Clinical trial NCT03088267
Conditions: Attention Deficit Hyperactivity Disorder
Sponsor: Tris Pharma, Inc.
Start date: 2017-02-11; Completion date: 2017-10-30
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study was conducted to assess the efficacy and safety of DYANAVEL XR (amphetamine extended-release oral suspension, CII) for the treatment of symptoms of attention-deficit/hyperactivity disorder (ADHD) in children aged 6-12 years.

Detailed description:
This is a randomized, double-blind, two treatment, two sequence, placebo-controlled crossover study to assess the efficacy and safety of dose Dyanavel XR in reducing signs and symptoms of ADHD compared with placebo in pediatric subjects ages 6 to 12 years with ADHD.

Arms: arm 1: Double blind amphetamine extended-release oral suspension, 2.5 mg/mL, 6, 7 or 8 mL po QAM arm 2: Double blind placebo, 6, 7 or 8 mL po QAM
Interventions: intervention 1: amphetamine extended-release oral suspension, 2.5 mg/mL intervention 2: Placebo extended-release oral suspension
Intervention descriptions: intervention 1: 5 mL1 (5 mg), 7 mL (17.5 mg) or 8 mL (20 mg) PO intervention 2: 6, 7 or 8 mL PO

Protocol documents:
Prot_000.pdf: 
Tris Pharma, Inc. 
 
Protocol v. 2.0 
TRI102-ADD-300 
 
02 February 2017 
 
Page 1 of 53 
Confidential 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Title:  Dyanavel® XR Extended-Release Oral Suspension in the Treatment of Children with ADHD:  A 
Laboratory School Study. 
 
 
Protocol Number:  
TRI102-ADD-300 
Investigational Drug: 
Dyanavel® XR 
Version: 
v. 2.0 (02 February 2017) 
IND Applicant/Sponsor: 
Tris Pharma, Inc. 
2033 Route 130 
Monmouth Junction, NJ 08852 
Authorized Signatory: 
Sally A. Berry, MD, PhD 
Chief Medical Officer  
Tris Pharma, Inc. 
Primary Study Contact: 
Antonio Pardo, MD 
Manager, Clinical Affairs 
Tris Pharma, Inc. 
Protocol Amendments:  
N/A 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and all 
applicable regulatory requirements.  
 
Confidentiality Statement 
The confidential information in this document is provided to you as an investigator or consultant for review by you, your staff, 
and the applicable Institutional Review Board.  Your acceptance of this document constitutes agreement that you will not 
disclose the information contained herein to others without written authorization from the Sponsor. 


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INVESTIGATOR’S SIGNATURE 
 
 
I have read protocol TRI102-ADD-300 and agree to conduct the study as outlined.  I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Title of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 


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SPONSOR’S SIGNATURE 
 
Approved by: 
 
 
 
 
 
 
Sally A. Berry, MD, PhD 
Chief Medical Officer  
Tris Pharma, Inc. 
 
 
Date 
 


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PROCEDURES IN CASE OF EMERGENCY 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Clinical Study Leader  
Antonio Pardo, MD 
Tris Pharma, Inc. 
2033 Route 130, Suite D 
Monmouth Junction, NJ 08552 
(732) 823-4755 (office) 
(917) 514-9058 
Chief Medical Officer 
Sally Berry, MD 
Tris Pharma, Inc. 
2033 Route 130, Suite D 
Monmouth Junction,  NJ 08552 
(732) 823-4720 (office) 
(609) 865-6816 
Please include ClinicalAffairs@trispharma.com and Safety@trispharma.com on all your correspondence 


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SYNOPSIS 
Title: 
Dyanavel® XR Extended-Release Oral Suspension in the Treatment of Children with 
ADHD:  A Laboratory School Study 
Study number 
 
TRI102-ADD-300 Version: 2.0 (02 February, 2017) 
Study Center(s) 
1 site 
Clinical Phase 
III - IV 
Indication 
ADHD (Attention-deficit/hyperactivity disorder) 
Objectives 
Primary Efficacy Objective: To demonstrate that Dyanavel® XR extended-release  oral 
suspension has an onset of action of 30 minutes post-dose as determined by change from 
pre-dose in SKAMP-Combined scores at 30 minutes post-dose during the laboratory school 
days (Visits 3 and 4), relative to placebo.  
Safety Objective: To assess the safety and tolerability of Dyanavel XR in pediatric subjects 
with ADHD.   
Study Design 
Double-blind, Two Treatment, Two Sequence 
 
Sample Size/ 
Study Population 
Up to 18 males or females aged 6 to 12 with ADHD 
1 cohort 
Treatment 
Duration 
• 
Screening 
• 
Baseline (Visit 1) 
• 
Practice Classroom (Visit 2)  
• 
Double blind Classroom  (Visit 3) 
• 
Double blind Classroom  (Visit 4) 
Test Product 
Dose / Route / 
Regimen 
Open label Dyanavel XR:  
Dyanavel XR as determined by the study doctor, up to 8 mL (20mg)/ day 
 
Double-Blinded Classroom: 
One dose of Dyanavel XR 6 mL (15mg), 7mL (17.5 mg) or 8 mL (20mg)  
One dose of Dyanavel XR Placebo 6 mL, 7mL  or 8 mL 
Pharmacokinetics 
NA 
Methodology 
Inclusion Criteria 
1. 
Males or females aged 6 to 12 years at the time of screening, inclusive 
2. 
Diagnosed with ADHD by a psychiatrist within 6 months of study enrolment or 
newly diagnosed with ADHD using the DSM-5 criteria for ADHD 
3. 
An ADHD-RS-5 score at Screening ≥90th percentile for sex and age in at least one 
of the following categories: 
a) Hyperactive-impulsive subscale, 


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b) Inattentive subscale, or 
c) Total score. 
Subjects who do not meet this criteria at screening can have ADHD-RS-5 repeated 
at baseline, after washout of stimulant medication for a minimum of 24 hours prior 
to baseline. 
4. 
In the clinical judgment of the Investigator, the subject must be in need of 
pharmacological treatment for ADHD.   
5. 
Females of childbearing potential must be non-lactating and must have a negative 
serum pregnancy test at screening 
6. 
Provide written informed consent (parent/guardian) and assent (child aged 10 – 12 
years only) prior to participation in the study 
 
Exclusion Criteria 
1. 
Diagnosed with any DSM-5 active disorder (other than ADHD) with the exception 
of specific phobias, learning disorders, motor skills disorders, communication 
disorders, oppositional defiant disorder, elimination disorders, and sleep disorders 
2. 
Known history of chronic medical illnesses including severe hypertension, 
untreated thyroid disease, peripheral vasculopathy, known structural cardiac 
disorders, serious cardiac conditions, serious arrhythmias, cardiomyopathy, known 
family history of sudden death   
3. 
Known history or presence of significant renal or hepatic disease, as indicated by 
clinical laboratory assessment (liver function test results ≥ two times the upper 
limit of normal, blood urea nitrogen, or creatinine). 
4. 
Clinically significant abnormal ECG or cardiac findings on physical examination 
(including the presence of a pathologic murmur) 
5. 
Use of the following medications within 30 days of Baseline Visit: 
 
MAOI - monoamine oxidase inhibitors (e.g., Selegiline, isocarboxazid, 
phenelzine, tranylcypromine) 
 
Tricyclic Antidepressants (e.g. Desipramine, protriptyline) 
6. 
Use of the following medications within 3 days of Baseline Visit 
 
Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic 
acid HCl, ascorbic acid) 
 
Urinary acidifying agents (e.g., ammonium chloride, sodium acid 
phosphate, methenamine salts) 
7. 
Use of atomoxetine within 14 days of Baseline Visit 
8. 
Planned use of prohibited drugs or agents from the Screening visit through the end 
of the study  
9. 
Abnormal clinically significantly laboratory test value at screening that, in the 
opinion of the Investigator, would preclude study participation 
10. Known history of allergy/hypersensitivity to amphetamine or any of the 
components of Dyanavel XR, or topical anaesthetics 
11. Known history of lack of response to amphetamine 
12. Parent or guardian’s inability or unwillingness to follow directions of the 
Investigator or study research staff.   
13. Any uncontrolled medical condition that in the opinion of the Investigator would 
preclude study participation 


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14. History of significant illness requiring hospitalization, or surgery requiring 
anaesthetics within 30 days of Baseline Visit 
Assessments 
 
SKAMP Assessments 
 
PERMP 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
 
ADHD-Rating Scale-5 (ADHD-RS-5) 
 
Adverse Events 
 
Electrocardiogram 
 
Safety Labs 
 
Physical Exam 
 
Vital Signs 
 
Medical History 
 
Concomitant Medications 
Statistical 
Analysis 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from pre-dose in model-adjusted 
SKAMP-Combined scores at 30 minutes post-dose measured during the laboratory school 
days (Visit 3 and 4).  The difference between Dyanavel XR and placebo will be assessed at 
the alpha = 0.05 level of significance.   
 
Secondary Efficacy Endpoints 
Efficacy will also be assessed by the following measures during the laboratory school day 
(Visits 3 and 4): 
Change from pre-dose in SKAMP scores at 3 hours post-dose 
Change from pre-dose in PERMP scores at 30 minutes and 3 hours post-dose 
Safety Endpoints 
Safety will be monitored by adverse events (AEs) assessed at each visit.  In addition, the 
Columbia Suicide Severity Rating Scale (C-SSRS) will be administered at Screening, 
Baseline and all subsequent visits to assess emergent suicidal thoughts or behaviors.  Medical
history will capture all medical conditions at Screening.  Physical examinations, vital signs, 
height and/or weight assessments, 12-lead electrocardiogram (ECG), and clinical laboratory 
tests will be conducted at Screening.  
 
