center staff becoming aware of the 
pregnancy. The Sponsor provides the Pregnancy Event Form. 
If the subject received blinded study medication, unblinding of the study medication will be 
offered to the subject when knowledge of such treatment may have an impact on further 
treatment decisions. Otherwise, information regarding to what treatment the subject was assigned 
may be provided when the study has ended. 
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 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 the 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 (specify). 
• Lost to follow-up (specify). 
• Pregnancy. 
• Withdrawal by subject (specify). 
• Non-compliance with study drug (specify). 
• Protocol deviation (specify). 
• Death. 
• Other (specify). 
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 (e.g., experiences an AE, becomes 
pregnant), the subject must be discontinued from the study treatment. 
The reason for discontinuation and information will be recorded on the appropriate CRF. In case 
of death, the date of death should be captured on the CRF. 
Subjects who prematurely terminate the study participation may be replaced. 
Subjects who discontinue study drug prior to completion will be asked to return to the clinic and 
complete the EOS visit 7 (± 2) days later (Section 11.5.3). 


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14. 
STUDY TERMINATION 
The Sponsor reserves the right to discontinue the study at this study center or at multiple centers 
for safety or administrative reasons at any time while safeguarding that early termination does 
not compromise subjects’ safety or well-being. In particular, a study center that does not recruit 
at an acceptable rate may be closed. Should the study be terminated and/or the study center 
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 to the clinic and 
complete the EOS visit 7 (± 2) days after their last dose of study drug and provided with access 
to standard care. 


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15. 
STATISTICS 
An analysis of covariance (ANCOVA) will be applied to evaluate the treatment effect for the 
primary efficacy endpoint between the dasotraline 2 mg/day and placebo groups for the intent-to-
treat (ITT) population. The model will include treatment, mean SKAMP-Combined score at 
baseline, and site as fixed effects. The primary efficacy analysis will be repeated for the per 
protocol (PP) population. To explore the robustness of the primary efficacy analysis of change 
from baseline at Day 15 in ADHD symptoms in mean SKAMP-Combined score, 2 sensitivity 
analyses will be performed, a placebo-based multiple imputation pattern-mixture model (PMM) 
and a tipping point analysis using the PMM. 
A similar ANCOVA model, as described above, will be used for the secondary efficacy 
endpoints for the ITT population. 
The Statistical Analysis Plan (SAP) will provide details on the statistical methods planned for 
this study and will be finalized before the study database lock (DBL). 
15.1. 
Sample Size  
A post-hoc ANCOVA-LOCF analysis of data from the SEP360-305 laboratory classroom study 
was conducted to examine the effect of dasotraline 4 mg/day versus placebo in a subset of 
pediatric patients with ADHD aged 6-9 years old. This analysis showed an effect size in this 
subgroup of 0.95 (LS mean difference at Week 2 was 7.2 with a standard error of 2.2). Assuming 
a smaller effect size for dasotraline 2 mg/day vs. placebo than that of dasotraline 4 mg/day vs. 
placebo, an effect size of 0.7 was utilized for the sample size calculation. 
The .7 effect size also derives from a data analysis showing that in a weight-adjusted dose range 
of 0.065 mg/kg to 0.115 mg/kg , the SKAMP effect size was observed to be 0.70. The weight 
adjusted dosing in the proposed study (SEP360-311) will likely range from 0.057 mg/kg to 
0.125 mg/kg given that six year old females are expected to be the lightest subjects (CDC 
estimates 16 kg = 3rd percentile). Thus, the estimated effect size of .7 is a reasonable assumption 
and will be employed in the power and sample size calculation. 
Therefore, assuming an effect size of 0.7 for dasotraline 2 mg/day compared to placebo on the 
primary efficacy endpoint of mean SKAMP-Combined score obtained from the average of 
7 assessments collected across the 12 hour classroom day, 88 subjects (44 per treatment group) 
will provide 90% power to detect a treatment effect between dasotraline and placebo at the 
two-sided alpha level of 0.05, based on the two-sample t-test with equal variance procedure. 
The study will target approximately 100 subjects (50 per treatment group) randomized to either 
placebo or dasotraline 2 mg/day in an attempt to have 88 subjects complete the trial (assuming a 
12% overall dropout rate). 
15.2. 
Analysis Populations 
The analysis populations are defined below. Subjects will be analyzed based on the treatment to 
which they are randomly assigned. 


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ITT (Intent-to-Treat) population: The ITT population is defined as all subjects who are 
randomized. The ITT population will be used for the efficacy analyses. 
Safety population: The safety population includes all subjects who are randomized and receive at 
least 1 dose of study medication. All safety analyses will be performed using the safety 
population. 
Per Protocol (PP) population: The PP population will consist of all subjects from the ITT 
population without any important protocol deviation (see Section 15.3.3). This supplemental 
efficacy population will be used to assess robustness of the primary analysis results. 
15.3. 
Data Analysis 
15.3.1. 
Subject Disposition 
Subject disposition will be summarized for all randomized subjects. Subjects who complete the 
study and discontinue from the study will be summarized. The reason for discontinuation from 
the study will also be presented. 
15.3.2. 
Drug Exposure and Compliance 
A descriptive summary will be performed for exposure to study medication. Treatment 
compliance will be determined and summarized descriptively using the safety population. 
15.3.3. 
Important Protocol Deviations 
Protocol deviations (PDs) will be collected during monitoring visits. Protocol deviations will be 
placed, but not limited to, into the following categories: concomitant medications, dosing, 
enrollment inclusion/exclusion criteria, laboratory, non-compliance, and other. Each instance of 
a protocol deviation will be reviewed and determined to be important or minor before the study 
DBL. 
A summary of protocol deviations will be provided as number (%) of subjects with at least 
1 protocol deviation and number (%) of subjects in each category in all randomized subjects. 
The definition of important protocol deviations will be detailed in the study SAP and the subjects 
with important protocol deviations will be pre-identified (prior to unblinding of the study). 
15.3.4. 
Demographic and Baseline Characteristics 
Demographics (sex, race, ethnicity, age [years], baseline weight [kg], height [cm], and BMI 
[kg/m2]) will be summarized for the safety and ITT populations. Sex, race, age group, and 
ethnicity will be summarized using summary statistics (n and percentage) for categorical 
variables. Age, baseline height, baseline weight, and baseline BMI will be summarized using 
summary statistics (n, mean, standard deviation, median, minimum, and maximum) for 
continuous variables. 
15.3.4.1. Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The count and percentage of subjects under each history term, coded by system 
organ class (SOC) and preferred term (PT) will be summarized using the safety population. 


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15.3.4.2. Psychiatric History 
Psychiatric history will be summarized by DSM-5. The count and percentage of subjects under 
each DSM-5 code will be summarized using the safety population. 
15.3.4.3. Family Psychiatric History 
Family psychiatric history, as reported by the parent/guardian, will be summarized by DSM-5. 
The count and percentage of subjects with any first degree relative (biological parent or sibling) 
considered to have a DSM-5 disorder will be summarized under the DSM-5 disorder deemed 
most appropriate by the rater, using the safety population. 
15.3.5. 
Efficacy Analyses 
15.3.5.1. Primary Efficacy Endpoint Analysis 
The primary endpoint of change from baseline at Day 15 in ADHD symptoms as measured by 
mean SKAMP-Combined score obtained from an average of the 7 assessments collected across 
the 12-hour classroom day (12 to 24 hours postdose) will be evaluated. 
An analysis of covariance (ANCOVA) model will be applied to evaluate the treatment effect for 
the primary efficacy endpoint between the dasotraline 2 mg/day and placebo groups for the ITT 
population. The model will include treatment, mean SKAMP-Combined score at baseline, and 
site as fixed effects. 
In addition, the primary efficacy analysis will be repeated for the PP population. 
15.3.5.2. Secondary Efficacy Endpoint Analysis 
A similar ANCOVA model, as described above, will be used for the secondary efficacy 
endpoints for the ITT population. 
• Change from baseline at Day 15 in SKAMP-Combined score at each of the 
assessment times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours postdose) during the 
classroom day 
• Change from baseline at Day 15 in mean SKAMP-Attention subscale score obtained 
from the 7 assessments collected across the 12 hour classroom day (12 to 24 hours 
postdose) 
• Change from baseline at Day 15 in SKAMP-Attention subscale score at each of the 
assessment times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours postdose) during the 
classroom day 
• Change from baseline at Day 15 in mean SKAMP-Deportment subscale score 
obtained from the 7 assessments collected across the 12 hour classroom day (12 to 
24 hours postdose) 
• Change from baseline at Day 15 in SKAMP-Deportment subscale score at each of the 
assessment times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours postdose) during the 
classroom day 


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• Change from baseline at Day 15 in PERMP-Attempted and Correct Problems scores 
at each of the assessment times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours postdose) 
during the classroom day 
• Mean SKAMP-Combined score from the 7 assessments collected across the 12 hour 
classroom day (12 to 24 hours postdose) on Day 15 
• SKAMP-Combined score at each of the assessment times (12-, 14-, 16-, 18-, 20-, 22-, 
and 24-hours postdose) during the classroom day on Day 15 
• SKAMP-Attention subscale score at each of the assessment times (12-, 14-, 16-, 18-, 
20-, 22-, and 24-hours postdose) during the classroom day on Day 15 
• SKAMP-Deportment subscale score at each of the assessment times (12-, 14-, 16-, 
18-, 20-, 22-, and 24-hours postdose) during the classroom day on Day 15 
• PERMP-Attempted and Correct Problems scores at each of the assessment times (12-, 
14-, 16-, 18-, 20-, 22-, and 24-hours postdose) during the classroom day on Day 15 
• Change from baseline at Day 15 in mean PERMP-Attempted score obtained from an 
average of the 7 assessments collected across the 12-hour classroom day (12 to 
24 hours postdose).  
• Change from baseline at Day 15 in mean PERMP-Correct score obtained from an 
average of the 7 assessments collected across the 12-hour classroom day (12 to 
24 hours postdose). 
• Secondary weight based efficacy analyses will also be conducted on the SKAMP and 
PERMP. 
15.3.5.3. Adjustment for Multiplicity 
There will be no adjustment for multiplicity for the primary efficacy analysis, secondary efficacy 
analyses, or safety analyses. 
15.3.5.4. Subgroup Analysis 
The following safety analyses will be performed using the ITT population. 
• Gender 
• Race 
• Age group (6 - 9 years and 10 - 12 years). 
15.3.6. 
Safety Analyses 
All safety analyses will be performed on the safety population. Unless specifically specified, all 
safety summaries will be presented by descriptive statistics, such as number of subjects (n) and 
percentage for categorical variables and number of subjects (n), mean, standard deviation, 
median, minimum, and maximum for continuous variables. 


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15.3.6.1. Adverse Events 
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 19.0 or higher. AEs are untoward medical occurrences: 
• that occurred on or after the first dose of study medication, 
• with a missing start date and a stop date on or after the first dose of study medication, 
or 
• with both a missing start and stop date. 
AEs will be summarized by treatment and by MedDRA system organ class (SOC) and Preferred 
Term (PT). 
The following AEs will be summarized and presented by treatment group and by MedDRA SOC 
and PT for the Safety population: 
• All AEs (including number of events and subject incidence). 
• Serious AEs. 
• AEs leading to discontinuation. 
• AEs by maximum severity (mild, moderate, severe). 
• AEs by relationship to the study treatment (related, or not related). 
• Serious AEs by relationship to the study treatment. 
• AEs leading to death. 
The following conventions will be followed in summarizing AEs: 
• For subject incidence summaries, each subject will be counted only once within each 
SOC and within each preferred term. 
• If a subject reports more than one AE within a preferred term and/or a body system, 
the AE with the highest known severity within each body system and within each 
preferred term will be included in the summaries by severity. 
• For summaries by relationship to the study medication, AEs will be grouped as 
“related” or “not related.” AEs assessed as “possible,” “probable,” or “definite,” will 
be grouped as “related.” If a subject reports more than one AE within the same 
treatment regimen, SOC and PT, and any are related, it will be summarized as related. 
AEs whose relationship to treatment is assessed as “not related” or “unlikely” will be 
grouped as “not related.” 
A listing of AEs, as well as a listing of deaths, SAEs, or AEs leading to discontinuation, will be 
presented. 
A listing of AEs of special concern and AEs leading to discontinuation, stratified by weight, will 
be presented. 
 


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15.3.6.2. Clinical Laboratory Assessments 
Summary statistics for protocol-specified laboratory parameters (hematology, serum chemistry, 
and urinalysis) will be provided. Laboratory data will also be summarized by presenting shift 
tables, by presenting summary statistics of raw data and change from baseline values (means, 
standard deviations, medians, ranges), and by the flagging of abnormal values in data listings. 
15.3.6.3. ECGs 
Electrocardiogram interval data (ventricular heart rate, RR, PR, QRS, QT, QTc, QTcB, and 
QTcF) will be summarized using descriptive statistics for baseline, each postdose evaluation, and 
change from baseline to each postdose evaluation. 
15.3.6.4. Vital Signs 
Vital signs (respiratory rate, body temperature, supine and standing blood pressure, supine and 
standing pulse rate, body weight) will be summarized at each visit for the absolute value and 
change from baseline using descriptive statistics. 
15.3.6.5. Neurological Examination 
Neurological examination assessments will be summarized using summary statistics for 
categorical variables (normal/abnormal) by visit. A shift table for baseline condition vs the worst 
result during the course of the study period (Abnormal > Normal) will be presented by treatment. 
15.3.6.6. Concomitant Medications 
All medications will be coded using World Health Organization drug dictionary (WHO-DD). 
The prior medications will include medications reported by the subject that started within 
30 days prior to screening. The concomitant medications will include medications started on or 
after the first dose date of study drug 
Frequency counts and percentages of previous and concomitant medications will be presented by 
the WHO-DD Anatomic Therapeutic Chemical (ATC) classification and preferred term for each 
subject group. 
15.3.6.7. Columbia-Suicide Severity Rating Scale (C-SSRS) 
The number of subjects having any suicidal behavior or suicidal ideation from the C-SSRS 
evaluation will be summarized. 
15.3.6.8. Subgroup Analysis 
No subgroup analysis will be conducted for safety endpoints. 
15.3.7. 
Treatment of Missing Data 
Missing data handling for efficacy endpoints will be detailed in the statistical analysis plan 
(SAP). No missing data handling will be applied for safety endpoints. 


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15.3.8. 
Sensitivity Analyses 
To explore the robustness of the primary efficacy analysis of change from baseline at Day 15 in 
ADHD symptoms in mean SKAMP-Combined score, 2 sensitivity analyses will be performed, a 
placebo-based multiple imputation pattern-mixture model (PMM) and a tipping point analysis 
using the PMM. The detail of the sensitivity analyses will be documented in the final SAP. 


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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 Screening and data collected during the study (except clinical laboratory test 
results) will be recorded in the subject’s electronic CRF. K-SADS-PL, C-SSRS, 
ADHD-RS-IV HV, SKAMP, and PERMP will be completed on paper and then entered into the 
electronic data capture (EDC) system. The study centers will use an EDC system that is 
compliant with relevant FDA regulatory requirements per 21 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. 
Table 7: 
Computerized Systems Used for Source Data 
Protocol Step  
Computerized System Type or Description 
Obtain informed consent 
A 
Obtain informed assent 
A 
Inclusion/Exclusion criteria 
A 
Randomization 
A,D 
Dispense study drug 
A,D 
Study drug accountability 
A 
Medical History 
A 
Psychiatric History 
A 
Prior/concomitant medication review 
A 
K-SADS-PL 
A 
Physical examination 
A 
Neurological examination 
A 
Height 
A 
Weight (including body mass index) 
A 
Vital signs 
A 


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Table 7: 
Computerized Systems Used for Source Data (Continued) 
Protocol Step  
Computerized System Type or Description 
Electrocardiogram (ECG) 
C 
Adverse event monitoring 
A 
Columbia Suicide Severity Rating Scale (C-SSRS) 
A 
ADHD-RS-IV HV 
A 
Classroom Practice Session 
A 
SKAMP 
A 
Math pretest for determination of math level 
A 
PERMP 
A 
Dosing diary distribution/review 
A 
Hematology/Chemistry 
B 
TSH 
B 
Serum β-hCG (in females ≥ 8 years of age) 
B 
Urinalysis 
B 
Urine drug screen 
A 
Urine β-hCG (in females ≥ 8 years of age) 
A 
Statistical analysis 
SAS®, version 9 or higher 
 A = EDC (Medidata Rave®); B = LIMS; C = Core Lab Over-read; D = IXRS.  
 Abbreviations: ADHD-RS-IV HV = ADHD Rating Scale Version IV Home Version (modified for investigator 
administration), β-hCG = beta-human chorionic gonadotropin, EDC = electronic data capture; IXRS = interactive 
recognition system; K-SADS-PL = Schedule for Affective Disorders and Schizophrenia for School-Age 
Children- Present and Lifetime version, LIMS = laboratory information management system, 
PERMP = Permanent Product Measure of Performance, SKAMP = Swanson, Kotkin, Agler, M-Flynn, and Pelham 
Scale, TSH = thyroid stimulating hormone. 
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 granting consent/assent 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 


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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 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 Good 
Clinical Practice (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 
Documented approval for conducting the study from appropriate Institutional Review Board 
(IRB) will be obtained for all participating study 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 approval must be obtained and also forwarded to the Sponsor. 
The IRB must supply the Sponsor a list of the IRB membership, and a statement to confirm that 
the IRB is organized and operates according to ICH GCP, applicable law(s) and regulation(s). 
A copy of written IRB approval or favorable opinion of the protocol, informed consent 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 chairman or designee 
identify the IRB 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 complies with the requirements in 21 CFR Part 56 for a study conducted 
under a US Investigational New Drug (IND) or ICH GCP, as applicable. 
The Investigator/CRO is responsible for obtaining from the IRB continued review of the clinical 
research or submitting periodic progress reports, in accordance with applicable regulations, at 
intervals not to exceed one year and (if applicable) as otherwise additionally specified by the 


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IRB. The Sponsor must be supplied with written documentation of continued review of the 
clinical research. 
The Investigator must promptly inform their IRB 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 form and informed assent form will be approved by the Sponsor/CRO 
prior to submission to the IRB. The Sponsor/CRO may provide a template informed consent/ 
informed 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 approval. The Sponsor/CRO may submit informed consent forms to a central IRB 
for review and approval or favorable opinion contingent upon prior Investigator permission and 
review. 
Before recruitment and enrollment, each prospective subject/parent/legal guardian will be given 
a full explanation of the study, allowed to read the approved informed consent form and assent 
form(s), as appropriate, 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 
to participate in the study by signing the informed consent and assent form(s), as appropriate. As 
part of the consent process, each prospective subject and at least one parent/legal guardian must 
consent to direct access to the subject’s medical records for study-related monitoring, auditing, 
IRB 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/parent/legal guardian will continue to participate in the 
study through the final visit/assessment. The Investigator will provide a copy of the signed 
informed consent form and assent forms to each subject/parent/legal guardian, and will record 
the date of the informed consent and assent 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(s) must be revised, 
submitted to the IRB for review and approval or favorable opinion. The revised informed 
consent/assent form(s) 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 from any new subjects who are enrolled into the study after the 
date of the approval or favorable opinion of the protocol amendment. 
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 only; full names will be masked 


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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. 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, except 
where necessary to eliminate an apparent immediate hazard to a study subject. 
Emergency deviations or modifications may be initiated without Sponsor or IRB 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 immediately/within 5 business days of the occurrence, 
or in accordance with applicable regulatory requirements. 
17.6. 
Records Retention 
The Investigator/the study center must arrange for retention of study records at the study center 
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 study center 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 and, 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. 
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 


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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. 
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;35:1097-1108. 
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. 
Childress AC, Brams M, Kollins SH, Northcutt J, Padilla A, Turnbow JM. The efficacy and 
safety of Evekeo, racemic amphetamine sulfate, for treatment of attention-deficit/hyperactivity 
disorder Symptoms: A multicenter, dose-optimized, double-blind, randomized, placebo-
controlled crossover laboratory classroom study. Journal of Child and Adolescent 
Psychopharmacology. 2015;25(5):402-14. 
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. 
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.  
Koblan KS, Hopkins SC, Sarma K, Gallina N, Jin F, et al. Assessment of human abuse potential 
of dasotraline compared to methylphenidate and placebo in recreational stimulant users. Drug 
and Alcohol Dependence 2016;159:26–34. 
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. 


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Passarotti AM, Pavuluri MN. Brain functional domains inform therapeutic interventions in 
attention deficit/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. 
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. 
Wigal S, Greenhill L, Nordbrock E, Connor D, Kollins SH, Adjei A, Childress A, Stehli A, 
Kupper R. A randomized placebo-controlled double-blind study evaluating the time course of 
response to methylphenidate hydrochloride extended-release capsules in children with attention-
deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology 
2014;24(10):562-9. 
Wigal SB and Wigal TL. The Laboratory School Protocol: Its Origin, Use, and New 
Applications. J Atten Disord 2006;10; 92-111. 
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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19. 
INVESTIGATOR APPROVAL 
I have read the protocol, SEP360-311, Version 3.00, “Dasotraline (2mg) in Children Aged 6 to 
12 Years with Attention-Deficit Hyperactivity Disorder (ADHD): A Randomized, Multicenter, 
Double-blind, Placebo-controlled, Parallel-group Study of Efficacy and Safety in a Laboratory 
Classroom Setting”, 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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20. 
APPENDIX I. CARDIAC SAFETY MONITORING (ECG) 
1. Requirements for Testing 
ECG equipment and supplies will be provided by 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 study center 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. 
2. Subject Restrictions and Instructions 
• Prior to ECG acquisition, the subject will have rested 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 study 
center 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 study center. 
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. BODY MASS INDEX DETERMINATION 
Body mass index (BMI) will be calculated by measuring the subject’s height and weight (both 
determined without subject wearing shoes) and using these measurements (in centimeters and 
kilograms) in the following formula. 
Formula: 
BMI = weight (kg) ÷ [height (m) x height (m)] 
BMI will be automatically calculated at screening by EDC, and not by the site staff. 


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22. 
APPENDIX III. CLINICAL LABORATORY TESTS 
The following clinical laboratory tests are to be performed. 
 
Clinical Safety Panel 
HEMATOLOGY: (Differential reported as % and absolute value) 
Hemoglobin, Hematocrit, Platelet Count, RBC Count, WBC - Total Count, WBC Differential, 
(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: Thyroid stimulating hormone (TSH) 
 
URINE DRUG SCREENING: Amphetamines, Barbiturates, Benzodiazepines, Cannabinoids, 
Cocaine, Cotinine, Methamphetamines, Methadone, Methylenedioxymethamphetamine 
(MDMA), Phencyclidine (PCP), Opiates, Oxycodone 
 
OTHER TESTS: Serum Pregnancy (β-HcG) (in female subjects only ≥ 8 years of age), Urine 
Pregnancy Test (in female subjects only ≥ 8 years of age) 
Laboratory reports will be initialed and dated on all pages by the Investigator listed on the Form 
FDA 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. 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 
4 March 2016. 
 


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24. 
APPENDIX V. GROWTH CHART (MALE). 
 


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25. 
APPENDIX VI. GROWTH CHART (FEMALE). 
 

SAP_001.pdf: 
Sunovion Pharmaceuticals Inc. 
 
Statistical Analysis Plan 
Protocol No. SEP360-311 
 
26 March 2019 
Version:  1.0 
 
Page 1 of 59 
 
STATISTICAL ANALYSIS PLAN 
 
 
Dasotraline (2mg) in Children Aged 6 to 12 Years with Attention-Deficit Hyperactivity 
Disorder (ADHD): A Randomized, Multicenter, Double-blind, Placebo-controlled, 
Parallel-group Study of Efficacy and Safety in a Laboratory Classroom Setting 
 
Protocol SEP360-311 
 
 
 
 
 
 
SPONSORED BY 
 
Sunovion Pharmaceuticals Inc. 
84 Waterford Drive 
Marlborough, MA 01752, USA 
(508) 481-6700 
 
 
 
PREPARED BY 
 
Rho, Inc. 
6330 Quadrangle Drive 
Chapel Hill, NC  27517 
 
 
 
 
 
 
 
 
 
 
This document is confidential and proprietary to Sunovion Pharmaceuticals Inc.  Acceptance of this 
document constitutes agreement by the recipient that no unpublished information contained herein will be 
reproduced, published, or otherwise disclosed without the prior written approval of Sunovion except that 
this document may be disclosed to appropriate Institutional Review Boards under the condition that they 
keep the information confidential. 


Sunovion Pharmaceuticals Inc. 
 
Statistical Analysis Plan 
Protocol No. SEP360-311 
 
26 March 2019 
Version:  1.0 
 
Page 2 of 59 
DOCUMENT VERSION CONTROL 
 
Version 
Number 
Date 
Comments/Changes 
1.0 
26 March 2019 
Original SAP. 
 
 


Sunovion Pharmaceuticals Inc. 
Protocol No. SEP360-311 
Statistical Analysis Plan 
26 March 2019 
APPROVALS 
Approved: 
 
 
 
 
 
 
 
Approved: 
Approved: 
Reviewer: 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version: 1.0 
Page 3 of 59 


Sunovion Pharmaceuticals Inc. 
 
Statistical Analysis Plan 
Protocol No. SEP360-311 
 
26 March 2019 
Version:  1.0 
 
Page 4 of 59 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................. 6 
1. PURPOSE OF THE STATISTICAL ANALYSIS PLAN .................................. 8 
2. PROTOCOL SUMMARY ................................................................................ 9 
2.1 
Study Objectives .................................................................................. 9 
2.2 
Overall Study Design and Plan ............................................................ 9 
2.3 
Study Population ................................................................................ 12 
2.4 
Method of Assigning Subjects to Treatment Groups .......................... 12 
2.5 
Treatment Regimens .......................................................................... 13 
2.6 
Sample Size Determination ................................................................ 13 
3. GENERAL ANALYSIS, REPORTING, AND PROGRAMMING CONVENTIONS
 ...................................................................................................................... 14 
4. ANALYSIS POPULATIONS ......................................................................... 16 
4.1 
Intent-to-Treat Population .................................................................. 16 
4.2 
Safety Population ............................................................................... 16 
4.3 
Per-Protocol Population ..................................................................... 16 
4.4 
Disposition of Patients ........................................................................ 16 
4.5 
Protocol Deviations ............................................................................ 17 
5. DEMOGRAPHICS AND BASELINE CHARACTERISTICS ......................... 19 
5.1 
Prior, Concomitant, and Post-Treatment Medications ........................ 19 
5.2 
Medical History ................................................................................... 20 
5.3 
Psychiatric History .............................................................................. 20 
5.4 
Family Psychiatric History .................................................................. 20 
6. MEASUREMENT OF TREATMENT COMPLIANCE .................................... 21 
7. EFFICACY EVALUATION ............................................................................ 22 
7.1 
Overview of Efficacy Analysis Issues ................................................. 22 
7.1.1 
Handling of Dropouts or Missing Data ....................................... 22 
7.1.1.1 
Missing Individual Items in the SKAMP Scale ....................... 22 
7.1.1.2 
Missing SKAMP Combined Scores at Individual Time Points 22 
7.1.2 
Multicenter Studies .................................................................... 24 
7.1.3 
Assessment Time Windows....................................................... 25 
7.2 
Efficacy Measurements ...................................................................... 25 
7.2.1 
Swanson, Kotin, Agler, M-Flynn, and Pelham (SKAMP) Rating 
Scale ......................................................................................... 25 
7.2.2 
Permanent Product Measurement of Performance (PERMP) ... 26 
7.3 
Eligibility Criteria and ADHD Symptom Control Assessments ............ 26 
7.3.1 
Schedule for Affective Disorders and Schizophrenia for School-Age 
Children Present and Lifetime version (K-SADS-PL) ................. 26 
7.3.2 
ADHD Rating Scale Version IV - Home Version (modified for 
investigator administration) (ADHD-RS-IV HV) .......................... 27 
7.4 
Efficacy Outcomes ............................................................................. 27 
7.4.1 
Primary Efficacy Outcome ......................................................... 27 


Sunovion Pharmaceuticals Inc. 
 