 
 
 


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TABLE OF CONTENTS  
INVESTIGATOR’S SIGNATURE .................................................................................................2 
SPONSOR’S SIGNATURE ............................................................................................................3 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4 
SYNOPSIS .......................................................................................................................................5 
TABLE OF CONTENTS .................................................................................................................8 
LIST OF TABLES .........................................................................................................................12 
LIST OF ABBREVIATIONS ........................................................................................................13 
1. 
INTRODUCTION ........................................................................................................14 
2. 
OBJECTIVES ...............................................................................................................15 
 
Efficacy Objective .........................................................................................................15 
 
Safety Objective ............................................................................................................15 
3. 
STUDY DESIGN ..........................................................................................................16 
 
Design ...........................................................................................................................16 
 
Study Endpoints ............................................................................................................17 
3.2.1. 
Primary Efficacy Endpoint ............................................................................................17 
3.2.2. 
Secondary Endpoint ......................................................................................................17 
3.2.3. 
Safety Endpoint .............................................................................................................17 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................18 
 
Inclusion Criteria ...........................................................................................................18 
 
Exclusion Criteria..........................................................................................................18 
 
Subject Withdrawal Criteria ..........................................................................................19 
 
Study Stopping Rules ....................................................................................................20 
5. 
STUDY SCHEDULE AND PROCEDURES ...............................................................21 
 
Study Schedule ..............................................................................................................21 
 
Efficacy and Safety Assessments ..................................................................................21 
5.2.1. 
Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale (SKAMP) ....................21 
5.2.2. 
Permanent Product Measurement of Performance (PERMP) .......................................21 
5.2.3. 
ADHD-Rating Scale-5 (ADHD-RS-5) .........................................................................21 


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Study Visits and Procedures .........................................................................................21 
5.3.1. 
Study Periods ................................................................................................................22 
5.3.1.1. 
Screening .......................................................................................................................22 
5.3.1.2. 
Baseline (Visit 1) ..........................................................................................................23 
5.3.1.3. 
Practice Laboratory School Day (Visit 2) .....................................................................23 
5.3.1.4. 
Randomized, Double-blind, Placebo-Controlled Treatment Period (Visits 3 
and 4) .............................................................................................................................25 
5.3.1.5. 
Early Termination Visit ................................................................................................26 
6. 
INVESTIGATIONAL DRUG INFORMATION AND MANAGEMENT ..................27 
 
Drug Dose Regimen ......................................................................................................27 
 
Drug Packaging and Labeling .......................................................................................27 
 
Drug Storage .................................................................................................................27 
 
Drug Dispensing ...........................................................................................................28 
 
Drug Administration .....................................................................................................28 
 
Drug Accountability ......................................................................................................28 
 
Drug Handling and Disposal .........................................................................................29 
7. 
SUBJECT COMPLIANCE ...........................................................................................30 
 
Concomitant Medication and/or Therapy .....................................................................30 
 
Prohibited Concomitant Medications and Foods ..........................................................30 
7.2.1. 
Prohibited Concomitant Medications ............................................................................30 
 
Treatment Compliance ..................................................................................................31 
8. 
RANDOMIZATION AND BLINDING PROCEDURES ............................................32 
9. 
ADVERSE AND SERIOUS ADVERSE EVENTS .....................................................33 
 
Definitions of Adverse Events ......................................................................................33 
9.1.1. 
Adverse Event (AE) ......................................................................................................33 
9.1.2. 
Serious Adverse Event (SAE) .......................................................................................33 
9.1.3. 
Adverse Reaction (AR) and Suspected Adverse Reaction (SAR) ................................34 
9.1.4. 
Unanticipated Adverse Reaction (UAR) .......................................................................34 
 
Severity of AEs/SAEs ...................................................................................................35 
 
Relationship to Investigational Drug Treatment ...........................................................35 
 
Collecting and Recording Adverse Events ...................................................................36 


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9.4.1. 
Period of Collection ......................................................................................................36 
9.4.2. 
Methods of Collection ...................................................................................................36 
9.4.3. 
Recording Method .........................................................................................................37 
9.4.3.1. 
Adverse Events .............................................................................................................37 
9.4.3.2. 
Serious Adverse Events.................................................................................................37 
 
Reporting Adverse Events.............................................................................................37 
9.5.1. 
Reporting SAEs to the Sponsor ....................................................................................37 
9.5.2. 
Reporting SAEs to Health Authorities ..........................................................................38 
9.5.3. 
Reporting SAEs to the Central IRB(s) ..........................................................................38 
9.5.4. 
Reporting Pregnancy .....................................................................................................38 
10. 
STATISTICS ................................................................................................................40 
 
Power and Sample Size Determination .........................................................................40 
 
Analysis Populations .....................................................................................................40 
 
Efficacy and Safety Analyses........................................................................................41 
10.3.1. 
Background and Demographic Characteristics .............................................................41 
10.3.2. 
Efficacy Analyses .........................................................................................................41 
10.3.2.1.  Primary Efficacy Analysis ............................................................................................41 
10.3.3. 
Safety Analyses .............................................................................................................41 
 
Concomitant Medications and Concomitant Therapies ................................................41 
 
Other Statistical Considerations ....................................................................................41 
10.5.1. 
Significance Levels .......................................................................................................41 
10.5.2. 
Missing Data .................................................................................................................41 
11. 
DIRECT ACCESS TO PROCEDURAL DOCUMENTS ............................................43 
 
Study Monitoring ..........................................................................................................43 
 
Source Documents ........................................................................................................43 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................44 
13. 
ETHICS .........................................................................................................................45 
 
Ethics Review................................................................................................................45 
 
Ethics Committees ........................................................................................................45 
 
General Considerations .................................................................................................45 


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Informed Consent ..........................................................................................................46 
 
Subject Confidentiality .................................................................................................46 
 
Publications of the Clinical Study .................................................................................47 
 
Protocol Amendments and Deviations ..........................................................................47 
14. 
DATA HANDLING AND RECORD KEEPING.........................................................48 
 
Inspection of Records ....................................................................................................48 
 
Retention of Records .....................................................................................................48 
15. 
REFERENCES ..............................................................................................................49 
APPENDIX A.  SCHEDULE OF EVENTS ................................................................................50 
APPENDIX B.  REVISION HISTORY ......................................................................................51 
 


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LIST OF TABLES 
Table 1:  Study Design ...................................................................................................................16 
Table 2:  Laboratory Tests at Screening ........................................................................................23 
Table 3:  Dyanavel XR Content by Volume ..................................................................................28 
Table 4:  Attribution of Adverse Events ........................................................................................36 


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LIST OF ABBREVIATIONS 
Abbreviation or specialist term 
Explanation 
ADHD 
Attention-deficit hyperactivity disorder 
ADHD-RS-5 
ADHD-Rating Scale-5 
AE 
Adverse event 
AR 
Adverse reaction 
CFR 
Code of Federal Regulations 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
Electrocardiogram/electrocardiography 
CRF 
Case Report Form 
ER 
Extended Release 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
ICH 
International Conference on Harmonization 
ID 
Identification 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
PERMP 
Permanent Product Measure of Performance 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SKAMP 
Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale 
SOP 
Standard Operating Procedure 
UAR 
Unanticipated Adverse Reaction 
WASI 
Wechsler Abbreviated Scale of Intelligence 
 
 


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1. 
INTRODUCTION 
Amphetamine has been a well-established therapeutic agent for the treatment of Attention Hyperactivity 
Disorder (ADHD) for decades.  Since the original amphetamine approval, various dosage forms have 
been approved for use: 
 
immediate release (IR) dosage forms, oral solution and tablets.  
 
extended release (ER) dosage forms, capsules, and tablets with various release technologies 
Dyanavel XR is an extended-release oral suspension (EROS) that contains 2.5mg/mL amphetamine base.  
Drug-resin complexation is formed with the amphetamine and Sodium Polystyrene Sulfonate USP, an ion 
exchange resin. The extended release feature of the product is achieved by coating some drug/resin 
complexes with an extended-release coating. Dyanavel XR contains approximately a 3:1 ratio of d-
amphetamine compared to l-amphetamine. 
The efficacy of Dyanavel XR in the treatment of ADHD in children ages 6-12 has been established in a 
Phase 3 placebo-controlled laboratory classroom study: TRI102-ADD-001. ADHD symptoms in children 
on an individually optimized dose of amphetamine (range 10-20 mg/day) were significantly lower 
compared to symptoms experienced by children treated with placebo. Symptom control was demonstrated 
1 hour after dosing and efficacy was observed through 13 hours beyond dosing. The effect size in this 
study was in line with effect sizes demonstrated for other psychostimulants tested in a similar study 
design. The adverse events in this study were expected for amphetamine treatment with respect for type 
of adverse event, frequency and severity. 
Study TRI102-PPK-200 was conducted in children ages 6 to 12 years old with ADHD to 
evaluate the single-dose (10 mg) pharmacokinetics of orally administered Dyanavel XR. 
Following a single 10 mg oral dose of Dyanavel XR in 12 pediatric subjects under fasting 
conditions, d-amphetamine and l-amphetamine peak plasma concentrations occurred at a median 
time of 3.9 and 4.5 hours after dosing, respectively. The mean plasma terminal elimination half-
life of d-amphetamine was 10.43 (± 2.01 h) hours and the mean plasma terminal half-life for l-
amphetamine was 12.14 (± 3.15 h) hours. 
 
Study 2014-3401 was conducted in 29 healthy adult subjects in a crossover study under fasting 
conditions, following a single, 18.8 mg oral dose of DYANAVEL XR. d-amphetamine and l-
amphetamine, the median (range) time to peak plasma concentrations (Tmax) were 4.0 (2 – 7) 
hours after dosing and peak concentration (Cmax) were 102% and 106%, respectively of the Cmax 
of immediate-release (IR) mixed amphetamine salts tablets. The relative bioavailability of 
DYANAVEL XR compared to an equal dose of mixed amphetamine salts IR tablets is 106% of 
d-amphetamine and 111% for l-amphetamine. 
 
See the Dyanavel XR Package Insert for further information1. 


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2. 
OBJECTIVES 
 
Efficacy Objective 
To demonstrate that Dyanavel XR has an onset of action as early as 30 minutes post-dose as determined 
by change from pre-dose in SKAMP-Combined scores at 30 minutes post-dose during the laboratory 
school days (Visits 3 & 4), relative to placebo.  
 