Statistical Analysis Plan 
Protocol No. SEP360-311 
 
26 March 2019 
Version:  1.0 
 
Page 5 of 59 
7.4.2 
Secondary Efficacy Outcomes................................................... 27 
7.5 
Analysis Methods ............................................................................... 29 
7.5.1 
Primary Efficacy Analyses ......................................................... 29 
7.5.2 
Secondary Efficacy Analyses .................................................... 30 
7.5.3 
Examination of Subgroups ........................................................ 32 
8. SAFETY EVALUATION ............................................................................... 33 
8.1 
Overview of Safety Analysis Issues ................................................... 33 
8.2 
Overview of Safety Analysis Methods ................................................ 33 
8.3 
Extent of Exposure ............................................................................. 34 
8.4 
Adverse Events .................................................................................. 34 
8.5 
Adverse Events of Special Concern ................................................... 37 
8.6 
Clinical Laboratory Evaluations .......................................................... 37 
8.7 
Physical and Neurological Examinations ........................................... 38 
8.8 
Vital Signs .......................................................................................... 38 
8.9 
Electrocardiography (ECG) ................................................................ 39 
8.10 
Columbia Suicide Severity Rating Scale (C-SSRS) ........................... 39 
9. PHARMACOKINETIC EVALUATION .......................................................... 41 
10. OTHER ANALYSES ..................................................................................... 42 
11. INTERIM ANALYSES AND DATA MONITORING ....................................... 43 
12. CHANGES TO STUDY CONDUCT OR ANALYSES PLANNED IN THE 
PROTOCOL ................................................................................................. 44 
12.1 
Changes in the Conduct of the Study ................................................. 44 
12.2 
Changes in the Analysis Planned in the Protocol ............................... 44 
13. REFERENCES ............................................................................................. 45 
14. APPENDICES .............................................................................................. 46 
14.1 
Schedule of Events ............................................................................ 46 
14.2 
Sample Laboratory Classroom Day Schedule (Day 15) ..................... 48 
14.3 
SKAMP Rating Scale and Subscales ................................................. 49 
14.4 
Laboratory Criteria for Markedly Abnormal Values ............................. 50 
14.5 
Vital Signs Criteria for Markedly Abnormal Values ............................. 51 
14.6 
12-Lead ECG Criteria for Markedly Abnormal Values ........................ 52 
14.7 
Preferred Term for Adverse Events of Special Concern .................... 52 
 


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Protocol No. SEP360-311 
 
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LIST OF ABBREVIATIONS 
Commonly used abbreviations (such as units and abbreviations used for 
electrocardiogram assessments) are not included in this list. 
Abbreviation 
Definition 
ADHD 
attention deficit hyperactivity disorder 
ADHD-RS-IV HV 
ADHD Rating Scale Version IV Home Version based on DSM-
IV criteria 
AE(s) 
adverse event(s) 
ANCOVA 
analysis of covariance 
ATC 
Anatomic Therapeutic Chemical 
CSR 
clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, Fourth 
Edition 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
ECG 
electrocardiogram  
EOS 
End of Study 
ICH 
International Conference on Harmonization 
ITT 
intent-to-treat 
LS Mean 
least-squares mean 
MAPLV 
Markedly abnormal post-baseline values 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
PCS 
potentially clinically significant 


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Protocol No. SEP360-311 
 
26 March 2019 
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Abbreviation 
Definition 
PERMP 
Permanent Product Measure of Performance 
PERMP-A 
PERMP-number of PERMP problems attempted 
PERMP-C 
PERMP-number of PERMP problems correctly completed 
PMM 
pattern mixture model 
PP 
per protocol 
PT 
preferred term 
RBC 
red blood cell 
ROC 
Receiver Operating Characteristic 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SKAMP 
Swanson, Kotin, Agler, M-Flynn, and Pelham Rating Scale 
SKAMP-CS 
SKAMP-Combined Score 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
WBC 
white blood cell 
WHO 
World Health Organization 
WHO DRUG E 
World Health Organization – Enhanced Drug Dictionary 
 
 


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Statistical Analysis Plan 
Protocol No. SEP360-311 
 
26 March 2019 
Version:  1.0 
 
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1. 
PURPOSE OF THE STATISTICAL ANALYSIS PLAN 
The purpose of the analyses described in this document is to compare the safety and 
efficacy of dasotraline to placebo in pediatric patients with attention deficit hyperactivity 
disorder (ADHD). 
The statistical analysis plan (SAP) is written with due consideration of the 
recommendations outlined in the most recent International Conference on 
Harmonization (ICH) E9 Guideline entitled Guidance for Industry: Statistical Principles 
for Clinical Trials [1] and the most recent ICH E3 Guideline, entitled Guidance for 
Industry: Structure and Content of Clinical Study Reports [2]. 
This SAP describes the populations that will be analyzed, the subject characteristics 
parameters, the efficacy parameters, and the safety parameters.  The details of the 
specific statistical methods that will be used will be provided.  If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be 
completed and will be identified in the clinical study report (CSR).  Table, figure, and 
listing specifications are provided in separate documents. 
 
 


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Protocol No. SEP360-311 
 
26 March 2019 
Version:  1.0 
 
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2. 
PROTOCOL SUMMARY 
2.1 Study Objectives 
The primary objective of this study is to evaluate the efficacy of dasotraline 2 
mg/day compared to placebo on attention-deficit hyperactivity disorder (ADHD) 
symptoms in children (6 – 12 years of age), who weigh ≤ 30 kg, in a laboratory 
classroom setting as measured by the change from baseline at Day 15 in SKAMP 
Combined Score (SKAMP-CS). 
The secondary objectives are to evaluate the efficacy of dasotraline 2 mg/day 
compared to placebo on ADHD symptoms throughout the day (12 to 24 hours 
post-dose) in children in a laboratory classroom setting and to evaluate the safety 
and tolerability of dasotraline 2 mg/day using physical examinations, 12-lead 
electrocardiograms (ECG), vital signs, adverse event (AE) reports, clinical 
laboratory results, and the Columbia – Suicide Severity Rating Scale (C-SSRS) 
Children’s Assessment. 
2.2 Overall Study Design and Plan 
This is a randomized, double-blind, placebo-controlled, parallel-group, efficacy 
and safety study in children with ADHD in a laboratory classroom setting. The 
study will target 100 subjects (50 per treatment group) in an attempt to have 88 
subjects complete the study (assuming a 12% overall dropout rate). Completers 
will be defined as any subject who participates throughout the duration of the 
study, up to and including both visits 5 and 6. 
The study will be comprised of 3 periods:  
1. 
Period 1: Screening (up to 42 days) including a 3 - 5 day ADHD 
medication washout, if necessary, prior to Day -1; 
2. 
Period 2: Double-blind randomized treatment with either dasotraline 
2 mg/day or placebo for 14 days; and 
3. 
Period 3: End of Study (EOS) visit (7 (± 2) days after last dose)  
Prior to the start of treatment (Day 1) and following the conclusion of the 14-day 
double-blind period (Day 15), subjects will undergo a full-day laboratory classroom 
evaluation in cohorts of up to 18 subjects. Each laboratory classroom day will 
include seven 30-minute simulated classroom sessions where trained observers 
will assess subjects using the Swanson, Kotin, Agler, M-Flynn, and Pelham 
(SKAMP) Rating Scale. In addition during each classroom session, a 10-minute 


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Protocol No. SEP360-311 
 
26 March 2019 
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math test (Permanent Product Measure of Performance [PERMP]) will be 
administered to evaluate sustained attention and effort. The appropriate math 
level for each subject is determined based on results of the math pre-test 
administered during the laboratory classroom practice session at screening. 
The primary efficacy endpoint will be the change from baseline to Day 15 in 
ADHD symptoms as measured by the mean SKAMP-Combined score, obtained 
from an average of the 7 SKAMP assessments collected across the 12-hour 
classroom day. 
Safety and tolerability will be monitored throughout the study by physical and 
neurological examinations, 12-lead ECG, vital signs, AEs, clinical laboratory 
evaluations (hematology, chemistry, and urinalysis), and the C-SSRS. 
Screening: The screening period will be completed within a maximum of 42 days 
prior to the first dose of study drug and will begin with acquisition of informed 
assent from the subject and informed consent from at least one of the subject’s 
parents/legal guardians. 
Subjects will be confirmed as meeting DSM-5 criteria for a diagnosis of ADHD. 
Subjects may be either currently untreated or receiving stimulant ADHD 
medication at Screening.  On Day -7 the ADHD Rating Scale Version IV - Home 
Version (modified for investigator administration) (ADHD-RS-IV HV) will be 
completed and subjects will attend a half-day practice laboratory classroom 
session intended to familiarize them with classroom schedules and procedures 
related to SKAMP evaluations, PERMP tests, and other planned activities. Any 
subjects receiving stimulant medication for ADHD will discontinue that ADHD 
treatment for 3-5 days prior to Day -1 in order to ensure that there is at least a 72-
hour washout before the assessment of ADHD symptoms on Day -1. The day 
before randomization, the subject’s parent/legal guardian will be contacted by 
study site staff in order to confirm the presence of clinically significant ADHD 
symptoms since discontinuation of stimulant medication. Clinically significant is 
defined as an ADHD-RS-IV HV total score ≥ 26 following a minimum 72-hour 
washout from any prior ADHD treatment. Subjects who do not demonstrate 
clinically significant ADHD symptoms (i.e., ADHD-RS-IV ≥ 26) on Day -1 will be 
considered screen failures and will not be eligible for randomization. 
Double-blind Period: On Day 1 subjects will return to the clinic in the morning 
and those meeting all inclusion and no exclusion criteria will be randomized (1:1) 
to receive 2 mg/day dasotraline, or placebo, and will attend classroom sessions in 
which they will be evaluated for ADHD symptoms using the SKAMP assessment. 
During this baseline classroom assessment (Day 1), subjects will be evaluated at 
regular intervals: approximately 8 AM, 10 AM, 12 PM, 2 PM, 4 PM, 6 PM, and 8 


Sunovion Pharmaceuticals Inc. 
 
Statistical Analysis Plan 
Protocol No. SEP360-311 
 
26 March 2019 
Version:  1.0 
 
Page 11 of 59 
PM. Subjects will begin taking study drug on the evening of Day 1 (with or without 
food) after the final, 8:00 PM baseline classroom assessment.  Subjects will take 
one dose each evening before bedtime for a total of 14 days. Study drug should 
be taken at approximately the same time each evening. The first dose of study 
drug may be administered in the clinic after all assessments are completed and 
before the subject leaves, or at home. On the night (Day 14) before the second 
classroom day, study drug must be taken at 8 PM plus or minus 30 minutes. 
During the double-blind period, the clinical site will attempt to contact the subject’s 
parent/legal guardian daily with a reminder to administer study drug. A dosing 
diary will be provided to the parent/legal guardian to record the date and time of 
each administration of study drug. On Day 15 subjects will return to the clinic in 
the morning at 6:30 AM and classroom sessions will be started at approximately 8 
AM, 10 AM, 12 PM, 2 PM, 4 PM, 6 PM and 8 PM to coincide with 12, 14, 16, 18, 
20, 22, and 24 hours following the Day 14 dose. 
End of Study: Seven (± 2) days after the last dose of study drug, all subjects will 
return to the clinic and complete assessments. After the EOS visit, all subjects will 
be referred for continuation of their care as determined by the investigator. 
Additionally, for subjects who complete the study or discontinue for tolerability or 
lack of efficacy reasons, the sponsor will provide support for approved ADHD 
medication costs for up to 3 months after participation in the study, if deemed 
medically appropriate by the subject’s healthcare provider. 
A study schematic is presented in  
 


Sunovion Pharmaceuticals Inc. 
 
Statistical Analysis Plan 
Protocol No. SEP360-311 
 
26 March 2019 
Version:  1.0 
 
Page 12 of 59 
Figure 1. Details of the study assessments and other procedures to be performed 
at each visit are presented in Appendix 14.1, Schedule of Events. If necessary, 
subjects may return to the clinic at any time for an unscheduled visit. The timing of 
events during a sample laboratory classroom day is provided in Appendix 14.2. 
 
 


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Sunovion Pharmaceuticals Inc. 
 
Statistical Analysis Plan 
Protocol No. SEP360-311 
 
26 March 2019 
Version:  1.0 
 
Page 14 of 59 
Study medication will be assigned by an IXRS based on the randomization schedule. 
The IXRS will generate instructions on which medication number to assign to a subject. 
2.5 Treatment Regimens 
Under supervision from the subject’s parent/legal guardian, subjects will self-administer 
the study drug on an outpatient basis for 14 days beginning the evening of Day 1. Study 
drug should be taken at approximately the same time each evening. The first dose of 
study drug may be administered in the clinic, after all assessments are completed, 
before the subject leaves, or at home. On Day 14, the night before the second 
classroom day, study drug must be taken at 8 PM plus or minus 30 minutes. All study 
medication doses will consist of 1 capsule per day taken by mouth. 
2.6 Sample Size Determination 
A post-hoc ANCOVA-LOCF analysis of data from the SEP360-305 laboratory 
classroom study was conducted to examine the effect of dasotraline 4 mg/day versus 
placebo in a subset of pediatric patients with ADHD aged 6-9 years old. This analysis 
showed an effect size in this subgroup of 0.95 (LS mean difference at Week 2 was 7.2 
with a standard error of 2.2). Assuming a smaller effect size for dasotraline 2 mg/day vs. 
placebo than that of dasotraline 4 mg/day vs. placebo, an effect size of 0.7 was utilized 
for the sample size calculation. 
The 0.7 effect size also derives from a data analysis showing that in a weight-adjusted 
dose range of 0.065 mg/kg to 0.115 mg/kg, the SKAMP effect size was observed to be 
0.70. The weight adjusted dosing in the proposed study (SEP360-311) will likely range 
from 0.057 mg/kg to 0.125 mg/kg given that six year old females are expected to be the 
lightest subjects (CDC estimates 16 kg = 3rd percentile). Thus, the estimated effect size 
of .7 is a reasonable assumption and will be employed in the power and sample size 
calculation. 
Therefore, assuming an effect size of 0.7 for dasotraline 2 mg/day compared to placebo 
on the primary efficacy endpoint of mean SKAMP-Combined score obtained from the 
average of 7 assessments collected across the 12 hour classroom day, 88 subjects (44 
per treatment group) will provide 90% power to detect a treatment effect between 
dasotraline and placebo at the two-sided alpha level of 0.05, based on the two-sample 
t-test with equal variance procedure. 
The study will target approximately 100 subjects (50 per treatment group) randomized 
to either placebo or dasotraline 2 mg/day in an attempt to have 88 subjects complete 
the trial (assuming a 12% overall dropout rate). 