Safety Objective 
To assess the safety and tolerability of Dyanavel XR in pediatric subjects with ADHD.   


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3. 
 STUDY DESIGN 
 
Design 
This is a randomized, double-blind, two treatment, two sequence, placebo-controlled crossover study to 
assess the efficacy and safety of dose Dyanavel XR in reducing signs and symptoms of ADHD compared 
with placebo in pediatric subjects ages 6 to 12 years with ADHD as early as 30 minutes post-dose. Up to 
18 pediatric subjects with ADHD are planned to be enrolled at one investigational site in the United 
States.   
After Screening and Baseline evaluations are complete, eligible subjects will enroll in the study to take 
open-label Dyanavel XR orally once daily in the morning beginning the day after the baseline visit.  
Subjects will be randomized at Visit 2 to sequence to take double-blind study drug (Dyanavel XR 15 mg, 
17.5 mg or 20 mg or placebo) orally once during visits 3 and 4 (Double Blind Classroom Visits).  
During visits 3 and 4, subjects will be evaluated for ADHD symptoms in a laboratory classroom setting 
utilizing the Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale (SKAMP) and Permanent 
Product Measure of Performance (PERMP) assessments.  An abbreviated practice laboratory session to 
acclimate site staff and subjects to the timing and procedures of the analog classroom specific to this 
protocol will occur during Visit 2. Subjects will received open label Dyanavel XR (15 mg, 17.5 mg or 20 
mg) at the study site during the practice laboratory session at Visit 2. 
Safety parameters will be evaluated throughout the study.   
A schematic of the overall study design is included below.  The full schedule of events is found in 
Appendix A. 
Table 1:  Study Design 
 


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Study Endpoints 
3.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from pre-dose in model-adjusted SKAMP-Combined scores 
at 30 minutes post-dose measured during the laboratory school days (Visit 3 and 4).  The difference 
between Dyanavel XR and placebo will be assessed at the alpha = 0.05 level of significance.   
3.2.2. 
Secondary Endpoint 
Efficacy will also be assessed by the following measures during the laboratory school day (Visits 3 and 
4): 
 
Change from pre-dose in SKAMP scores at 3 hours post-dose 
 
Change from pre-dose in PERMP scores at 30 minutes and 3 hours post-dose 
 
Subscales of these measures will also be assessed 
3.2.3. 
Safety Endpoint 
Safety will be monitored by adverse events (AEs) assessed at each visit.  In addition, the Columbia 
Suicide Severity Rating Scale (C-SSRS) will be administered at Screening, Baseline and all subsequent 
scheduled visits to assess emergent suicidal thoughts or behaviors.  Medical history will capture all 
medical conditions at Visit 1 (Screening Visit).  Physical examinations, vital signs, height and/or weight 
assessments, 12-lead electrocardiogram (ECG), and clinical laboratory tests will be conducted at 
Screening, or at the discretion of the Principal Investigator. 


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4. 
 SELECTION AND WITHDRAWAL OF SUBJECTS 
 
Inclusion Criteria 
All subjects must meet all of the following inclusion criteria to be eligible to enroll in this study: 
1. 
Males or females aged 6 to 12 years at the time of screening, inclusive 
2. 
Diagnosed with ADHD by a psychiatrist, psychologist, developmental pediatrician, 
pediatrician, or an experienced licensed allied health professional approved by the Sponsor within 
6 months of study enrolment or newly diagnosed with ADHD using the DSM-5 criteria for 
ADHD 
3. 
An ADHD-RS-5 score at Screening ≥90th percentile for sex and age in at least one of the 
following categories: 
a) Hyperactive-impulsive subscale, 
b) Inattentive subscale, or 
c) Total score. 
Subjects who do not meet this criteria at screening can have ADHD-RS-5 repeated at baseline, 
after washout of stimulant medication for a minimum of 24 hours prior to baseline. 
4. 
In the clinical judgment of the Investigator, the subject must be in need of 
pharmacological treatment for ADHD.  5. 
Females of childbearing potential must be non-
lactating and must have a negative serum pregnancy test at screening 
6. 
Provide written informed consent (parent/guardian) and assent (child aged 10 -12 years 
only) prior to participation in the study 
 
Exclusion Criteria 
The presence of any of the following exclusion criteria precludes a subject from study enrollment:   
1. 
Diagnosed with any DSM-5 active disorder (other than ADHD) with the exception of 
specific phobias, learning disorders, motor skills disorders, communication disorders, 
oppositional defiant disorder, elimination disorders, and sleep disorders 
2. Known history of chronic medical illnesses including severe hypertension, untreated thyroid 
disease, peripheral vasculopathy, known structural cardiac disorders, serious cardiac conditions, 
serious arrhythmias, cardiomyopathy, known family history of sudden death   
3. 
Known history or presence of significant renal or hepatic disease, as indicated by clinical 
laboratory assessment (liver function test results ≥ two times the upper limit of normal, blood 
urea nitrogen, or creatinine). 
4. 
Clinically significant abnormal ECG or cardiac findings on physical examination 
(including the presence of a pathologic murmur) 


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5. 
Use of the following medications within 30 days of Baseline Visit: 
o MAOI - monoamine oxidase inhibitors (e.g., Selegiline, isocarboxazid, 
phenelzine, tranylcypromine) 
o Tricyclic Antidepressants (e.g. Desipramine, protriptyline) 
6. 
Use of the following medications within 3 days of Baseline Visit 
o Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic 
acid HCl, ascorbic acid) 
o Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, 
methenamine salts) 
7. 
Use of atomoxetine within 14 days of Baseline Visit 
8. 
Planned use of prohibited drugs or agents from the Screening visit through the end of the 
study  
9. 
Abnormal clinically significantly laboratory test value at screening that, in the opinion of 
the Investigator, would preclude study participation 
10. 
Known history of allergy/hypersensitivity to amphetamine or any of the components of 
Dyanavel XR, or topical anesthetics 
11. 
Known history of lack of response to amphetamine 
12. 
Parent or guardian’s inability or unwillingness to follow directions of the Investigator or 
study research staff.   
13. 
Any uncontrolled medical condition that in the opinion of the Investigator would 
preclude study participation 
14. 
History of significant illness requiring hospitalization, or surgery requiring anesthetics 
within 30 days of Baseline Visit 
 
Subject Withdrawal Criteria 
Within the provisions of informed consent/assent and good clinical judgment with respect to the subject’s 
safety, every attempt should be made to have subjects complete the study.  The following are possible 
reasons to terminate the participation of any subject from the study: 
 
Signs and symptoms of intolerance to the study medication. 
 
A treatment-related, serious adverse event (SAE) is observed. 
 
The subject or parent/guardian is grossly non-compliant, as determined by the Investigator. 
 
Continued participation, in the opinion of the Investigator, is no longer in the best interest of the 
subject.  
 
The subject or parent/guardian wishes to withdraw for any reason. 


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 
Unblinding of the Investigator, site personnel performing assessments, or subject/parent to a 
subject’s treatment assignment during the double-blind Randomization Treatment Period of the 
study. 
Subjects will be encouraged to adhere to the protocol and complete all required assessments for the study.  
A subject may also be discontinued from the study for any of the following medical and/or administrative 
reasons: 
 
Pregnancy 
 
At the discretion of the Investigator at any time 
 
At the subject’s request 
 
Occurrence of a treatment-emergent AE or considerable worsening of an AE that represents an 
unacceptable risk to the subject and when continued participation in the investigational study is 
not warranted, in the judgment of the Investigator or the Sponsor.  The Investigator must follow 
the subject until the AE resolves or satisfactorily stabilizes. 
Any enrolled subjects desiring to discontinue prior to study completion should be encouraged to continue 
in the study and adhere to the protocol and subsequent regularly scheduled safety and effectiveness 
evaluations.  Subjects who are discontinued outside of any scheduled visit will be encouraged to complete 
the final study visit at the time of withdrawal.  Subjects who are discontinued during a scheduled visit will 
be encouraged to complete all assessments for both that study visit and the final study visit at the time of 
withdrawal.  A subject who withdraws following study drug administration will not be replaced.   
 
Study Stopping Rules  
This study may be discontinued at any time if, in the opinion of the Principal Investigator or the Sponsor, 
continuation of the study represents a significant medical risk to participating subjects.   


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5. 
STUDY SCHEDULE AND PROCEDURES 
 
Study Schedule 
The study schedule table can be found in Appendix A. 
 
Efficacy and Safety Assessments 
5.2.1. 
Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale (SKAMP) 
The SKAMP scale will be administered pre-dose, at 30 minutes and 3 hours post-dose during classroom 
sessions (visits 2, 3 and 4).  Training on the SKAMP scale will be required for those who have not 
received training in the 12 months prior to performing this study assessment.  Designated, qualified 
individuals from the study research team will perform the assessment.   
5.2.2. 
Permanent Product Measurement of Performance (PERMP) 
The PERMP scales will be administered pre-dose, at 30.minutes and 3 hours post-dose during classroom 
sessions (visits 2, 3 and 4). Training on the PERMP will be required for those who have not received 
training in the 12 months prior to performing this study assessment.  Designated, qualified individual 
from the study research team will perform the assessment.   
A placement math test will be administered at Baseline (Visit 1), or at Screening to determine the 
appropriate level of math test difficulty. 
5.2.3. 
ADHD-Rating Scale-5 (ADHD-RS-5) 
The ADHD-RS-5 will be used to determine study eligibility.  An ADHD-RS-5 assessment will be done at 
Screening and/or Baseline (Visit1). The Investigator or other designated, qualified individual from the 
study research team will perform the assessment.  
 