Sunovion Pharmaceuticals Inc. 
 
Statistical Analysis Plan 
Protocol No. SEP360-311 
 
26 March 2019 
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3. 
GENERAL ANALYSIS, REPORTING, AND PROGRAMMING 
CONVENTIONS 
This section discusses general policies to be employed in the analysis and reporting of 
the data from the study.  Departures from these general policies may be given in the 
specific detailed sections of this SAP.  When this situation occurs, the rules set forth in 
the specific section take precedence over the general policies. 
All continuous study assessments will be summarized by treatment group (2 mg/day 
dasotraline and placebo) and time point (as applicable) using descriptive statistics (n, 
mean, median, standard deviation, minimum, and maximum). All categorical study 
assessments will be summarized by treatment group and time point (as applicable) 
using frequency counts and percentages.  All study data will be listed by subject, 
treatment group, and time point (as applicable).   
Hypothesis testing, unless otherwise indicated, will be 2-sided and performed at the 5% 
significance level.  When confidence intervals are presented, they will be 2-sided with a 
confidence coefficient of 95%.  P-values will be reported to 3 decimal places if greater 
than 0.001.  If less than 0.001, ‘<0.001’ will be displayed.  P-values and significance 
levels will be reported as 0.05 rather than .05. 
No preliminary rounding will be performed; rounding will only occur after analysis.  To 
round, the digit to right of last significant digit will be considered:  if <5 then round down, 
if ≥5 then round up.  Minimums and maximums will be presented with the same 
precision as the original data.  Means and medians will be presented with one more 
decimal place than the precision of the data.  Standard deviations will be presented with 
two more decimal places than the precision of the data.  Percentages will be presented 
with one decimal place.   
Medical history and AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 19.0.  Medications will be coded with the World Health 
Organization – Enhanced Drug Dictionary (WHO DRUG E, 2016 Q1 version). 
All analyses will be performed using the SAS System® version 9.3 or higher. 
The following general programming conventions will apply: 
Exposure days:  (Last dosing date – first dosing date + 1) 
Compliance: [(Number of doses taken)/(number of doses planned)]*100 
Duration days: (End/resolution date – start/onset date +1) 


Sunovion Pharmaceuticals Inc. 
 
Statistical Analysis Plan 
Protocol No. SEP360-311 
 
26 March 2019 
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Study day: (Date of interest – first dosing date + 1) if date of interest is on or after the 
first dosing date.  (Date of interest – first dosing date) if date of interest is before the first 
dosing date. 
 
 
 
 


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26 March 2019 
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4. 
ANALYSIS POPULATIONS 
The 3 analysis populations are defined below. Subjects will be analyzed based on the 
treatment to which they are randomly assigned.  Identification of the subjects to be 
included in each analysis population will be determined prior to database unblinding.  
The database will be locked and unblinded after the SAP is signed and authorized, 
there are no outstanding data issues, and the final analysis populations are imported 
into the study database. 
4.1 Intent-to-Treat Population 
The Intent-to-Treat (ITT) population is defined as all subjects who are randomized. The 
ITT population will be used for the efficacy analyses.  Efficacy data will be analyzed 
according to the treatment the subject was randomized to receive. 
4.2 Safety Population 
The safety population includes all subjects who are randomized and receive at least 1 
dose of study medication. All safety analyses will be performed using the safety 
population. 
Safety data will be analyzed according to the treatment the subject actually received, 
regardless of the treatment to which the subject was originally randomized.  For 
subjects who inadvertently received treatment from more than one treatment arm due to 
site conduct error, the subject will be categorized by the treatment he/she received the 
most.  
4.3 Per-Protocol Population 
The per-protocol (PP) population is defined as all subjects from the ITT population 
without any important protocol deviations (see Section 4.5). This supplemental efficacy 
population will be used to assess robustness of the primary analysis results. 
4.4 Disposition of Patients 
Subject disposition will be summarized for all screened subjects, for each treatment 
group and overall. The following subject disposition information will be presented: 
 The number and percentage of patients who were screened, who were screen 
failures, who were randomized, who completed the study, and who prematurely 
discontinued from the study 
 The number and percentage of patients who discontinued prematurely, by reason 
for premature discontinuation 


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 The number and percentage of patients in the ITT, safety, and PP populations 
In addition to these summaries, a listing by subject will be provided that shows 
treatment assignment, patient number, sex, age, race, reason for discontinuation, and 
any specific comments related to discontinuation. 
4.5 Protocol Deviations 
Protocol deviations (PDs) will be collected during monitoring visits. Protocol deviations 
will be placed into, but not limited to, the following categories: prohibited concomitant 
medications, dosing, enrollment inclusion/exclusion criteria, laboratory, non-compliance, 
and others which are deemed to be study PDs. Each instance of a PD will be reviewed 
and determined to be important or minor before the study DBL. 
A summary of important PDs will be provided as number (%) of subjects with at least 1 
important PD and number (%) of subjects in each category in all randomized subjects.  
A listing by subject will also be provided that will include all PDs, deviation date, type, 
and any specific comments related to the deviation.  
The following conditions, if met, would constitute an important PD.  As such, any subject 
meeting one or more of these conditions would be omitted from the PP population.  
Important PDs are not limited to the list below.  All protocol deviations within the 
monitoring report and the clinical database will be reconciled and adjudicated by the 
clinical team after the study is complete for the identification of all other important PDs. 
 
Category 
Explanation 
1 
No proof of randomization 
or subjects mistakenly 
randomized 
At Visit 4, there is no randomization number 
indicated on CRF field or subject mistakenly 
assigned randomization number. 
2 
Subject is non-compliant 
Subject is not lost to follow-up and is <75% or 
>125% compliant with study drug. 
3 
Prohibited medications 
taken 
Subject took any of the prohibited medications 
listed in Section 10.3.1 of the protocol during the 
study from screening through the EOS visit, 
unless the medication is clinically adjudicated as 
permissible.  


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4 
Treated subject who did not 
meet inclusion/exclusion 
criteria 
Subject failed one or more of the inclusion or 
exclusion criteria listed in Section 8 of the 
protocol, but continued in the double-blind period 
of the study. 
5 
Subject tests positive for 
substance abuse 
Subject has one or more positive urine drug 
screen test at any visit during the course of the 
study. 
6 
Subject is unblinded during 
study 
Subject is unblinded to treatment at any time 
during the course of the study. 
7 
Subject receives incorrect 
treatment 
Subject’s actual treatment received does not 
match randomized planned treatment. 
8 
Subject misses Day 15 visit 
Subject is randomized and receives treatment, 
but is not present for the Day 15 classroom 
assessments 
 


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5. 
 DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographics and baseline characteristics including sex, race, ethnicity, age (both 
continuous and categorized: 6-9 years and 10-12 years), baseline weight (kg), height 
(cm), and BMI (kg/m2) will be summarized by treatment group and overall for the safety 
and ITT populations. Sex, race, age group, and ethnicity will be summarized using 
summary statistics (n and percentage) for categorical variables. Age, baseline height, 
baseline weight, and baseline BMI will be summarized using summary statistics (n, 
mean, standard deviation, median, minimum, and maximum) for continuous variables.  
Demographic and baseline characteristics will also be provided in a listing by subject. 
5.1 Prior, Concomitant, and Post-Treatment Medications 
Prior medications are defined as the following: 
 Medications with a start date prior to the first date of study drug. 
Concomitant medications are defined as the following: 
 Medications with a start date prior to the first date of study drug and with a stop 
date after the first date of study drug, or 
 Medications with a start date prior to the first date of study drug and is ongoing, 
or 
 Medications with a start date on or after the first date of study drug, and on or 
prior to the last date of study drug. 
 
Post treatment medications are defined as the following: 
 Medications with a start date after the last dose of study drug, or 
 Medications with a start date on or prior to last date of study drug and is ongoing, 
or 
 Medications with a start date on or prior to last date of study drug and stop date 
after last date of study drug 
 
All medications will be coded using World Health Organization drug dictionary (WHO 
DRUG E, 2016 Q1 version).  Medications with partial start and/or end dates will be 
described as prior, concomitant, or post-treatment medications by using available non-
missing information.  Medications with completely missing start dates (i.e., missing 
information for medication start day, month, and year) are assumed to be both prior and 
concomitant medications. 
The frequency and percentages of subjects using prior, concomitant, and post-
treatment medications at any stage of the study will be summarized according to the 


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WHO-DD Anatomical Therapeutic Chemical (ATC) classification Level 2 and preferred 
term, by treatment group for the safety population.  The ATC levels will be presented in 
decreasing order of the total number of subjects (frequency).  The ATC levels with the 
same frequency will be presented alphabetically. Preferred terms within each ATC level 
will be presented in decreasing order of the total number of subjects (frequency). The 
prior and concomitant medications will also be presented in listings by subject. 
5.2 Medical History 
Medical history will be coded using MedDRA Version 19.0. The count and percentage of 
subjects under each history term, coded by system organ class (SOC) and preferred 
term (PT) will be summarized descriptively by treatment group using the safety 
population. The SOC terms and PTs will be presented in decreasing order of the total 
number of subjects (frequency) who experienced each history term.  System organ 
class terms and PTs with the same frequency will be presented alphabetically. Medical 
history information will also be provided in a listing by subject. 
5.3 Psychiatric History 
Psychiatric history will be summarized by DSM-5 code and disorder. The count and 
percentage of subjects under each DSM-5 code and disorder will be summarized by 
treatment group using the safety population. The summary will be presented in 
decreasing order of the total number of subjects (frequency) who experienced each 
psychiatric diagnosis. Psychiatric history information will also be provided in a listing by 
subject. 
ADHD diagnostic history information, including ADHD subtype and date of diagnosis, 
will be provided in a listing by subject.  
5.4 Family Psychiatric History 
Family psychiatric history, as reported by the parent/guardian, will be summarized by 
DSM-5 disorder. The count and percentage of subjects in the safety population with any 
first degree relative (biological parent or sibling) considered to have a DSM-5 disorder 
will be summarized under the DSM-5 disorder deemed most appropriate by the rater. 
The summary will be presented in decreasing order of the total number of subjects 
(frequency) with any first degree relative who experienced each psychiatric diagnosis. 
Family psychiatric history information will also be provided in a listing by subject, 
including which first degree relative had the diagnosis. 


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6. 
MEASUREMENT OF TREATMENT COMPLIANCE 
Compliance with study drug will be monitored closely and determined at each visit. 
Subjects and their parent(s)/legal guardian(s) will be instructed to bring all unused study 
drug with them to the Day 15 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. Treatment compliance (number of 
missed days) and treatment exposure (e.g. time in trial, time on treatment) will be 
tabulated overall and by the following groups: <75%, 75%-125%, and >125%.  Subjects 
who are lost to follow-up and/or subjects who do not return unused study drug will have 
missing compliance data. 
Each subject’s compliance and treatment exposure data will be listed. 
 
 


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7. 
EFFICACY EVALUATION 
7.1 Overview of Efficacy Analysis Issues 
7.1.1 
Handling of Dropouts or Missing Data 
The SKAMP scale is a 13-item independent observer rating of subject impairment 
of classroom observed behaviors.  Each item is rated on a 7-point impairment 
scale (0 = normal to 6 = maximal impairment).  The combined scores for the 
SKAMP (SKAMP-CS) are obtained by summing the values of corresponding 
items in the assessment. The mean SKAMP-CS over the entire visit is derived 
from the SKAMP-CS at the individual 7 time points. 
Missing data could occur under either or both of the following scenarios: (1) missing or 
invalid data for individual items in the SKAMP for a specific assessment; and (2) 
missing SKAMP-CS at individual time points.  The approach to handling missing data 
under these scenarios is described below.    
7.1.1.1 
Missing Individual Items in the SKAMP Scale 
Missing or invalid data for individual items will be handled by rules specific to the 
validated SKAMP scale as follows: 
 If 3 or more individual items in the SKAMP have missing or invalid data, the 
SKAMP-CS will be set to missing. 
 If 1 or 2 individual items in the SKAMP are missing or invalid, the values for the 
missing individual items will be imputed using the mean of the non-missing 
individual items for the particular subject at that visit and time point, rounded to 
the nearest integer. 
 If any item within a SKAMP subscale is missing or invalid, the entire subscale 
score will be set to missing. 
7.1.1.2 
Missing SKAMP Combined Scores at Individual Time Points 
Primary Analysis 
Subjects with missing SKAMP-CS data at all individual time points at either the baseline 
or Day 15 visit will not be included in the primary analysis. If 3 or more time points have 
missing or invalid SKAMP-CS data, the mean SKAMP-CS will be set to missing. If one 
or two time points have missing or invalid SKAMP-CS data, the mean SKAMP-CS will 
be calculated as the average of the SKAMP-CS at the remaining 5 or 6 time points. No 
imputation of missing SKAMP-CS at individual time points will be done for the primary 
efficacy analysis.   