Study Visits and Procedures 
All study visit assessments will be collected on paper case report forms (CRFs).  
Safety will be monitored by observation of and direct inquiry regarding AEs at each post-dose visit.  
Subjects may experience AEs that necessitate an unscheduled visit. Situations may also arise wherein the 
Investigator asks a subject to report for an unscheduled visit following the report of an AE or SAE.  
Additional examinations may be conducted at these visits as necessary to ensure the safety and well-being 
of subjects during the study.  CRFs should be completed for each unscheduled visit. Refer to Section 9.4 
for information on AE collection, recording, and reporting.   
In addition, the Columbia Suicide Severity Rating Scale (C-SSRS) will be administered at Screening, and 
all subsequent visits to assess emergent suicidal thoughts or behaviors. 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.  The baseline 
version of the C-SSRS will be administered to all subjects at Screening. The “Since Last Visit” version 


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will be used at all subsequent study visits (and Early Termination, if applicable).  The Investigator or 
other designated, qualified individuals from the study research team will perform the assessment.   
Medical history will capture all medical conditions at Screening.  Physical examinations, height and body 
weight assessments, 12-lead ECG, and clinical laboratory tests will be conducted at Screening.  Blood 
pressure and pulse will be assessed at all study visits and will be taken using automated machines 
programmed to take 3 consecutive readings (at least 2 minutes apart); manual blood pressure readings 
will be taken if necessary.  Subjects should be comfortably seated for at least a few minutes prior to blood 
pressure readings.  Respiratory rate and temperature will be measured at Screening only. 
5.3.1. 
Study Periods 
Study duration is 6-8 weeks consisting of the following: 
 
Screening 
 
Baseline (Visit 1) 
 
Practice Classroom (Visit 2)  
 
Double Blind Classroom  (Visit 3) 
 
Double Blind Classroom  (Visit 4) 
5.3.1.1. 
Screening  
Before any study-specific procedures are performed, the subject and parent/guardian must receive an 
explanation of all study procedures and must sign and date an Institutional Review Board (IRB) approved 
written assent and informed consent, respectively. Potential subjects who give their informed consent 
(parent/guardian) and assent (children aged 10 – 12 years only) will undergo a screening period (up to 4 
weeks) to determine eligibility prior to the Baseline Visit. 
During the Screening visit, the following activities will be performed: 
 
Subject assent and parent/guardian informed consent 
 
Review of inclusion/exclusion criteria 
 
Review of medical history 
 
Review of medication history 
 
Demographics (i.e., sex, age, ethnicity and race) 
 
C-SSRS 
 
Physical examination 
 
Body weight and height 
 
Blood pressure, pulse, respiratory rate, and temperature 
 
Resting 12-lead ECG 


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 
Laboratory tests: 
Table 2:  Laboratory Tests at Screening 
Serum chemistry panel: 
Hematology CBC: 
Alanine aminotransferase  
Aspartate aminotransferase  
Blood Urea Nitrogen  
Creatinine  
Glucose 
gamma-glutamyl transpeptidase 
WBC - White blood cell count  
RBC - Red blood cell count  
Hemoglobin 
Hematocrit  
MCV - Mean cell volume  
MCH - Mean cell hemoglobin  
MCHC - Mean cell hemoglobin concentration 
RDW – Red blood cell distribution width  
Platelet count 
Other: 
Serum pregnancy test (females of child-bearing 
potential) 
 
 
PERMP math pre-test (may be performed at Baseline) 
 
Establish that DSM-5 diagnostic criteria for ADHD are met as performed by a psychiatrist, 
psychologist, developmental pediatrician, or pediatrician or permitted licensed allied health 
professional. 
 
ADHD-RS-5 
 
Cognitive functioning assessment by Investigator or WASI 
5.3.1.2. 
Baseline (Visit 1) 
Once the subject is determined to be initially eligible at Screening, the Baseline (Visit 1) evaluations will 
be performed.  If the subject continues to meet eligibility criteria at the Baseline Visit, the subject may be 
enrolled into the study.  Subjects will be instructed to take open-label Dyanavel XR orally once daily.  
Open-label Dyanavel XR will be dispensed to enrolled subjects.  Subjects will be instructed to take open-
label Dyanavel XR.  Subjects who are stimulant naive will take Dyanavel XR beginning at 2 mL daily in 
the morning. Subjects who have a history of stimulant treatment may be initiated on open label Dyanavel 
XR at whole mL doses between 2 and 6mL per day, inclusive, as selected by the investigator based on 
required doses for adequate symptom control with previous stimulant medication treatment. The dose for 
all subjects may be increased as tolerated as often as daily up to a maximum dose of 8 mL (20 mg) daily 
or until an optimal dose is reached as determined by the study doctor. The Investigator may decrease a 
subject’s dose at any time during the open-label period to ensure tolerability.  Subjects who find the 
maximum study dose of 8 mL (20 mg)/day is insufficient to treat their symptoms of ADHD and thus are 
not adequately controlled will be discontinued from the study.   


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The parents or guardians of the subjects will be instructed to administer the medication orally to their 
child once daily prior to 10 am with or without food. Children should not self-administer study 
medication. 
The following assessments will occur at the Baseline Visit: 
 
Review of inclusion/exclusion criteria 
 
Blood pressure and pulse 
 
PERMP placement test (if not performed during Screening) 
 
Urine pregnancy test (females of child-bearing potential only) 
 
Follow –up C-SSRS 
 
ADHD-RS-5 (if subject did not meet ADHD-RS-5 eligibility criteria at screening) 
 
AE assessment 
 
Concomitant medications assessment 
 
Open-label Dyanavel XR dispensing, accountability, and subject/parent/guardian training 
regarding investigational product 
5.3.1.3. 
Practice Laboratory School Day (Visit 2) 
Visit 2 should be scheduled after the last child enrolled in the study has had a minimum of 3 days of open 
label study medications administered prior to Visit 2. All subjects will have their Baseline visit within 4 
weeks of their screening visit. Visit 2 will occur on the same day for all subjects in the cohort and the date 
of the visit will be determined to permit the last enrolled subject to have 3 days of exposure to open label 
study medication prior to Visit 2. The maximum length of exposure to study medication prior to Visit 2 
shall be limited to 5 weeks.  
At Visit 2, efficacy assessments will occur during the practice laboratory school day. Assessments for 
ADHD symptoms and behaviors will be measured by SKAMP and PERMP in an abbreviated analog 
classroom.  Pre-dose assessments will be performed prior to the morning study drug dose on the day of 
the visit approximately 30 minutes prior to dosing.  After the pre-dose classroom assessments are 
completed, all subjects will be administered 15 mg, 17.5 mg or 20 mg of open-label Dyanavel XR.  The 
individual dose of study medication will be determined by the Investigator considering symptom control 
and tolerability.  
The following activities will be performed during Study Visit 2: 
 
Blood pressure and pulse (should be conducted any time after dosing) 
 
Investigator dose evaluation (should be determined prior to dosing) 
 
Follow-up C-SSRS 
 
AE assessment 
 
Concomitant medications assessment 


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 
Pre-dose:   
o SKAMP (in classroom setting) 
o PERMP (in classroom setting) 
 
Administer the investigator-assigned open-label dose of Dyanavel XR at study site 
 
Post-dose: 
o SKAMP (in classroom setting) at 30 minutes and 3 hours post-dose  
o PERMP (in classroom setting) at 30 minutes and 3 hours post-dose 
5.3.1.4. 
Randomized, Double-blind, Placebo-Controlled Treatment Period (Visits 3 and 
4) 
The subjects will be randomized to the treatment sequence to take double-blind study drug: 
o Dyanavel XR 6 mL (15 mg), 7 mL (17.5 mg) or 8 mL (20 mg) at Visit 3, then Placebo 6 
mL, 7 mL or 8 mL at Visit 4, or, 
o Placebo 6 mL, 7 mL or 8 mL at Visit 3, then Dyanavel XR 6 mL (15 mg), 7 mL (17.5 
mg) or 8 mL (20 mg) at Visit 4.  
Visit 3 will be scheduled the day following Visit 2. Visit 4 will be scheduled to occur the weekend 
following Visit 3. After the completion of visit 3, open label study medication will be dispensed to each 
subject. The study medication may continue to be adjusted as often as daily in increments of 1- 4 mL per 
day up to a maximum dose of 8 mL (20 mg) per day between visits 3 and 4 as instructed by the 
investigator considering symptom control and tolerability.  
The double blind laboratory school day will be performed at Study Visits 3 and 4 and will take 
approximately 5 hours. 
Pre- and post-dose study visit assessments will also be performed at visits 3 and 4.   
The following activities will be performed during Study Visits 3 and 4: 
 
Blood pressure and pulse (should be conducted any time after dosing) 
 
Follow-up C-SSRS 
 
AE assessment 
 
Concomitant medications assessment 
 
Pre-dose:   
o SKAMP 
o PERMP 
 
Administration double-blind study drug at study site 
 
Post-dose: 


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o SKAMP at 30 minutes and 3 hours  
o PERMP at 30 minutes and 3 hours 
 
Double-blind study drug accountability and reconciliation 
For all activities performed, the results are to be recorded in the CRF.   
5.3.1.5. 
Early Termination Visit 
The following activities may be done for subjects that withdraw prior to completion of Study Visit 4 (i.e., 
terminate early): 
 
Blood pressure and pulse  
 
AE assessment 
 
Concomitant medications assessment 
 
Follow-up C-SSRS 
 
Study drug accountability and reconciliation 
 
A urine pregnancy test (for females of child-bearing potential only) may be performed in the 
event of a suspected pregnancy per Investigator’s clinical judgment 
For all activities performed, the results are to be recorded in the CRF.   


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6. 
INVESTIGATIONAL DRUG INFORMATION AND 
MANAGEMENT 
 
Investigational Drug Dose Regimen 
Open-label Dyanavel XR will be dispensed to enrolled subjects.  Subjects will be instructed to take open-
label Dyanavel XR.  Subjects who are stimulant naive will take Dyanavel XR beginning at 2 mL daily in 
the morning. Subjects who have a history of stimulant treatment may be initiated on open label Dyanavel 
XR at whole mL doses between 2 and 6 mL per day, inclusive, as selected by the investigator based on 
required doses for adequate symptom control with previous stimulant medication treatment. The dose for 
all subjects may be increased as tolerated as often as daily up to a maximum dose of 8 mL (20 mg) daily 
or until an optimal dose is reached as determined by the study doctor. The Investigator may decrease a 
subject’s dose at any time during the open-label period to ensure tolerability.  Subjects who find the 
maximum study dose of 8 mL (20 mg)/day is insufficient to treat their symptoms of ADHD and thus are 
not adequately controlled will be discontinued from the study.   
The parents or guardians of the subjects will be instructed to administer the medication orally to their 
child once daily prior to 10 am with or without food. Children should not self-administer study 
medication. 
During visits 3 and 4, and following randomization, subjects will receive Dyanavel XR 6 ml (15 mg), 7 
mL (17.5 mg) or 8 mL (20 mg) or Placebo 6 mL, 7 mL or 8 mL once. The crossover treatment will be 
administered at the following double blind classroom session (Visit 4). 
 
Investigational Drug Packaging and Labeling 
Dyanavel XR will be provided during Visit 1 and Visit 3 as a liquid suspension in 4-oz plastic bottles 
containing 90 mL of oral suspension with an adaptor and an oral syringe to dispense.  These bottles will 
be labeled appropriately and will be used for the open-label Period of the study.  
Dyanavel XR and placebo will be provided as a liquid suspension in blinded packaging during the 
double-blind visits 3 and 4. Double-blinded Dyanavel XR and placebo will have identical physical 
characteristics.   
All investigational products used in this study will be prepared, packaged, and labeled in accordance with 
the standard operating procedures (SOPs) of Tris Pharma or those of its designee, Good Manufacturing 
Practice (GMP) guidelines, International Conference on Harmonization (ICH) guidelines for Good 
Clinical Practice (GCP), and applicable regulations. 
 
Investigational Drug Storage 
The study drug should be stored between 15°C to 30°C (59°F to 86°F) at the study center in a secure, 
locked cabinet or room with limited access.  When dispensed, the parent/guardian will be instructed to 
store the drug at ambient temperature in a cool, dry place and out of reach of children.   


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Investigational Drug Dispensing 
To allow for flexible dosing options, 4-oz bottles containing 90 mL of Dyanavel XR will be manufactured 
for this study.  An oral syringe will be provided with the investigational product to facilitate accurate 
dosing of the subjects. Table 3 shows the amphetamine content for relative dosing volumes of Dyanavel 
XR. 
Table 3:  Dyanavel XR Content by Volume 
Dyanavel XR (Extended-release oral suspension containing 2.5 mg amphetamine base per mL) 
Dosing Volume 
1 mL 
2 mL 
3 mL 
4 mL 
5 mL 
6 mL 
7 mL 
8 mL 
Amphetamine Base 
Content 
2.5 mg 
5 mg 
7.5 mg 
10 mg 
12.5 
mg 
15 mg 
17.5 mg 
20 mg 
Beginning at Visit 1, subjects will receive a bottle of investigational product during his/her visit at the 
site.  The Investigator will determine the initial of investigational product and a titration schedule or plan. 
 
Drug Administration 
Study drug will be administered orally, once daily before 10 am with or without food.  Subjects will be 
instructed to take each study drug dose by swallowing.  The medication must always be administered to 
the child by the parent/caregiver or by another responsible adult; the study medication must not be 
self-administered regardless of the age of the child.  
 
Investigational Drug Accountability 
The Investigator or designee will verify and acknowledge receipt of study drug.  All medications must be 
stored in a secure area under the proper storage requirements with limited access.  Medication designated 
for this clinical study must not be taken by any subjects other than those enrolled in this specific 
investigation, and may not be utilized for any laboratory or animal research.  All study drug dispensed to 
subjects must be accurately recorded on the Drug Accountability Record maintained at the study center.  
Subjects should be instructed to return all study drug dispensed to them (including any unused bottles 
containing study drug and empty containers) at each study visit.   
Drug accountability will be performed at each Study Visit starting with Study Visit 1 (Baseline).  Subjects 
will be provided with a new bottle containing 90 mL of study drug at visit 3, and bottles containing study 
drug should be returned to the site at each subsequent visit.  Compliance will be estimated by visual 
inspection of the remaining bottle volume upon return to the site.  By Study Visit 4 (or Early 
Termination), subjects should return all medication dispensed to them.  In the event of a study drug spill 
during at-home administration, photographic evidence of the spill must be provided by the subject’s 
parental guardian for drug accountability when possible. All medication and empty containers will be 
retained at the site for Study Monitor and/ or Sponsor verification. All medication should be stored at the 
study site until further instruction from the Sponsor. 


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Investigational Drug Handling and Disposal 
All study drug (open –label Dyanavel XR, blinded Dyanavel XR and placebo) will be accounted for on 
drug inventory records (including records of study drug sent to the Investigator and records generated at 
the investigational site).  The Sponsor and/ or its designate will review inventory forms during the study 
and at the conclusion of the study.  The Investigator will sign the drug inventory record after resolving 
any questions resulting from the Sponsor and/ or its designate’s review.  The Investigator must retain a 
copy of all drug inventory records. 
All remaining used and unused study drug must be retained until final instructions are given by the 
Sponsor.   
Tris Pharma will provide detailed drug return instructions to the study site.  All post-treatment handling 
and disposal of study drug will be in accordance with GCP and GMP guidelines and federal and local 
regulations. 


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7. 
SUBJECT COMPLIANCE 
 
Concomitant Medication and/or Therapy 
Concomitant medications information will be collected beginning at Screening and will continue through 
Study Visit 4 (or Early Termination).   
 
Prohibited Concomitant Medications and Foods 
Psychotropic medications are not allowed during the study except for stimulants (other than study drug), 
which must be discontinued prior to starting study medication.  No anticonvulsant, antidepressant, or 
antipsychotic medications are permitted during the study. Melatonin is permitted.  Prohibited concomitant 
medications may be resumed 1 day after Study Visit 4.   
7.2.1. 
Prohibited Concomitant Medications 
Any stimulant (e.g., methylphenidate, dexmethylphenidate, amphetamine, dextroamphetamine) should be 
discontinued prior to beginning study medication the day after Visit 1 
SSRIs (e.g., fluoxetine, paroxetine) 
SNRIs (e.g. Desvenlafaxine, Duloxetine, Venlafaxine)                                                                         
MAOIs (monoamine oxidase inhibitors) 
Mood stabilizers (e.g., lithium, valproate, quetiapine) 
Antipsychotics (e.g., risperidone, olanzapine) 
Anticonvulsants (e.g., phenobarbital, phenytoin, primidone) 
Sedative hypnotics, except melatonin 
Anticoagulants 
Halogenated anesthetics 
Tricyclic antidepressants 
Atomoxetine 
Guanfacine 
Clonidine 
CYP2D6 inhibitors (e.g. Paroxetine and fluoxetine, quinidine, ritonavir) 
Fentanyl, tramadol, tryptophan, buspirone, St. John’s Wort 
Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid) 
Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts) 
 
Acetaminophen is permitted for control of fever or pain if needed.  Short courses of prescription and 
nonprescription medications needed for treatment of acute illnesses such as the common cold, viral 
illnesses, and ear infections are permitted as long as these do not contain medications listed above.   
All concomitant medications must be recorded on the Concomitant Medication CRF.   


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Treatment Compliance 
Parent/guardian and subject training at Baseline (Visit 1) and subsequent ongoing retraining regarding 
proper dosing of study drug will occur to ensure subject compliance.  After Visit 1, study staff will assess 
compliance by inspecting returned study drug bottles at every study visit to confirm that the subject is 
taking study drug according to the protocol. If the family forgets to bring the bottle to the visit, the visual 
inspection will occur when the bottle is returned.  In the event of a study drug spill during at-home 
administration, photographic evidence of the spill will be required to demonstrate treatment compliance if 
possible.   


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8. 
RANDOMIZATION AND BLINDING PROCEDURES 
Except for Visits 3 and 4, dosing will be conducted in an open-label fashion.  The laboratory school days 
(Visits 3 and 4) and associated classroom testing will be performed in a double-blind manner. All double-
blind study medication will be supplied in identical bottles and will be similar in physical characteristics 
(color, smell, and appearance), thereby enabling double-blind conditions. 
Enrollment will occur after all screening procedures have been performed and eligibility for the study is 
confirmed at the Baseline (Visit 1).   
At Visit 2 subjects will be randomized in a 1:1 ratio to treatment sequence: Dyanavel XR followed by 
Placebo or Placebo followed by Dyanavel XR.    
Unblinding should occur only when knowing the treatment assignment has a bearing on the medical 
treatment or evaluation of a subject.  Whenever possible, the need to unblind should be discussed with the 
Sponsor prior to unblinding. 
A subsequent written report, including all pertinent details, must be submitted to the Sponsor within 24 
hours of the unblinding. Whenever possible, the blind of the parent/guardian and subject should be 
maintained. 
If an Investigator, site personnel performing assessments, or subject/parent is unblinded, the subject must 
be withdrawn from the study, and procedures accompanying withdrawal are to be performed.   


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9. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
This section defines AEs and outlines the procedures for appropriately collecting, grading, recording, and 
reporting them.  Information in this section complies with 21 Code of Federal Regulations (CFR) 312, 
ICH Guideline E2A: Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, and ICH Guideline E-6: Guidelines for Good Clinical Practice. 
The Investigator is responsible for the detection and documentation of AEs regardless of treatment group 
or suspected causal relationship to the investigational drug.  For all AEs, the Investigator must pursue and 
obtain information adequate to determine the outcome of the AE and to assess whether it meets the 
criteria for classification as an SAE requiring immediate notification to the Sponsor or its designated 
representative. 
 