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Sensitivity Analyses 
To explore the robustness of the primary efficacy analysis of the change from baseline 
at Day 15 in ADHD symptoms in mean SKAMP-CS, two sensitivity analyses of the 
primary analysis may be performed: a placebo-based multiple imputation (MI) pattern-
mixture model (PMM) analysis and a tipping point analysis using the PMM. 
Sensitivity analysis one: Placebo-based MI PMM 
To explore the robustness of the primary analysis results, a sensitivity analysis will be 
carried out that assesses the situation where the data are not missing at random 
(NMAR).  More specifically, all subjects taking dasotraline who discontinue for any 
reason will be assumed to behave like placebo subjects. 
A controlled, multiple imputation approach based on PMM will be applied for those 
subjects on dasotraline using the ‘Copy Reference’ approach [3].  More specifically, 
missing data for those subjects taking dasotraline who discontinued will be imputed 
based on the posterior distribution of the placebo group.  Missing data for placebo 
subjects who discontinued will also be imputed using the observed values of the 
placebo group. 
Data will be imputed using SAS PROC MI (v9.3 or later) using the full conditional 
specification method (FCS).  200 burn-in iterations will be performed prior to each 
imputation.  The imputation model will include clinical site, observed non-missing 
baseline mean SKAMP-CS, observed non-missing baseline PERMP scores, age, and 
sex.  One hundred imputed datasets will be generated for analysis. 
The same model used in the primary analyses will be fit to each of the 100 datasets.  
The parameter estimates and standard errors will be combined using PROC 
MIANALYZE in SAS v 9.3 or higher. 
Sensitivity analysis two: Tipping Point Analysis using PMM 
The goal of the tipping point analysis is to determine how robust the results of the 
primary analysis are to varying its assumption that the change from baseline at Day 15 
mean SKAMP-CS for subjects that discontinue from the dasotraline group is the same 
as the completers in the dasotraline group.  In particular, this analysis examines how 
altering this assumption to allow the discontinued dasotraline subjects to have worse 
outcomes will impact the resulting estimates of the treatment effect.  This will quantify 
the range of values which the assumptions can take on and still provide the same 
conclusions as the primary analysis, giving a very direct measure of the sensitivity of 
the primary analysis to deviations from the assumptions using an approach that has 
missing values for dasotraline discontinuation subjects imputed.  Missing SKAMP-CS 


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data in the dasotraline group will be imputed based on observed values in the 
dasotraline group and likewise, missing SKAMP-CS values in the placebo group will be 
imputed based on observed values in the placebo group. 
Shift values of .05 (penalize imputed values for dasotraline subjects by 5% of the 
treatment difference of the primary endpoint from the primary analysis) through 1 
(penalize imputed values for dasotraline subjects by 100% of the treatment difference of 
the primary endpoint from the primary analysis) will be applied at increments of .05 and 
reported.  The primary analysis will be rerun for all shift values and the resulting 
treatment difference, 95% CI and p-value for each shift value will be reported. The 
higher penalty should result in a smaller treatment difference. The wider the range of 
values that result in no change in interpretation, the more robust the analysis results 
may be considered to be. 
The steps to implement the tipping point analysis are as follows: 
1) ANCOVA model will be run using all observed data and the LS mean in the 
Dasotraline 2mg/day group of mean change from baseline at Week 2 in SKAMP-
CS will be calculated. 
2) Missing data will be imputed based on the MAR assumption using multiple 
imputation procedure (PROC MI) to create 100 complete datasets with 200 burn-
in iterations.  
3) For subjects in the dasotraline dose group, the imputed values from Step 2 will 
be “penalized” by adding a percentage (i.e. 5%, 10%, 15%, 20%, etc. of the LS 
mean treatment difference) of the absolute value of the mean change calculated 
from Step 1; for the placebo group, no “penalty” will be taken for the imputed 
values.  
4) Each newly generated complete dataset from Step 3 will be analyzed using the 
primary analysis ANCOVA model and results from all 100 datasets will be 
combined (PROC MIANALYZE) to generate inferences.  
5) This analysis (Steps 3-4) will be repeated for a range of values (i.e. 5%, 10%, 
15%, 20%, etc. of the treatment difference) until either the tipping point (where 
statistical significance of the treatment effect is lost) is identified or the 100% 
penalty is applied.  
7.1.2 
Multicenter Studies  
This study will have up to 8 different clinical sites enrolling and treating subjects.  
Depending on enrollment, some sites may run multiple cohorts.  Each cohort is 


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expected to have a maximum of 18 subjects.  For all efficacy analyses where 
investigative site is an explanatory effect and in by-site subgroup analyses, pooling of 
sites will be performed because one site had only one cohort and a small sample size. 
The subjects at Padilla's site (007) will be pooled with the subjects for Marraffino's site 
(003) based on both sites being located in the same state and these being the two 
smallest-enrolling sites in the state. 
7.1.3 
Assessment Time Windows 
Data will be summarized based on the scheduled visits; no visit windowing will be 
conducted.  Visits 4 (Day 1) and 5 (Day 15) must be performed as scheduled based on 
the protocol, allowing for consistent and reliable efficacy measurements. However, for 
visit-based safety outcomes (laboratory tests, electrocardiograms, vital signs, 
neurological exams, ADHD-RS-IV HV, and C-SSRS), baseline is defined as the last 
recorded measurement prior to first administration of study drug (this can be a 
scheduled or unscheduled visit). 
7.2 Efficacy Measurements 
7.2.1 
Swanson, Kotin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale 
The SKAMP rating scale is a 13-item independent observer rating of subject impairment 
(7-point scale) of analog classroom-observed behaviors during the laboratory classroom 
assessments.  Items 1-4 represent an indication of subject attention, items 5-8 are an 
indication of deportment, items 9-11 assess quality of work, and items 12-13 assess 
subject compliance with teacher and classroom rules.  The specific items associated 
with these subscales are detailed in Appendix 14.3. In this study, the change from 
baseline at Day 15 in mean total score of all SKAMP items (or SKAMP-CS) is defined 
as the primary efficacy parameter.  The mean SKAMP-CS on Day 15, the SKAMP-CS 
at each of the post-dose assessment times on Day 15, the change from baseline at Day 
15 in SKAMP-CS at each of the post-dose assessment times, the change from baseline 
at Day 15 in mean SKAMP-Attention subscale scores (items 1-4), the SKAMP-Attention 
subscale scores at each of the post-dose assessment times on Day 15, the change 
from baseline at Day 15 in SKAMP-Attention subscale scores at each of the post-dose 
assessment times, the change from baseline at Day 15 in mean SKAMP-Deportment 
subscale scores (items 5-8), the SKAMP-Deportment subscale scores at each of the 
post-dose assessment times on Day 15, and the change from baseline at Day 15 in 
SKAMP-Deportment subscale scores at each of the post-dose assessment times are 
secondary outcome measures. Higher SKAMP-CS scores signify greater behavioral 
impairment. Therefore, decreases in SKAMP-CS scores over time will indicate 
improvement in behavior while increases in SKAMP-CS scores over time will indicate 
worsening of behavior. 


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The SKAMP rating scale will be collected during each of 7 class sessions at Visits 4 
(Day 1) and 5 (Day 15), occurring at 8:00 am, 10:00 am, 12:00 pm, 2:00 pm, 4:00 pm, 
6:00 pm, and 8:00 pm of the laboratory classroom days.  Three practice classroom 
sessions for the laboratory classroom day will be conducted at Visit 2. 
Missing or invalid data for individual items will be handled by rules specific to the 
validated SKAMP scale as described in Section 7.1.1.1.  
7.2.2 
Permanent Product Measurement of Performance (PERMP) 
The PERMP is a 5 page math test consisting of 80 problems per page (total of 400 
problems). Both attempted problems and correct problems will be assessed. Subjects 
are to complete as many problems as possible in 10 minutes.  The appropriate math 
level for each subject is determined based on results of a math pre-test administered at 
screening (Visit 2).  Performance is measured by the number of math problems 
attempted (PERMP-A) and the number of math problems correctly completed (PERMP-
C).  Like the SKAMP, the PERMP will be administered as a practice at Visit 2 and as 
the final tests at Visits 4 (Day 1) and 5 (Day 15), during each of 7 class sessions 
occurring at 8:00 am, 10:00 am, 12:00 pm, 2:00 pm, 4:00 pm, 6:00 pm, and 8:00 pm of 
the laboratory classroom days.  In this study, the change from baseline at Day 15 in 
PERMP-A, PERMP-C, and PERMP-Total (sum of PERMP-A and PERMP-C) scores at 
each of the post-dose assessment times, the PERMP-A, PERMP-C, and PERMP-Total 
scores at each of the post-dose assessment times on Day 15, and the change from 
baseline at Day 15 in mean PERMP-A, PERMP-C, and PERMP Total scores are 
defined as secondary efficacy measures. Higher PERMP scores signify higher 
performance and less severe ADHD symptoms. Therefore, increases in PERMP scores 
over time will indicate improvement of symptoms, while decreases in PERMP scores 
over time will indicate worsening of symptoms. 
No imputation for missing PERMP values will be performed. 
7.3 Eligibility Criteria and ADHD Symptom Control Assessments 
7.3.1 
Schedule for Affective Disorders and Schizophrenia for School-Age 
Children Present and Lifetime version (K-SADS-PL) 
The K-SADS-PL is used at screening to confirm the diagnosis of ADHD.  
The K-SADS-PL is a semi-structured diagnostic interview designed to assess current 
and past episodes of psychopathology in children and adolescents according to 
Diagnostic and Statistical Manual for Mental Disorders Fourth Edition; Text Revision 
(DSM-IV-TR) criteria. The K-SADS-PL covers a broad spectrum of most child 
psychiatric diagnoses, with the exception of pervasive development disorders and 
personality disorders. The K-SADS-PL includes questions about school performance 


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and other issues relevant to children and adolescents. There is a base instrument (82 
items) and 5 required diagnostic supplements which are completed depending on the 
results of the base screening: (1) Affective Disorders; (2) Psychotic Disorders; (3) 
Anxiety Disorders; (4) Behavioral Disorders; (5) Substance Abuse and Other Disorders. 
7.3.2 
ADHD Rating Scale Version IV - Home Version (modified for investigator 
administration) (ADHD-RS-IV HV) 
The ADHD-RS-IV HV is used to assess the presence of clinically significant ADHD 
symptoms on Day -1. 
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. 
Higher ADHD-RS-IV HV total scores signify greater severity in ADHD symptoms. 
The following ADHD-RS-IV HV scores will be assessed: 
 ADHD-RS Total score (all items). 
 ADHD-RS Hyperactivity/Impulsivity subscale score (even number items 2 through 
18). 
 ADHD-RS Inattentiveness subscale score (odd number items 1 through 17). 
No imputation for missing ADHD-RS data will be performed. Descriptive statistics for the 
ADHD-RS-IV HV scores will be presented for each time point and data will also be 
presented in a listing. 
7.4 Efficacy Outcomes 
7.4.1 
Primary Efficacy Outcome 
The primary efficacy outcome is the change from baseline (Visit 4) at Day 15 (Visit 5) in 
ADHD symptoms as measured by mean SKAMP-CS obtained from an average of the 7 
assessments collected across the 12 hour classroom day (12 to 24 hours post-dose).   
7.4.2 
Secondary Efficacy Outcomes 
Secondary efficacy outcomes include:  
 Mean SKAMP-Combined score from the 7 assessments collected across the 12-


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hour classroom day (12 to 24 hours post-dose) on Day 15 
 SKAMP-Combined score at each of the assessment times (12-, 14-, 16-, 18-, 20-
, 22-, and 24-hours post-dose) during the classroom day on Day 15 
 Change from baseline at Day 15 in SKAMP-Combined score at each of the 
assessment times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours post-dose) during 
the classroom day 
 Change from baseline at Day 15 in mean SKAMP-Attention subscale score 
obtained from the 7 assessments collected across the 12-hour classroom day 
(12 to 24 hours post-dose) 
 SKAMP-Attention subscale score at each of the assessment times (12-, 14-, 16-, 
18-, 20-, 22-, and 24-hours post-dose) during the classroom day on Day 15 
 Change from baseline at Day 15 in SKAMP-Attention subscale score at each of 
the assessment times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours post-dose) 
during the classroom day 
 Change from baseline at Day 15 in mean SKAMP-Deportment subscale score 
obtained from the 7 assessments collected across the 12-hour classroom day 
(12 to 24 hours post-dose) 
 SKAMP-Deportment subscale score at each of the assessment times (12-, 14-, 
16-, 18-, 20-, 22-, and 24-hours post-dose) during the classroom day on Day 15 
 Change from baseline at Day 15 in SKAMP-Deportment subscale score at each 
of the assessment times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours post-dose) 
during the classroom day 
 Change from baseline at Day 15 in Permanent Product Measure of Performance 
(PERMP)-Attempted and Correct Problems scores at each of the assessment 
times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours post-dose) during the classroom 
day 
 PERMP-Attempted and Correct Problems scores at each of the assessment 
times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours post-dose) during the classroom 
day on Day 15 
 Change from baseline at Day 15 in mean PERMP-Attempted scores obtained 
from the 7 assessments collected across the 12-hour classroom day (12 to 24 
hours post-dose) 


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 Change from baseline at Day 15 in mean PERMP-Correct scores obtained from 
the 7 assessments collected across the 12-hour classroom day (12 to 24 hours 
post-dose) 
 
 Change from baseline at Day 15 in mean PERMP total score (PERMP-
Attempted + PERMP-Correct) obtained from the 7 assessments collected across 
the 12-hour classroom day (12 to 24 hours post-dose) 
7.5 Analysis Methods 
7.5.1 
Primary Efficacy Analyses 
The primary efficacy analysis will be performed on the ITT population.  The primary 
efficacy outcome is the change from baseline (Visit 4) at Day 15 (Visit 5) in ADHD 
symptoms as measured by mean SKAMP-CS obtained from an average of the 7 
assessments collected across the 12 hour classroom day (12 to 24 hours post-dose).  
The key elements of the primary efficacy analysis are as follows: 
Data:  Change from baseline at Day 15 of mean SKAMP-CS measured on the 
laboratory classroom days, Visits 4 (baseline) and 5 (Day 15). Mean SKAMP-CS will be 
calculated by taking the average across all 7 assessment time points (8:00 am, 10:00 
am, 12:00 pm, 2:00 pm, 4:00 pm, 6:00 pm, and 8:00 pm) both at baseline and at Day 
15.  The mean SKAMP-CS will not be rounded prior to analysis. Missing individual item 
data will first be imputed as described in Section 7.1.1.1 before taking the mean across 
all assessment time points. 
Model:  ANCOVA 
Fixed effects:  The following fixed effects are planned: 
 Treatment 
 Mean SKAMP-CS at baseline (Visit 4) 
 Site (or pooled site if some sites to be pooled) 
The null hypothesis: 
H0:  Change from baseline at Day 15 of the mean SKAMP-CS over all time points from 
8:00 am to 8:00 pm on the laboratory classroom days are the same for dasotraline 2 
mg/day and placebo  
will be tested against the 2-sided alternative hypothesis: 


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H1:  Change from baseline at Day 15 of the mean SKAMP-CS over all time points from 
8:00 am to 8:00 pm on the laboratory classroom days are not the same for dasotraline 2 
mg/day and placebo. 
The average treatment difference over all post-dose time points will be estimated using 
LS means from the ANCOVA.  The treatment comparison will be conducted as a 2-
sided test at the 5% level of significance.  The standard error and 95% confidence 
interval for the treatment difference as well as the treatment effect size will be provided.  
Effect size will be calculated as the absolute value of the LS mean treatment difference 
divided by the observed pooled standard deviation, which will be calculated using the 
following formula: 
𝑆𝐷 = 𝑆𝐸(𝑥̅𝑑)  √1 𝑁𝑃𝐵𝑂
⁄
+ 1/𝑁𝐷𝐴𝑆
⁄
 , where 𝑥̅𝑑 is the LS mean treatment difference. 
 