Definitions of Adverse Events 
9.1.1. 
Adverse Event (AE) 
An AE is defined as any untoward or unfavorable medical occurrence associated with the subject’s 
participation in the research, whether or not considered related to the subject’s participation in the 
research (ICH E6 Guidelines for GCP).  Any medical condition that is present at the time that the subject 
is screened will be considered as medical history and not recorded as an AE; however, if the condition 
worsens at any time during the study, it will be recorded and reported as an AE.  
9.1.2. 
Serious Adverse Event (SAE) 
An AE is considered “serious” if, in the view of either the Investigator or the Sponsor, it results in any of 
the following outcomes (21 CFR 312.32[a]): 
 
Death:  A death that occurs during the study or that comes to the attention of the Investigator 
during the protocol-defined follow-up period must be reported to the Sponsor whether it is 
considered treatment related or not. 
 
A life-threatening event:  An AE or suspected adverse reaction (SAR) is considered “life 
threatening” if, in the view of either the Investigator or the Sponsor, its occurrence places the 
participant at immediate risk of death.  It does not include an AE or SAR that, had it occurred in a 
more severe form, might have caused death. 
 
Inpatient hospitalization or prolongation of existing hospitalization. 
 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical judgment, it may 
jeopardize the participant and may require 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 


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that do not result in subject hospitalization, or the development of drug dependency or drug 
abuse. 
 
Congenital anomaly or birth defect. 
If an event meets any of the above definitions, regardless of the severity or relationship of the event to the 
study drug, the event must be reported to the Sponsor as described in Section 9.5.1. 
Adverse events reported from clinical studies associated with hospitalization or prolongation of 
hospitalization is considered serious.  Any initial admission (even if less than 24 hours) to a hospital 
meets these criteria.  Admission also includes transfer within the hospital to an acute/intensive care unit 
(e.g., from the medical floor to the intensive care unit). 
Hospitalization does not include the following: 
 
Rehabilitation facilities, hospice facilities, or respite care (e.g., caregiver relief) 
 
Nursing homes or skilled nursing facilities 
 
Emergency room visits 
 
Same-day surgeries (as outpatient/same day/ambulatory procedures) 
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical AE is not in 
itself an SAE.  Examples include: 
 
Admission for treatment of a pre-existing condition that did not worsen 
 
Protocol-specified admission (e.g., for a procedure required by the study protocol) 
 
Hospitalizations for cosmetic elective surgery, social, and/or convenience admissions 
 
Pre-planned treatments or procedures should be noted in the baseline documentation for the 
individual subject. 
Diagnostic and therapeutic procedures, such as surgery, should not be reported as AEs; however, the 
medical condition for which the procedure was performed should be reported if it occurs during the 
reporting period and meets the definition of an AE.  For example, an acute appendicitis that begins during 
the AE reporting period should be reported as the AE, and the resulting appendectomy should be recorded 
as treatment of the AE.   
9.1.3. 
Adverse Reaction (AR) and Suspected Adverse Reaction (SAR) 
An adverse reaction (AR) means any AE caused by a drug.   
Suspected adverse reaction means any AE for which there is a reasonable possibility that the drug caused 
the AE.  For the purposes of safety reporting, ‘reasonable possibility’ means there is evidence to suggest a 
causal relationship between the drug and the AE.  Suspected adverse reaction implies a lesser degree of 
certainty about causality than an AR (21 CFR 312.32[a]).  
9.1.4. 
Unanticipated Adverse Reaction (UAR) 
The Sponsor is responsible for assessing AEs for expectedness.  With regards to reporting to the Health 
Authority, an AE is considered “unexpected” when its nature (specificity), severity, or rate of occurrence 
is not consistent with applicable product information as described in the safety information provided in 
the protocol/package insert/Investigator’s Brochure/prescribing information for Dyanavel XR.  


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"Unexpected," as used in this definition, also refers to AEs or SARs that are mentioned in the 
Investigator’s Brochure as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug but are not specifically mentioned as occurring with the particular drug under 
investigation (21 CFR 312.32[a]).  
 
Severity of AEs/SAEs 
The study site will grade the severity of AEs experienced by study participants according to the following 
criteria: 
 
Mild; awareness of signs or symptoms but easily tolerated; are of minor irritant type; no loss of 
time from normal activities; symptoms would not require medication or a medical evaluation; 
signs and symptoms may be transient. 
 
Moderate; discomfort enough to interfere with usual daily activities. 
 
Severe; incapacitating with an inability to perform usual daily activities; signs and symptoms may 
be of systemic nature or require medical evaluation. 
Note:  The terms serious and severe are not synonymous.  Serious criteria as defined in Section 9.1.2 
serve as a guide for defining regulatory reporting obligations.  The term severe is often used to describe 
the intensity (severity) of a specific event (as in mild, moderate, or severe headache); the event itself, 
however, may be of relatively minor medical significance.  This is not the same as 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.  Therefore, an AE of severe headache might not be considered serious, but a moderate 
infection for which a subject is hospitalized should be reported as an SAE. 
 
Relationship to Investigational Drug Treatment 
An Investigator’s causality assessment is the determination of whether a reasonable possibility exists that 
the investigational drug caused or contributed to an AE.  This assessment must be provided for all AEs 
(serious and non-serious).  
The Sponsor’s determination of attribution will be used for reporting to the appropriate health authorities.  
The relation of an AE to study participation will be determined using the descriptors and definitions 
provided in Table 4.   


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Table 4:  Attribution of Adverse Events 
Not Related 
The AE is clearly/most probably caused by other etiologies such as participant’s 
underlying condition, therapeutic intervention or concomitant therapy, or the delay 
between administration and the onset of the AE is incompatible with a causal relation, 
or the AE started before administration (screening phase).  Therefore, there is not a 
reasonable possibility that the AE was caused by the investigational drug. 
Possible 
Related 
An adverse event that has a timely relationship to the administration of the 
investigational drug/study procedure, follows no known pattern of response, but a 
potential alternative cause does not exist. 
Probably 
Related 
An adverse event that has a timely relationship to the administration of the 
investigational drug/study procedure and follows a known pattern of response, but for 
which a potential alternative cause may be present. 
Definitely 
Related: 
An adverse event that has a timely relationship to the administration of the 
investigational drug and follows a known pattern of response for which no alternative 
cause is present. 
 
Collecting and Recording Adverse Events 
9.4.1. 
Period of Collection 
All AEs will be collected from the completion of informed consent through Visit 4. All AEs and SAEs 
should be treated as medically appropriate. AEs that occur after at least one dose of study medication has 
been administered will be considered treatment-emergent AEs. 
9.4.2. 
Methods of Collection 
Adverse events may be collected as follows: 
 
Observing the subject 
 
Questioning the subject in an unbiased and non-leading manner 
 
Receiving an unsolicited complaint from the subject or parent/guardian 
An abnormal value or result from a clinical or laboratory evaluation (e.g., physical examination, 
laboratory assessment, or ECG) can also indicate an AE if it is determined by the Investigator to be 
clinically significant.  If this is the case, it must be recorded in the source document and as an AE on the 
appropriate AE form(s).  The evaluation that produced the value or result should be repeated until that 
value or result returns to normal or is stabilized and the participant’s safety is not at risk. 


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9.4.3. 
Recording Method 
9.4.3.1. 
Adverse Events 
All AEs occurring during this clinical study will be recorded by the Investigator on the appropriate CRF 
in precise medical terms, along with the date and time of onset and the date and time of resolution.  To 
avoid vague, ambiguous, or colloquial expressions, the AE should be recorded in standard medical 
terminology rather than the subject’s own words.  Whenever possible, the Investigator should combine 
signs and symptoms into a single term that constitutes a single diagnosis.  Each AE is to be evaluated for 
duration, severity, seriousness, and relatedness to the study medication.  The severity of the AE and its 
relationship to the study medication will be assessed by the Investigator.   
The Investigator will treat participants experiencing AEs appropriately and observe them at suitable 
intervals until their symptoms resolve or their status stabilizes.  If any medication is administered in 
response to the AE, this medication should be noted on the concomitant medication CRF as a concomitant 
medication administered.  The action taken and the outcome must also be recorded.  Adverse events will 
be followed until resolution or stabilization or until 30 days after a participant terminates from the study, 
whichever comes first.  The terms of AE resolution (i.e., not recovered/not resolved, recovering/resolving, 
recovered/resolved, recovered/resolved with sequelae, fatal, unknown) should also be recorded.   
9.4.3.2. 
Serious Adverse Events 
Serious adverse events will be recorded on the AE CRF and on the SAE Report Form Provided by the 
sponsor  as described in Section 9.4.3.1, and health authorities will be notified as outlined in Section 
9.5.2. 
 
Reporting Adverse Events 
9.5.1. 
Reporting SAEs to the Sponsor 
The following process for reporting an SAE ensures compliance with 21 CFR 312 and ICH guidelines.  
After learning that a participant has experienced an SAE, the Investigator or designee is responsible for 
reporting the SAE to the sponsor, regardless of relationship or expectedness, within 24 hours of becoming 
aware of the event.  The initial SAE report should include as much information as possible, but at a 
minimum must include the following: 
 
Name of the reporter 
 
Subject identification 
 
Study drug  
 
Serious AE term 
 
Date of onset 
 
Relationship to study drug 
 
Reason why the event is serious 


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Supplemental CRF pages should be current at the time of SAE reporting:  medical history, concomitant 
medications, demographics, study drug administration, and death (as applicable).  
Unavailability of certain event details should not delay submission of the known information.  As 
additional details become available, the SAE CRF should be updated and re-submitted.  Every time the 
SAE CRF is submitted, it should be signed by the Investigator or sub-investigator.  
The following Sponsor Representative is to be contacted immediately after the occurrence of an SAE: 
 
Antonio Pardo, MD 
Manager, Clinical Affairs 
Tris Pharma Inc. 
Phone: (732) 823-4755 
Mobile: (917) 514-9058 
Email:  apardo@trispharma.com 
safety@trispharma.com 
9.5.2. 
Reporting SAEs to Health Authorities 
The Sponsor or Sponsor designee will report Investigational New Drug (IND) Safety Reports to the FDA 
and Investigators in accordance with the FDA regulations detailed in the 21 CFR 312.32.  
9.5.3. 
Reporting SAEs to the Central IRB(s) 
It is the responsibility of the Sponsor or Sponsor designee to promptly notify their respective IRB(s) of 
IND Safety reports or other matters involving risk to subjects as mandated by the IRB(s). 
9.5.4. 
Reporting Pregnancy 
During the study, all subjects should be instructed to contact the Investigator immediately if they suspect 
they might be pregnant (e.g., missed or late menstrual period).  If pregnancy is confirmed, the subject will 
be withdrawn from the study and followed until the pregnancy comes to term.   
The Investigator is responsible for reporting all available pregnancy information on the pregnancy CRF 
within 24 hours of becoming aware of the event, although pregnancy itself is not an SAE.  The 
Investigator should counsel the participant and discuss the risks of continuing with the pregnancy and the 
possible effects on the fetus.  The subject should be referred to an obstetrician/gynecologist 
experienced in reproductive toxicity for further evaluation and counseling.  Monitoring of the 
participant should continue until the conclusion of the pregnancy.  Follow-up information detailing the 
outcome of the pregnancy should be reported as it becomes available.   
Any pregnancy complication or premature terminations including miscarriage, spontaneous abortion, or 
elective termination of a pregnancy for medical reasons will be reported as an SAE, as described in 
Section 9.5.1.  Should the pregnancy result in a congenital abnormality or birth defect, a separate SAE 


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report must be submitted.  Furthermore, all neonatal deaths that occur within 30 days of the birth should 
be reported as SAEs, without regard to causality.  In addition, any infant death that occurs after the 
30-day reporting period that the Investigator suspects is related to the in-utero exposure to the study 
treatment should also be reported.  


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10. 
STATISTICS 
 
Power and Sample Size Determination 
The primary efficacy outcome is change from pre-dose in the model-adjusted SKAMP-Combined score at 
30 minutes  hours post-dose as measured during the laboratory school days (Visits 3 and 4).  Assuming an 
effect size of 1.00 between Dyanavel XR and placebo and approximately 15 subjects randomized to 
double-blind treatment, this study will have 90% power at the level of alpha = 0.05 (2-sided) to detect a 
treatment effect.  To allow for an estimated 15% potential drop-out rate, this study plans to enroll 
approximately 18 subjects.  
The assumed effect size is based on differences measured between active and placebo in previous 
laboratory school studies conducted with similar drug formulations at the earliest measured timepoint and 
reducing that by 20%.   
A detailed statistical analysis plan (SAP) will be written and finalized prior to unblinding of the data. 
 
Analysis Populations 
The analysis populations are defined as follows:   
 
The enrolled safety population is defined as all enrolled subjects who receive at least 1 dose of 
open-label study drug treatment.   
 
The randomized safety population is defined as all randomized subjects who receive at least 
1 dose of double-blind study drug treatment.   
 
The ITT population is defined as randomized subjects who receive at least 1 dose of double-blind 
study drug treatment and have at least 1 post-dose assessment of the primary efficacy variable at 
both Visits 3 and 4.   
 
The clinically evaluable population is defined as all ITT subjects who have no major protocol 
deviations.  This includes any subject who: 
o Received the morning dose of double-blind study medication at Visits 3 and 4 
o Completed all laboratory classroom assessments 
o Did not use prohibited medication during the double-blind Treatment Period. 
The primary efficacy analyses will be performed on the ITT population.  Secondary efficacy analyses on 
the ITT and clinically evaluable populations will be supportive of the primary analysis.  
The safety analyses will be performed on the enrolled and randomized safety populations. 
Deviations from the original statistical plan as planned in this protocol will be reported and justified in the 
SAP and clinical study report (CSR) as appropriate.   


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Efficacy and Safety Analyses 
10.3.1. 
Background and Demographic Characteristics 
Baseline demographic variables will be reported. 
10.3.2. 
Efficacy Analyses 
10.3.2.1. Primary Efficacy Analysis 
The primary efficacy analysis will be performed on the ITT population.  The primary efficacy outcome is 
change from pre-dose in the model-adjusted average of SKAMP-Combined score at 30 minutes post-
dose. 
The treatment difference will be estimated using least squares means from a mixed-effects 
repeated-measures model.  The treatment comparison will be conducted as a 2-sided test at the 5% level 
of significance.   All available data will be used; there will be no imputation of missing data. Effect size 
will be calculated.  
10.3.3. 
Safety Analyses 
All safety data will be analyzed descriptively by treatment group  
The frequency of subjects reporting AEs will be summarized within each system organ class and 
preferred term during the open-label period, double-blind period.   
The C-SSRS analyses will be summarized.  
 
Concomitant Medications and Concomitant Therapies 
Concomitant medications and therapies will be summarized and listed by subject.   
 
Other Statistical Considerations 
10.5.1. 
Significance Levels 
The type I error significance level for each set of study analyses as applicable will be set at alpha = 0.05. 
10.5.2. 
Missing Data 
Although the rate of missing data is expected to be low, missing data could occur under either or both of 
the following scenarios:  missing or invalid data for individual questions in the SKAMP and missing 
SKAMP-Combined scores at individual time points.   
In general, missing or invalid data for individual questions will be handled by rules specific to the 
validated SKAMP questionnaire and will be described in the SAP.  No additional imputation for missing 
or invalid SKAMP responses will be performed.   
No imputation of missing SKAMP-Combined scores will be done for the primary efficacy analysis.  The 
mixed-model repeated-measures method used to analyze the primary endpoint has been designed to 


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utilize all available data and provides valid estimates under the assumption of data which are missing 
completely at random or missing at random.  To evaluate the sensitivity of the primary analysis results to 
the use or non-use of imputation, analyses using single imputation (last observation carried forward) and 
multiple imputation methods may be conducted.  This decision will be made prior to database unblinding, 
and the methods will be described in the SAP.   
 


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11. 
DIRECT ACCESS TO PROCEDURAL DOCUMENTS 
 
Study Monitoring 
According to GCP guidelines, the Sponsor of the study is responsible for ensuring the proper conduct of 
the study with regard to protocol adherence and validity of data recorded on the CRFs.  The Sponsor is 
responsible for assigning the study monitor(s) to this study.  The study monitors’ duties are to aid the 
Investigator and the Sponsor in the maintenance of complete, accurate, legible, well-organized, and easily 
retrievable data.  The study monitor will advise the Investigator of the regulatory necessity for 
trial-related monitoring, audits, IRB review, and inspection by providing direct access to the source 
data/documents.  In addition, the study monitor will explain to and interpret for the Investigator all 
regulations applicable to the clinical evaluation of an investigational drug as documented in ICH 
guidelines. 
It is the study monitors’ responsibility to inspect the CRFs throughout the study to protect the rights of the 
subjects; to verify adherence to the protocol; to verify completeness, accuracy, and consistency of the 
data; and to confirm adherence of study conduct to any local regulations.  Details may be outlined in the 
study monitoring plan.  
 
Source Documents 
Tris Pharma requires that the Investigator prepare and maintain adequate and accurate records for each 
subject treated with the investigational drug.  Source documents such as any hospital, clinic, or office 
charts and the signed informed consent forms are to be included in the Investigator’s files with the 
subject’s study records. 
No database will be created for this study. The source documents will be considered the study CRFs.  If 
any data are first recorded onto documents such as laboratory reports, these documents will be considered 
source.  
Adverse events will be coded with the Medical Dictionary for Regulatory Activities .  Concomitant 
medications will be coded using World Health Organization – Drug Reference List.   


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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Quality assurance includes all the planned and systematic actions that are established to ensure that the 
clinical study is performed and the data are generated, documented (recorded), and reported according to 
ICH GCP and local/regional regulatory standards. 
A quality assurance representative from Tris Pharma (or a qualified delegate), who is independent of and 
separated from routine monitoring, may periodically arrange inspections/audits of the clinical study by 
reviewing the data obtained and procedural aspects.  These inspections may include on-site 
inspections/audits and source data checks.  Direct access to source documents is required for the purpose 
of these periodic inspections/audits.  


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13. 
ETHICS 
 
Ethics Review 
This study will be conducted according to GCP; US 21 Code of Federal Regulations (CFR) Part 50 
(Protection of Human Subjects); US 21 CFR Part 56 (IRBs); US 21 CFR Part 54 (Financial Disclosure); 
International Conference on Harmonization (ICH) Guidance for Industry, E6 GCP: Consolidated 
Guidance; the Nuremberg Code; and, where applicable the principles of the Declaration of Helsinki 
(Recommendations guiding Medical Doctors in Biomedical Research Involving Human Subjects), and 
with the NH&MRC National Statement on Ethical Conduct in Human Research (2007).  The conduct of 
the study will be in accordance with the Notes for Guidance on Good Clinical Practice 
(CPMP/ICH/135/95), as adopted by the Australian Therapeutic Goods Administration (2000).   
 
Ethics Committees 
The investigator (or sponsor, where applicable) is responsible for ensuring that this protocol, the site’s 
informed consent form, and any other information that will be presented to potential subjects (e.g., 
advertisements or information that supports or supplements the informed consent form) are reviewed and 
approved by the appropriate IRB or IEC.  The investigator agrees to allow the IRB or IEC direct access to 
all relevant documents.  The IRB or IEC must be constituted in accordance with all applicable regulatory 
requirements.  The sponsor will provide the investigator with relevant documents or data needed for IRB 
or IEC review and approval of the study.  Before investigational products and CRFs can be shipped to the 
site, the sponsor must receive copies of the IRB or IEC approval, the approved informed consent form, 
and any other information that the IRB or IEC has approved for presentation to potential subjects. 
If the protocol, the informed consent form, or any other information that the IRB or IEC has approved for 
presentation to potential subjects is amended during the study, the investigator is responsible for ensuring 
that the IRB or IEC reviews and approves, where applicable, these amended documents.  The investigator 
must follow all applicable regulatory requirements pertaining to the use of an amended informed consent 
form, including obtaining IRB or IEC approval of the amended form, before new subjects consent to take 
part in the study using the new version of the form.  The investigator must promptly forward to the 
sponsor copies of the IRB or IEC approval of the amended informed consent form or other information 
and the approved amended informed consent form or other information.  IRB or IEC approval of the 
consent forms must be obtained in addition to the approval given for the clinical study.  Regulatory 
review and approval may be required in some countries before IRB or IEC approval can be sought. 
 