The estimand of this primary efficacy analysis is the LS mean treatment difference, 
Dasotraline 2mg vs. placebo, of mean change from baseline in mean SKAMP-CS 
among all randomized subjects who remain in the study for the duration of the two-week 
double-blind period, regardless of treatment adherence. 
The primary efficacy analysis will also be repeated for the per protocol (PP) population. 
 
7.5.2 
Secondary Efficacy Analyses 
The secondary efficacy outcomes include: 
 Mean SKAMP-Combined score from the 7 assessments collected across the 12-
hour classroom day (12 to 24 hours post-dose) on Day 15 
 SKAMP-Combined score at each of the assessment times (12-, 14-, 16-, 18-, 20-
, 22-, and 24-hours post-dose) during the classroom day on Day 15 
 Change from baseline at Day 15 in SKAMP-Combined score at each of the 
assessment times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours post-dose) during 
the classroom day 
 Change from baseline at Day 15 in mean SKAMP-Attention subscale score 
obtained from the 7 assessments collected across the 12-hour classroom day 
(12 to 24 hours post-dose) 
 SKAMP-Attention subscale score at each of the assessment times (12-, 14-, 16-, 
18-, 20-, 22-, and 24-hours post-dose) during the classroom day on Day 15 


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 Change from baseline at Day 15 in SKAMP-Attention subscale score at each of 
the assessment times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours post-dose) 
during the classroom day 
 Change from baseline at Day 15 in mean SKAMP-Deportment subscale score 
obtained from the 7 assessments collected across the 12-hour classroom day 
(12 to 24 hours post-dose) 
 SKAMP-Deportment subscale score at each of the assessment times (12-, 14-, 
16-, 18-, 20-, 22-, and 24-hours post-dose) during the classroom day on Day 15 
 Change from baseline at Day 15 in SKAMP-Deportment subscale score at each 
of the assessment times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours post-dose) 
during the classroom day 
 Change from baseline at Day 15 in Permanent Product Measure of Performance 
(PERMP)-Attempted and Correct Problems scores at each of the assessment 
times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours post-dose) during the classroom 
day 
 PERMP-Attempted and Correct Problems scores at each of the assessment 
times (12-, 14-, 16-, 18-, 20-, 22-, and 24-hours post-dose) during the classroom 
day on Day 15 
 Change from baseline at Day 15 in mean PERMP-Attempted score obtained 
from an average of the 7 assessments collected across the 12-hour classroom 
day (12 to 24 hours postdose). 
 Change from baseline at Day 15 in mean PERMP-Correct score obtained from 
an average of the 7 assessments collected across the 12-hour classroom day 
(12 to 24 hours postdose). 
 Change from baseline at Day 15 in mean PERMP total score (PERMP-
Attempted + PERMP-Correct) obtained from the 7 assessments collected across 
the 12-hour classroom day (12 to 24 hours post-dose) 
Secondary weight-adjusted dose-level efficacy analyses will also be conducted on the 
SKAMP.  See section 10 for details. 
For secondary efficacy outcomes of mean SKAMP-Attention subscale scores, mean 
SKAMP-Deportment subscale scores, mean PERMP-A, mean PERMP-C, and mean 
PERMP total score, missing time points will be handled as follows: 
If 3 or more time points have missing or invalid scores, the mean score will be set to 


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missing. If one or two time points have a missing or invalid score, the mean score will 
be calculated as the average of the scores at the remaining time points. Missing 
individual items will not be imputed. 
Descriptive statistics for the SKAMP-CS, SKAMP-Attention subscale scores, SKAMP-
Deportment subscale scores, PERMP-A, PERMP-C, and PERMP total scores will be 
calculated for the change from baseline (Visit 4) at Day 15 (Visit 5), average across all 
time points and for each time point individually for the laboratory classroom day on Day 
15, and will be presented for each treatment as well for the differences between the 
treatments (dasotraline 2 mg/day vs. placebo) based on the ITT population. 
In addition, the secondary SKAMP and PERMP efficacy variables will be analyzed 
based on a similar ANCOVA model to the one described above for the ITT population.  
These models will mirror the model used in the primary analysis, with the relevant 
SKAMP/PERMP score at baseline as a fixed effect in place of the mean SKAMP-CS at 
baseline. 
The observed means, LS means and associated standard error bars will be plotted over 
time for SKAMP-CS and the PERMP scores for the laboratory classroom day at 
Baseline (Visit 4) and Day 15 (Visit 5) by treatment group. Change from baseline 
SKAMP-CS, change from baseline SKAMP subscale scores, and change from baseline 
PERMP scores will be plotted over time at Day 15 (Visit 5) by treatment group, as well 
as by subgroup (sex, race, age).  
 
7.5.3 
Examination of Subgroups 
The primary efficacy analyses will be repeated on the ITT population based on the 
following subgroups: 
 Sex (Male and Female) 
 Race (White, Black or African American, and Other) 
 Age (6-9 years and 10-12 years) 
 Previous treatment (stimulant and treatment-naïve) 
 
The interaction of each subgroup with the treatment effect will also be measured.  The 
primary efficacy analysis will be repeated on the ITT population once for each subgroup 
above, with the subgroup of interest added as a fixed effect, along with the interaction 
between the subgroup of interest and the treatment effect.  The p-values from the 
resulting tests for interaction will be summarized. 


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8. 
SAFETY EVALUATION 
All safety analyses will be performed on the safety population.  All subjects who were 
randomized and received at least 1 dose of study medication will be assessed for 
safety.  Safety will be monitored by physical and neurological examinations, vital signs, 
AEs assessed at each visit, electrocardiography, and clinical laboratory tests.  In 
addition, the C-SSRS will be administered at Screening (Visit 1) and all subsequently 
scheduled visits to assess emergent suicidal thoughts or behaviors. 
8.1 Overview of Safety Analysis Issues 
Missing end dates for AEs will not be imputed.  If end date information is not available, it 
will be assumed that the finding or event is ongoing. 
Missing AE start dates will be imputed based on the following rules: 
 If only the year is known, the date will be set to 01 January of that year.  If the 
year is the same as the year of the first dose of study medication, the date will 
be set to the date of the first dose of study medication. 
 If the year and day are known, the date will be set to January of that year.  If the 
year and day is the same as the year and day of the first dose of study 
medication, the date will be set to the date of the first dose of study medication. 
 If the year and month are known, the date will be set to first day of the month.  If 
the year and month are the same as the year and month of the first dose of 
study medication, the date will be set to the date of the first dose of study 
medication. 
 If the start date is completely missing, it will be set to the date of the first dose of 
study medication. 
8.2 Overview of Safety Analysis Methods 
Safety data will be analyzed descriptively using the safety population described in 
Section 4.2.  Unless specified, all safety summaries will be presented by descriptive 
statistics, such as number of subjects (n) and percentage for categorical variables and 
number of subjects (n), mean, standard deviation, median, minimum, and maximum for 
continuous variables. 


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8.3 Extent of Exposure 
The length of exposure (in days) of study medication will be calculated based on the 
dates of first and last dosing of study medication (last dosing date - first dosing date + 
1). Length of exposure will be summarized by treatment group on the safety population 
as continuous values. 
For subjects lost to follow-up, no imputation of the length of exposure will be conducted.  
For subjects who discontinue the study early but return for a follow-up visit, the 
follow-up data will be used to calculate the length of exposure. 
8.4 Adverse Events 
All AEs will be coded using MedDRA Version 19.0. An AE is any untoward medical 
occurrence: 
 that occurred on or after the first dose of study medication, 
 with a missing start date and a stop date on or after the first dose of study 
medication, or 
 with both a missing start and stop date. 
Untoward medical occurrences that occur between the time of informed consent/assent 
and first study drug administration are pre-treatment events. Those that occur after first 
administration of study drug are considered AEs.  Clinically significant abnormal 
objective findings (eg, clinical laboratory value, ECG value, and physical examination 
observation) will also be recorded as AEs. 
A serious adverse event (SAE) is an AE that meets one or more of the following criteria: 
• 
Results in death. 
• 
Is life threatening. 
• 
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 


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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. 
An AE is considered treatment emergent if it started during or after administration of the 
first dose of study medication, and started on or prior to the day of the subject’s final 
visit (including the follow-up visit).  In addition, medical history events that worsen in 
severity after the start of dosing will be considered treatment-emergent adverse events 
(TEAEs).  AEs with partial start dates will be imputed as outlined in Section 8.1 and 
assigned to the associated treatment period.  
Summary Tabulations 
An overview of the frequency, i.e., the number and percentage of subjects and events 
with at least one of the following AEs, will be presented by treatment group (placebo, 
dasotraline 2 mg/day, and total): 
 
 All TEAEs 
 SAEs 
 TEAEs leading to discontinuation 
 Severe TEAEs 
 TEAEs related to study medication 
 SAEs related to study medication 
 AEs leading to death 
System Organ Class and Preferred Term Tabulations 
The frequency of subjects reporting TEAEs, along with the frequency of events, will be 
summarized within each system organ class (SOC) and preferred term (PT) by 
treatment group.  The SOC terms and PTs will be presented in decreasing order of the 
total number of subjects (frequency) who experienced each AE.  System organ class 
terms and PTs with the same frequency will be presented alphabetically. 
Each subject will be counted only once within each SOC and within each PT. If a single 
subject experienced the same AE more than once within a treatment period, the subject 
will be counted once per SOC and PT for that AE.  For subjects that experienced AEs 
with multiple severities, the AE with the highest known severity within each SOC and PT 


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will be counted. Adverse events with unassigned/unknown severity will be categorized 
as severe. 
For summaries by relationship to the study medication, AEs will be grouped as “related” 
or “not related.” AEs assessed as “possible,” “probable,” or “definite,” will be grouped as 
“related.” If a subject reports more than one AE within the same treatment regimen, 
SOC and PT, and any are related, it will be summarized as related. AEs whose 
relationship to treatment is assessed as “not related” or “unlikely” will be grouped as 
“not related.”    Events with unassigned/unknown relationship to study medication will be 
considered related to study medication. 
The frequency of subjects reporting the following AEs, along with the frequency of 
events, will be summarized and presented by treatment group and MedDRA SOC and 
PT for the Safety population: 
 All TEAEs (including number of events and subject incidence) 
 SAEs 
 Non-SAEs (including number of events and subject incidence) 
 TEAEs leading to discontinuation 
 TEAEs by maximum severity (mild, moderate, severe) 
 TEAEs by relationship to the study treatment (related, or not related) 
 SAEs by relationship to the study treatment 
 AEs leading to death 
 AEs during the treatment period 
 AEs during the follow-up period (defined as any AE occurring after treatment 
stop date + 7 days) 
By-Subject Listings 
By-subject listings including relevant information (i.e. treatment, age, sex, race, duration 
of AE, severity, relationship, outcome, action taken, etc.) will be presented for: 
 All AEs 


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 SAEs 
 AEs leading to death 
 AEs leading to discontinuation (per the case report form) 
 AEs leading to discontinuation stratified by weight 
The onset of AEs will be calculated relative to the first dose of study medication.  The 
duration of AEs in days will be calculated as the difference between the onset and 
resolution dates of the AE.  If the AE is ongoing at the end of the study, or the resolution 
date is unknown, the duration will be presented as ‘Unknown’. 
8.5 Adverse Events of Special Concern 
Adverse events of special concern for this study are categorized into the following 
groups: 1) suicidal ideation, etc.; 2) spontaneous abortion/miscarriage; 3) 
neuropsychiatric events including a subset of psychosis/mania-related events; 4) 
cardiac arrhythmias; 5) combined insomnia; 6) weight decreased; 7) decreased 
appetiteAppendix 14.7 lists the PTs and corresponding MedDRA codes that fall under 
each category.  AEs of special concern will be summarized by category of interest, 
SOC, PT and treatment group. 
 
A listing of AEs of special concern, stratified by weight, will be presented. 
8.6 Clinical Laboratory Evaluations 
The following laboratory tests will be performed at Screening (Visit 1) and EOS (Visit 6):  
 Clinical Chemistry: 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 
 Hematology: Hemoglobin, Hematocrit, Platelet Count, RBC Count, WBC - Total 
Count, WBC Differential, (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils) 
 Urinalysis: Blood, Glucose, Ketones, Leukocyte esterase, Microscopic 
examination, Nitrites, pH, Protein  


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Summary statistics for these laboratory panels (clinical chemistry, hematology and 
urinalysis) will be provided by treatment group and visit. Laboratory data will also be 
summarized in shift tables presenting summary statistics of raw data and change from 
baseline values (means, standard deviations, medians, ranges). All clinical laboratory 
assessments will be listed for each panel. 
In addition, the incidence of markedly abnormal post-baseline laboratory values 
(MAPLV) will be presented to examine the frequency and percentage of subjects that 
have values that are potentially clinically significant (PCS). These abnormal values will 
also be flagged in the laboratory listings. These criteria are outlined in Appendix 14.4. 
8.7 Physical and Neurological Examinations 
A full physical examination will be performed at Screening (Visit 1) and at the EOS (Visit 
6).  Body weight will also be measured at Screening (Visit 1), Visit 4, Visit 5, and at the 
EOS (Visit 6).  Height will be measured at Screening (Visit 1).   
Clinically significant physical examination findings, as judged by the investigator, at 
screening will be recorded as medical history and after screening will be recorded as 
AEs or pre-treatment events depending on the timing in relationship to the first dose of 
study drug. Abnormal physical exam results will appear in medical history and/or AEs 
displays and will not be displayed separately.   
Neurological examinations will be performed at Screening (Visit 1) and at the EOS (Visit 
6) and the parameters will be assessed by the investigator as normal or abnormal. 
Neurological examination assessments will be summarized using summary statistics for 
categorical variables (normal/abnormal) by visit. A shift table for baseline condition 
versus the worst result during the course of the study period (normal/abnormal) will be 
presented by treatment. 
8.8 Vital Signs 
Vital signs, including respiratory rate; body temperature; supine, standing, and 
orthostatic blood pressure; supine, standing, and orthostatic heart rate; BMI; and body 
weight, will be measured at all scheduled in-person study visits (Screening [Visit 1 and 
Visit 2], Visit 4, Visit 5, and EOS [Visit 6]). 
Supine systolic blood pressure, standing systolic blood pressure, orthostatic systolic 
blood pressure, supine diastolic blood pressure, standing diastolic blood pressure, 
orthostatic diastolic blood pressure, supine heart rate, standing heart rate, orthostatic 
heart rate, respiratory rate, body temperature, body weight, and BMI will be summarized 
descriptively for each visit by treatment group for the absolute value and change from 
baseline values using descriptive statistics. 


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In addition, the incidence of sponsor-defined markedly abnormal post-baseline vital sign 
values will be presented to examine the frequency and percentage of subjects that meet 
the PCS criteria outlined in Appendix 14.5. Vital signs will also be presented in a listing 
by subject and visit. The listing will include a flag for abnormal values. 
8.9 Electrocardiography (ECG) 
A 12-lead ECG will be recorded at Screening (Visit 1) and the EOS visit (Visit 6).  All 
ECGs will be obtained in the supine position, after the subject has been resting supine 
for at least 5 minutes. The ECG parameters collected will include heart rate, PR 
interval, RR interval, QT interval, QTc with Bazett correction (QTcB) and QTc with 
Fridericia correction (QTcF) intervals, QRS duration, and interpretation, including any 
noted abnormalities.  The ECGs will be reviewed and interpreted by the investigator.  All 
data will be assessed for clinical significance.   
ECG measurements, overall interpretation and clinical significance will be summarized 
descriptively for baseline, each post-dose evaluation, and change from baseline to each 
post-dose evaluation by treatment group.  QT interval, QTcB, and QTcF will also be 
summarized by < 460 msec, >= 460 msec, < 500 msec, and >= 500 msec, as well as 
change from baseline < 30 msec, >= 30 msec, < 60 msec, and >= 60 msec, by visit, 
treatment and age group (6-9 years, 10-13 years (age range up to 13 to account for any 
subjects who were 12 years at screening but 13 years at time of ECG measurement). 
In addition, the incidence of sponsor-defined markedly abnormal post-baseline ECG 
values will be presented to examine the frequency and percentage of subjects that meet 
the PCS criteria outlined in Appendix 14.6. ECG results will also be presented in a 
listing by subject and visit. The listing will include a flag for abnormal values. 
Shifts from baseline to EOS visit ECG results will be presented by treatment group for 
the overall interpretation (e.g., normal to abnormal, or abnormal to normal). 
8.10 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a brief investigator-administered questionnaire that provides for the 
identification, quantification, and standardized assessment of the occurrences and 
severity of suicidal ideation and behavior.  Subjects will be assessed at Screening (Visit 
1) using the Children’s Baseline/Screening C-SSRS.  For all subsequent testing (Visits 
2, 4 and 5 and the EOS visit), the Children’s Since Last Visit assessment will be utilized. 
The frequency of suicidality using the C-SSRS will be summarized for each visit for 
each of the following outcomes: 
 Number of subjects reporting at least one occurrence of suicidal ideation or 


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behavior. 
 Number of subjects reporting any type of suicidal behavior. 
 Number of subjects reporting any type of suicidal ideation. 


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9. 
PHARMACOKINETIC EVALUATION 
No pharmacokinetic sampling is planned for this study.  
 
 


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10. 
OTHER ANALYSES 
Dose response and tolerability for dasotraline treated subjects will also be analyzed in a 
weight-based dose-level analysis.  Dose per weight (mg/kg) will be calculated for each 
dasotraline treated subject and then placed into the following groupings: 
 2 equal-sized groups: 2 groups will be formed based on the median number of 
dasotraline treated subjects. Each group will contain half of the population of 
dasotraline treated subjects. 
 3 equal-sized groups: 3 groups will be formed based on tertiles of the number of 
dasotraline treated subjects. Each group will contain a third of the population of 
dasotraline treated subjects. 
Each of these groupings will be analyzed using the same primary efficacy analysis 
method described in Section 7.5.1.  In addition, each of these groupings will be 
analyzed for safety summarized by PT in descending order for each of the following 
categories: AEs, SAEs, AEs leading to discontinuation, and AEs of special concern. 
A Receiver Operating Characteristic (ROC) analysis will also be conducted based on a 
logistic regression with dose per weight (mg/kg) as the predictor and AE of special 
concern as the outcome. An ROC curve for the model will be plotted. The predicted 
probability of having an AE of special concern event will also be plotted as a function of 
dose per weight (mg/kg). 
Any additional analyses performed after finalization of the SAP will be considered 
exploratory and will be identified as such in the CSR. 


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11. 
INTERIM ANALYSES AND DATA MONITORING 
No interim analyses are planned for this study. 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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12. 
CHANGES TO STUDY CONDUCT OR ANALYSES PLANNED IN THE 
PROTOCOL 
12.1 Changes in the Conduct of the Study 
The protocol underwent 3 amendments over the course of the study. 
 Protocol Version 2.00 Amendment 1.00, finalized 29 June 2017 
 Protocol Version 3.00 Amendment 2.00, finalized 19 November 2017 
 Protocol Version 4.00 Amendment 3.00, finalized 22 June 2018 
Refer to the individual protocol versions for details on each amendment. 
12.2 Changes in the Analysis Planned in the Protocol 
No changes are planned as of the date of the SAP. 
 
 


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13. 
REFERENCES 
1. US Federal Register. (1998) International Conference on Harmonization; Guidance 
for Industry: Statistical Principles for Clinical Trials. Department of Health and 
Human Services: Food and Drug Administration.  Federal Register, Vol. 63, No. 179, 
September 16, 1998, page 49583. 
2. US Federal Register. (1996) International Conference on Harmonization; Guidance 
for Industry: Structure and Content of Clinical Study Reports. Department of Health 
and Human Services: Food and Drug Administration.  Federal Register Vol. 61, July 
17, 1996, page 37320. 
3. Carpenter JR, Roger JH, Kenward MG.  Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via 
multiple imputation.  J Biopharm Stat.  2013;23(6):1352-71. 
 
 


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14. 
APPENDICES 
14.1 Schedule of Events 
Procedures 
Screening 
Double-blind Period 
End of 
Study 
Clinic 
Visit 
Practice 
Laboratory 
Classroom 
Session 
Telephone 
Contact 
First 
Laboratory 
Classroom 
Day  
Second 
Laboratory 
Classroom 
Day 
- 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Day -42 
to -8 
Day -7 
Day -1 
Day 1 
Day 15 
Day 
21a 
(± 2) 
Obtain informed 
consent 
X 
 
 
 
 
 
Obtain informed 
assent 
X 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
X 
X 
X 
 
 
Randomization 
 
 
 
X 
 
 
Dispense study drug 
 
 
 
X 
 
 
Study drug 
accountability 
 
 
 
 
X 
 
Medical History 
X 
 
 
 
 
 
Psychiatric History 
X 
 
 
 
 
 
Family Psychiatric 
History 
X 
 
 
 
 
 
Prior/concomitant 
medication review 
X 
X 
X 
X 
X 
X 
K-SADS-PL 
X 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
X 
Neurological 
examination 
X 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
Weight 
(including body mass 
index) 
X 
 
 
X 
X 
X 
Vital signs 
X 
X 
 
Xb 
Xb 
X 
Electrocardiogram 
(ECG) 
X 
 
 
 
 
X 
Adverse event 
monitoringf 
 
 
 
 
X 
X 


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Procedures 
Screening 
Double-blind Period 
End of 
Study 
Clinic 
Visit 
Practice 
Laboratory 
Classroom 
Session 
Telephone 
Contact 
First 
Laboratory 
Classroom 
Day  
Second 
Laboratory 
Classroom 
Day 
- 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Day -42 
to -8 
Day -7 
Day -1 
Day 1 
Day 15 
Day 
21a 
(± 2) 
Columbia Suicide 
Severity Rating Scale 
(C-SSRS) 
X 
X 
 
X 
X 
X 
ADHD-RS-IV HV 
X 
Xg 
X 
 
 
X 
Classroom Practice 
Sessionc 
 
X 
 
 
 
 
SKAMPd 
 
 
 
X 
X 
 
Math pre-test for 
determination of math 
level 
X 
 
 
 
 
 
PERMPd 
 
 
 
X 
X 
 
Dosing diary 
distribution/review 
 
 
 
X 
X 
 
Hematology/Chemistry 
X 
 
 
 
 
X 
TSH 
X 
 
 
 
 
 
Serum β-hCG (in 
females ≥ 8 years of 
age)e 
X 
 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
X 
Urine drug screen 
X 
 
 
X 
X 
X 
Urine β-hCG (in 
females ≥ 8 years of 
age)e 
 
 
 
X 
X 
 
Abbreviations: ADHD-RS-IV HV = ADHD Rating Scale Version IV Home Version (modified for investigator 
administration), β-hCG = beta-human chorionic gonadotropin, K-SADS-PL = Schedule for Affective Disorders and 
Schizophrenia for School-Age Children- Present and Lifetime version, PERMP = Permanent Product Measure of 
Performance, SKAMP = Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale, TSH = thyroid stimulating hormone 
a Seven (± 2) days after the last dose of study drug, all subjects will return to the clinic and complete assessments. 
b Heart rate and blood pressure will be measured at approximately the same time on Day 1 and Day 15.  
c Including practice SKAMP assessments, practice PERMP tests, and other planned activities intended to familiarize 
subjects with the classroom setting. 
d Classroom sessions will be started at approximately 8 AM, 10 AM, 12 PM, 2 PM, 4 PM, 6 PM, and 8 PM. 
e Any positive urine β-hCG test should be confirmed by serum β-hCG. 
f Pre-treatment events will be collected from the time of informed consent until the first study drug administration. 
g The ADHD-RS-IV HV may be completed in person or by telephone contact on Day -9, -8, or -7. 


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14.2 Sample Laboratory Classroom Day Schedule (Day 15) 
Nominal Time 
Actual Time 
Arrival 
PERMP/SKAMP 
Meal/snack 
Dismissal 
 
6:30 am 
X 
 
 
 
 
7:30 am 
 
 
X 
 
12 h post-dose 
8:00 am 
 
X 
 
 
 
9:45 am 
 
 
X 
 
14 h post-dose 
10:00 am 
 
X 
 
 
16 h post-dose 
12:00 pm 
 
X 
 
 
 
12:30 pm 
 
 
X 
 
18 h post-dose 
2:00 pm 
 
X 
 
 
 
2:30 pm 
 
 
X 
 
20 h post-dose 
4:00 pm 
 
X 
 
 
22 h post-dose 
6:00 pm 
 
X 
 
 
 
6:30 pm 
 
 
X 
 
24 h post-dose 
8:00 pm 
 
X 
 
 
 
8:45 pm 
 
 
 
X 
 


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14.3 SKAMP Rating Scale and Subscales 
Subscale 
Item 
  Attention 
1. Getting started on assignments for classroom periods 
2. Sticking with tasks or activities for the allotted time 
3. Attending to an activity or a discussion of the class 
4. Stopping and making transition to the next period 
 Deportment 
5. Interacting with other children (e.g., other students) 
6. Interacting with adults (e.g., teacher or aide) 
7. Remaining quiet according to classroom rules 
8. Staying seated according to classroom rules 
Quality of Work 
9. Completing assigned work 
10. Performing work accurately 
11. Being careful and neat while writing or drawing 
Compliance 
12. Complying with teacher’s usual requests or directions 
13. Following the rules established for the classroom 
 


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14.4 Laboratory Criteria for Markedly Abnormal Values 
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 
Haematocrit (fraction, %) 
≤ 30, ≥ 50 
1 / % 
≤ 30, ≥ 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 
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 
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 
Urinalysis 
 
 
 
RBC (hpf)  
> 15 
N/A 
> 15 
WBC (hpf)  
> 15 
N/A 
> 15 
 
 


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14.5 Vital Signs Criteria for Markedly Abnormal Values  
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 
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. 


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14.6 12-Lead ECG Criteria for Markedly Abnormal Values 
 
 
 
 
 
 
14.7 Preferred Term for Adverse Events of Special Concern 
1. Suicidal ideations, suicidal behavior, suicide attempts, and related events. 
 
2. Spontaneous abortion / miscarriage 
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 
12 to <16 
-- 
> 110 
≥16 
-- 
> 120 
SMQ 20000037: Suicide/self-injury 
PT 
Code 
Columbia suicide severity rating scale abnormal 
10075616 
Completed suicide 
10010144 
Depression suicidal 
10012397 
Intentional overdose 
10022523 
Intentional self-injury 
10022524 
Poisoning deliberate 
10036000 
Self injurious behaviour 
10063495 
Self-injurious ideation 
10051154 
Suicidal behaviour 
10065604 
Suicidal ideation 
10042458 
Suicide attempt 
10042464 
Suicide threat 
10077417 
SMQ 20000192:  Termination of pregnancy and risk of abortion  
PT 
Code 
Abnormal product of conception 
10060927 
Aborted pregnancy 
10000209 
Abortion 
10000210 
Abortion complete 
10061614 
Abortion complete complicated 
10000212 
Abortion complicated 
10061615 
Abortion early 
10052846 
Abortion incomplete 
10000217 
Abortion incomplete complicated 
10000218 
Abortion induced 
10000220 
Abortion induced complete 
10060928 
Abortion induced complete complicated 
10000221 
Abortion induced complicated 
10000223 
Abortion induced incomplete 
10053984 
Abortion induced incomplete complicated 
10000225 
Abortion infected 
10000228 
Abortion late 
10052847 
Abortion missed 
10000230 
Abortion of ectopic pregnancy 
10066266 
Abortion spontaneous 
10000234 
Abortion spontaneous complete 
10061616 
Abortion spontaneous complete complicated 
10000236 
Abortion spontaneous complicated 
10000238 
Abortion spontaneous incomplete 
10061617 


Sunovion Pharmaceuticals Inc. 
 
Statistical Analysis Plan 
Protocol No. SEP360-311 
 
26 March 2019 
Version:  1.0 
 
Page 54 of 59 
 
3. Neuropsychiatric events 
Abortion spontaneous incomplete complicated 
10000239 
Abortion threatened 
10000242 
Biochemical pregnancy 
10063639 
Blighted ovum 
10005160 
Ectopic pregnancy termination 
10014168 
Evacuation of retained products of conception 
10015550 
Foetal death 
10055690 
Foeticide 
10075033 
Habitual abortion 
10062935 
Imminent abortion 
10051459 
Induced abortion failed 
10053191 
Induced abortion haemorrhage 
10052844 
Induced abortion infection 
10052845 
Molar abortion 
10065942 
Mycoplasmal postabortal fever 
10028479 
Post abortion complication 
10036244 
Post abortion haemorrhage 
10036246 
Post abortion infection 
10061467 
Premature baby death 
10076700 
Prophylaxis of abortion 
10065000 
Retained products of conception 
10038773 
Selective abortion 
10067499 
Stillbirth 
10042062 
Twin reversed arterial perfusion sequence malformation 
10073455 
Vanishing twin syndrome 
10071398 
SMQ 20000117:   
Psychosis and psychotic disorders 
PT 
Code 
Abnormal behaviour 
10061422 
Abulia 
10050013 
Acute psychosis 
10001022 
Affect lability 
10054196 
Affective ambivalence 
10077173 
Affective disorder 
10001443 
Alcohol withdrawal syndrome 
10053164 
Alcoholic psychosis 
10001632 
Alice in wonderland syndrome 
10001666 
Anosognosia 
10068346 
Apathy 
10002942 
Asocial behaviour 
10003472 
Bipolar I disorder 
10004939 
Blunted affect 
10005885 
Bradyphrenia 
10050012 
Brief psychotic disorder with marked stressors 
10048549 
Brief psychotic disorder without marked stressors 
10056395 
Brief psychotic disorder, with postpartum onset 
10006362 
Catatonia 
10007776 
Charles Bonnet syndrome 
10063354 
Childhood psychosis 
10061040 
Clang associations 
10009232 
Constricted affect 
10010778 
Cotard's syndrome 
10059591 
Delusion 
10012239 
Delusion of grandeur 
10012241 
Delusion of reference 
10012244 
Delusion of replacement 
10012245 
Delusional disorder, erotomanic type 
10012249 
Delusional disorder, grandiose type 
10012250 
Delusional disorder, jealous type 
10012251 
Delusional disorder, mixed type 
10012252 
Delusional disorder, persecutory type 
10053195 
Delusional disorder, somatic type 
10012254 
Delusional disorder, unspecified type 
10012255 
Delusional perception 
10012258 


Sunovion Pharmaceuticals Inc. 
 
Statistical Analysis Plan 
Protocol No. SEP360-311 
 
26 March 2019 
Version:  1.0 
 
Page 55 of 59 
Dementia of the Alzheimer's type, with delusions 
10012295 
Depressive delusion 
10063033 
Derailment 
10012411 
Disorganised speech 
10076227 
Dyslogia 
10054940 
Echolalia 
10014127 
Echopraxia 
10014128 
Emotional poverty 
10014557 
Epileptic psychosis 
10059232 
Erotomanic delusion 
10015134 
Flat affect 
10016759 
Flight of ideas 
10016777 
Grandiosity 
10018671 
Hallucination 
10019063 
Hallucination, auditory 
10019070 
Hallucination, gustatory 
10019071 
Hallucination, olfactory 
10019072 
Hallucination, synaesthetic 
10062824 
Hallucination, tactile 
10019074 
Hallucination, visual 
10019075 
Hallucinations, mixed 
10019079 
Hypnagogic hallucination 
10020927 
Hypnopompic hallucination 
10020928 
Hypomania 
10021030 
Hysterical psychosis 
10062645 
Ideas of reference 
10021212 
Idioglossia 
10068366 
Illogical thinking 
10021402 
Illusion 
10021403 
Impaired reasoning 
10071176 
Inappropriate affect 
10021588 
Incoherent 
10021630 
Intrusive thoughts 
10077275 
Jealous delusion 
10023164 
Lack of spontaneous speech 
10023615 
Logorrhoea 
10024796 
Loose associations 
10024825 
Magical thinking 
10025429 
Major depression 
10057840 
Mania 
10026749 
Mixed delusion 
10076429 
Mutism 
10028403 
Neologism 
10028916 
Neuroleptic-induced deficit syndrome 
10075295 
Obsessive rumination 
10056264 
Paralogism 
10077175 
Paranoia 
10033864 
Paranoid personality disorder 
10033869 
Parkinson's disease psychosis 
10074835 
Paroxysmal perceptual alteration 
10063117 
Persecutory delusion 
10034702 
Perseveration 
10034703 
Postictal psychosis 
10070669 
Post-injection delirium sedation syndrome 
10072851 
Posturing 
10036437 
Poverty of speech 
10036467 
Poverty of thought content 
10036468 
Presenile dementia 
10036631 
Pressure of speech 
10036649 
Psychosis postoperative 
10065617 
Psychotic behaviour 
10037249 
Psychotic disorder 
10061920 
Psychotic disorder due to a general medical condition 
10061921 
Reactive psychosis 
10053632 
Rebound psychosis 
10074833 
Schizoaffective disorder 
10039621 


Sunovion Pharmaceuticals Inc. 
 
Statistical Analysis Plan 
Protocol No. SEP360-311 
 
26 March 2019 
Version:  1.0 
 
Page 56 of 59 
 
4. Cardiac arrhythmias 
Schizoaffective disorder bipolar type 
10068889 
Schizoaffective disorder depressive type 
10068890 
Schizophrenia 
10039626 
Schizophreniform disorder 
10039647 
Schizotypal personality disorder 
10039651 
Senile dementia 
10039966 
Senile psychosis 
10039987 
Shared psychotic disorder 
10040535 
Social avoidant behaviour 
10041243 
Somatic delusion 
10041317 
Somatic hallucination 
10062684 
Speech disorder 
10041466 
Substance-induced psychotic disorder 
10072388 
Suspiciousness 
10042635 
Tachyphrenia 
10064805 
Tangentiality 
10043114 
Thinking abnormal 
10043431 
Thought blocking 
10043495 
Thought broadcasting 
10052214 
Thought insertion 
10043496 
Thought withdrawal 
10043497 
Transient psychosis 
10056326 
Vascular dementia 
10057678 
Verbigeration 
10047313 
Waxy flexibility 
10047853 
Additional Terms 
Formication 
10017062 
Substance-induced mood disorder 
10072387 
SMQ 20000049: 
Cardiac arrhythmias 
PT 
Code 
Accelerated idioventricular rhythm 
10049003 
Accessory cardiac pathway 
10067618 
Adams-Stokes syndrome 
10001115 
Agonal rhythm 
10054015 
Anomalous atrioventricular excitation 
10002611 
Arrhythmia 
10003119 
Arrhythmia neonatal 
10003124 
Arrhythmia supraventricular 
10003130 
Arrhythmogenic right ventricular dysplasia 
10058093 
Atrial conduction time prolongation 
10064191 
Atrial fibrillation 
10003658 
Atrial flutter 
10003662 
Atrial parasystole 
10071666 
Atrial tachycardia 
10003668 
Atrioventricular block 
10003671 
Atrioventricular block complete 
10003673 
Atrioventricular block first degree 
10003674 
Atrioventricular block second degree 
10003677 
Atrioventricular conduction time shortened 
10068180 
Atrioventricular dissociation 
10069571 
Atrioventricular node dispersion 
10077893 
Baseline foetal heart rate variability disorder 
10074638 
Bezold-Jarisch reflex 
10076999 
Bifascicular block 
10057393 
Bradyarrhythmia 
10049765 
Bradycardia 
10006093 
Bradycardia foetal 
10006094 
Bradycardia neonatal 
10056471 
Brugada syndrome 
10059027 
Bundle branch block 
10006578 
Bundle branch block bilateral 
10006579 
Bundle branch block left 
10006580 
Bundle branch block right 
10006582 


Sunovion Pharmaceuticals Inc. 
 
Statistical Analysis Plan 
Protocol No. SEP360-311 
 
26 March 2019 
Version:  1.0 
 
Page 57 of 59 
Cardiac arrest 
10007515 
Cardiac arrest neonatal 
10007516 
Cardiac death 
10049993 
Cardiac fibrillation 
10061592 
Cardiac flutter 
10052840 
Cardiac telemetry abnormal 
10053450 
Cardio-respiratory arrest 
10007617 
Cardio-respiratory arrest neonatal 
10007618 
Chronotropic incompetence 
10068627 
Conduction disorder 
10010276 
Defect conduction intraventricular 
10012118 
ECG P wave inverted 
10057526 
Electrocardiogram abnormal 
10014363 
Electrocardiogram ambulatory abnormal 
10014369 
Electrocardiogram change 
10061116 
Electrocardiogram delta waves abnormal 
10014372 
Electrocardiogram P wave abnormal 
10050384 
Electrocardiogram PQ interval prolonged 
10053656 
Electrocardiogram PQ interval shortened 
10075328 
Electrocardiogram PR prolongation 
10053657 
Electrocardiogram PR shortened 
10014374 
Electrocardiogram QRS complex prolonged 
10014380 
Electrocardiogram QT prolonged 
10014387 
Electrocardiogram repolarisation abnormality 
10052464 
Electrocardiogram RR interval prolonged 
10067652 
Electrocardiogram U-wave abnormality 
10055032 
Extrasystoles 
10015856 
Foetal arrhythmia 
10016847 
Foetal heart rate acceleration abnormality 
10074642 
Foetal heart rate deceleration abnormality 
10074636 
Foetal heart rate disorder 
10061158 
Foetal tachyarrhythmia 
10077575 
Heart alternation 
10058155 
Heart block congenital 
10019263 
Heart rate abnormal 
10019300 
Heart rate decreased 
10019301 
Heart rate increased 
10019303 
Heart rate irregular 
10019304 
Junctional ectopic tachycardia 
10074640 
Lenegre's disease 
10071710 
Long QT syndrome 
10024803 
Long QT syndrome congenital 
10057926 
Loss of consciousness 
10024855 
Lown-Ganong-Levine syndrome 
10024984 
Neonatal tachycardia 
10049775 
Nodal arrhythmia 
10029458 
Nodal rhythm 
10029470 
Nonreassuring foetal heart rate pattern 
10074641 
Pacemaker generated arrhythmia 
10053486 
Pacemaker syndrome 
10051994 
Palpitations 
10033557 
Parasystole 
10033929 
Paroxysmal arrhythmia 
10050106 
Paroxysmal atrioventricular block 
10077503 
Pulseless electrical activity 
10058151 
Rebound tachycardia 
10067207 
Reperfusion arrhythmia 
10058156 
Retrograde p-waves 
10071187 
Rhythm idioventricular 
10039111 
Sinoatrial block 
10040736 
Sinus arrest 
10040738 
Sinus arrhythmia 
10040739 
Sinus bradycardia 
10040741 
Sinus node dysfunction 
10075889 
Sinus tachycardia 
10040752 
Sudden cardiac death 
10049418 


Sunovion Pharmaceuticals Inc. 
 
Statistical Analysis Plan 
Protocol No. SEP360-311 
 
26 March 2019 
Version:  1.0 
 
Page 58 of 59 
 
5. Combined insomnia 
 
6. Weight decreased 
 
7. Decreased appetite 
 
 
8. Psychosis/Mania (subgroup of neuropsychiatric events) 
Sudden death 
10042434 
Supraventricular extrasystoles 
10042602 
Supraventricular tachyarrhythmia 
10065342 
Supraventricular tachycardia 
10042604 
Syncope 
10042772 
Tachyarrhythmia 
10049447 
Tachycardia 
10043071 
Tachycardia foetal 
10043074 
Tachycardia paroxysmal 
10043079 
Torsade de pointes 
10044066 
Trifascicular block 
10044644 
Ventricular arrhythmia 
10047281 
Ventricular asystole 
10047284 
Ventricular dyssynchrony 
10071186 
Ventricular extrasystoles 
10047289 
Ventricular fibrillation 
10047290 
Ventricular flutter 
10047294 
Ventricular parasystole 
10058184 
Ventricular pre-excitation 
10049761 
Ventricular tachyarrhythmia 
10065341 
Ventricular tachycardia 
10047302 
Wandering pacemaker 
10047818 
Withdrawal arrhythmia 
10047997 
Wolff-Parkinson-White syndrome 
10048015 
Wolff-Parkinson-White syndrome congenital 
10049291 
PT 
Code 
Insomnia 
10022437 
Initial insomnia 
10022035 
Middle insomnia 
10027590 
Terminal insomnia 
10068932 
PT 
Code 
Weight decreased 
10047895 
PT 
Code 
Decreased appetite 
10061428 
PT 
Code 
Catatonia 
10007776 
Delusion 
10012239 
Somatic delusion 
10041317 
Delusional perception 
10012258 
Formication 
10017062 
Hallucination 
10019063 
Hallucination, auditory 
10019070 
Hallucination, gustatory 
10019071 
Hallucination, olfactory 
10019072 
Hallucination, tactile 
10019074 
Hallucination, visual 
10019075 
Hallucinations, mixed 
10019079 
Hypnagogic hallucination 
10020927 
Hypnopompic hallucination 
10020928 
Illusion 
10021403 
Paranoia 
10033864 
Psychotic disorder 
10061920 
Substance-induced psychotic disorder 
10072388 
Thinking abnormal 
10043431 
Hypomania 
10021030 
Mania 
10026749 


Sunovion Pharmaceuticals Inc. 
 
Statistical Analysis Plan 
Protocol No. SEP360-311 
 
26 March 2019 
Version:  1.0 
 
Page 59 of 59 
 
 
Substance-induced mood disorder 
10072387