General Considerations 
The Investigator must conduct the study in accordance with this protocol and ICH GCP guidelines which 
have their origins in the Declaration of Helsinki.  The Investigator and Tris Pharma will sign the protocol 
and study contract to confirm agreement.  The Investigator will not implement any amendment (deviation 
or changes of the protocol) without agreement by Tris Pharma and the IRB approval/information, except 
where necessary to eliminate immediate hazards to study subjects or when changes involve only logistical 
or administrative aspects of the study.  


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When any new and important information that may be relevant to the subject’s consent is obtained, the 
Investigator and Tris Pharma will consult with each other on how to deal with the information.  When 
Tris Pharma and a responsible Investigator judge it necessary, the Investigator must immediately provide 
the subjects with such information, revise the written information and other explanatory documents based 
on the new information, and obtain approval from the IRB(s).  In this instance, the Investigator should 
also immediately inform subjects currently participating in the clinical study of such information, confirm 
their intention to continue participation, re-explain the study to them using the revised written information 
and other explanatory documents, and obtain written consent to continue participation based on their 
voluntary decision. 
 
Informed Consent 
Subjects aged 10 to 12 years must sign an assent form and parent or legal guardian must sign the 
informed consent form. The sponsor will provide investigators with a sample informed consent form and 
assent form for this study.  Investigators are encouraged to use the sample form; however, they may adapt 
the information to suit the needs of their institution, if necessary (although it must reflect the required 
elements of informed consent specified in 21 CFR Part 50.25).  The final informed consent form must be 
accepted by the sponsor and approved by the IRB or IEC.  Investigators must provide the sponsor with an 
unsigned copy of the final informed consent form before and after it is approved by the IRB or IEC.  If 
any new information becomes available that might affect subjects’ willingness to participate in the study, 
or if any amendments to the protocol require changes to the informed consent form, the sponsor will 
provide investigators with a revised informed consent form.  The IRB or IEC must provide written 
approval of any revisions to the informed consent form in advance of its use. 
Investigators must provide subjects with all the information necessary to make an informed decision 
about their participation in the study, including the nature and intended purpose of the study, possible 
benefits, and possible risks. 
Before written informed consent is obtained, the subject should be given ample time and opportunity to 
inquire about the details of the study.  All questions must be answered to the satisfaction of the subject (or 
his or her legally authorized representative). 
Before a subject undergoes procedures specific to the protocol, the informed consent form and the assent 
form must be signed and dated by the subject (or his or her legally authorized representative) and any 
other signatories as required by the IRB or IEC. 
After all required signatures have been obtained, a copy of the informed consent form should be provided 
to the subject, and the original must be kept on file at the site and made available for review by the 
sponsor.  Documentation of the informed consent discussion must be noted in the subject’s case history. 
 
Subject Confidentiality 
Individual subject medical information obtained as a result of this study is considered confidential, and 
disclosure to third parties is prohibited.  Information will be accessible to authorized parties or personnel 
only.  Medical information may be given to the subject’s physician or to other appropriate medical 
personnel responsible for the subject’s well-being.  Each subject will be asked to complete a form 


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allowing the Investigator to notify the subject’s primary health care provider of his/her participation in 
this study.  
 
Publications of the Clinical Study 
The clinical study plan and the results of the study will be published on www.ClinicalTrials.gov in 
accordance with 21 CFR § 50.25(c).  The results of and data from this study belong to Tris Pharma.  
Investigators may not publish on the results from the study (including data specifically from their site) 
without prior written consent from Tris Pharma.   
 
Protocol Amendments and Deviations 
No change or amendment to this protocol may be made by the Investigator or Tris Pharma after the 
protocol has been agreed to and signed by all parties unless such change(s) or amendment(s) has (have) 
been agreed upon by the Investigator and Tris Pharma.  Any change agreed upon will be recorded in 
writing, and the written amendment will be signed by the Investigator and Tris Pharma.  Institutional 
review board approval is required prior to the implementation of an amendment, unless overriding safety 
reasons warrant immediate action, in which case the IRB(s) will be promptly notified. 
No deviation from the protocol or investigational plan will be made except to protect the life or physical 
well-being of a subject in an emergency.  Except in such emergencies, prior approval of the Sponsor and 
the regulatory authorities (e.g., FDA or the IRB[s] if applicable) is required before deviations from the 
planned protocol.  All protocol deviations that occur during the study will be documented and reported to 
Tris Pharma and to the IRB(s), if applicable, according to regulations.  Further details about the 
documentation, evaluation, and follow-up of protocol deviations are detailed in this study’s clinical 
monitoring plan.  


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14. 
DATA HANDLING AND RECORD KEEPING 
 
Inspection of Records 
Tris Pharma, its designee(s), the IRB(s), or regulatory authorities will be allowed to conduct site visits to 
the investigational facilities for the purpose of monitoring or inspecting any aspect of the study.  The 
Investigator agrees to allow Tris Pharma, its designee(s), the IRB(s), or regulatory authorities to inspect 
the investigational drug storage area, investigational drug stocks, investigational drug records, subject 
charts and study source documents, and other records relative to study conduct.   
 
Retention of Records 
The Principal Investigator must retain all documentation relating to the study for a period of at least 
2 years after the last marketing application approval or, if not approved, 2 years following the 
discontinuance of the test article for investigation.  If this requirement differs from any local regulations, 
the local regulations will take precedence unless the local retention policy is less than 2 years.   


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15. 
REFERENCES 
1 
DYANAVEL XR [Prescribing Information]. Monmouth Junction, NJ: Tris Pharma Inc.; 
2017.Available from: http://www.dyanavelxr.com/pdfs/pi.pdf. 
 
 
 


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APPENDIX A. SCHEDULE OF EVENTS 
 
Procedure 
 
Screening Visit  
Visit 1 
 
Visit 2 
 
Visit 3 
 
Visit 4 
 
Early 
Termination 
Parent/Guardian IC 
x 
 
 
 
 
 
Pediatric Subject Assent 
x 
 
 
 
 
 
Eligibility Assessment 
x 
x 
 
 
 
 
Medical History 
x 
 
 
 
 
 
Medication History 
x 
 
 
 
 
 
Physical Examination 
x 
 
 
 
 
 
Height &Weight c 
x 
 
 
 
x 
x 
Screening Laboratory f 
x 
 
 
 
 
 
ADHD-RS-5 Score 
x 
x 
 
 
 
 
Pregnancy test d 
x e 
x 
 
 
 
 
Cognitive Functioning a 
x 
 
 
 
 
 
Demographics  
x 
 
 
 
 
 
Vital Signs b  
x 
x 
x 
x 
x 
x 
12-Lead ECG 
x 
 
 
 
 
 
PERMP g,  
x j 
x j 
x 
x 
x 
 
SKAMP g 
 
 
x 
x 
x 
 
CSSRS i 
x 
x 
x 
x 
x 
x 
Open Label medication 
dispensed l 
 
x 
x 
x k 
 
 
Randomization 
 
 
x 
 
 
 
Double Blind Medication 
Administration h 
 
 
 
x 
x 
 
Drug Accountability 
 
x 
x 
x 
x 
x 
Concomitant 
Medications 
x 
x 
x 
x 
x 
x 
Adverse Events i 
x 
x 
x 
x 
x 
x 
a. When cognitive functioning level is not clear by clinical signs and symptoms, a Wechsler Abbreviated Scale 
of Intelligence (WASI) may be administered to estimate IQ.   
b. At Screening, vital signs will include respiratory rate and temperature. Visits 2, 3 and 4 will include only BP 
and HR, any time after dose 
c. Height measurement required only at Screening. 
d. Females of child bearing potential only. 
e. Serum pregnancy test will be performed at Screening; Urine dipstick pregnancy test will be performed at 
Baseline (Visit 2); pregnancy testing will also occur in the event of a suspected pregnancy.   
f. 
Laboratory tests will include: hematology (WBC, RBC, Hemoglobin, Hematocrit, MCV, MCH, MCHV, 
RDW, and platelet count) and Chemistry (glucose, blood urea nitrogen, creatinine, aspartate 
aminotransferase, alanine aminotransferase, and gamma-glutamy transpeptidase) 
g. Assessments will occur pre-dose, 30 minutes and 3 hours post-dose  
h. To be dosed in clinic 
i. 
Different versions of the C-SSRS will be used a Baseline and subsequent visits (Since Last Visit) 
j. 
PERMP math pre-test (PERMP placement test may be conducted at screening or baseline) 
k. After the completion of visit 3, open label study medication will be dispensed to each subject 


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APPENDIX B. REVISION HISTORY 
The following updates have been applied the present revision (crossed= deleted, bold= added): 
 
The following Inclusion Criteria have been modified: 
#2. Diagnosed with ADHD by a psychiatrist, psychologist, developmental pediatrician, 
pediatrician, or an experienced licensed allied health professional approved by the 
Sponsor within 6 months of study enrollment or newly diagnosed with ADHD using the 
DSM-5 criteria for ADHD 
#4. 
In the clinical judgment of the Investigator, the subject must be in need of 
pharmacological treatment for ADHD.  Subjects on current treatment with Dyanavel XR 
may be enrolled provided the ADHD-RS-5 entry criteria are not met while on treatment, 
but are met after treatment washout. 
#6. 
Provide written informed consent (parent/guardian) and assent (child aged 10 – 
12 years only) prior to participation in the study 
 
The following Exclusion Criteria have been modified: 
#1 Diagnosed with any DSM-5 active disorder (other than ADHD) with the 
exception of specific phobias, learning disorders, motor skills disorders, 
communication disorders, oppositional defiant disorder, elimination disorders, and 
sleep disorders (added) 
#5 From: Use of the following medications within 30 days of Baseline Visit: 
 
MAOI - monoamine oxidase inhibitors (e.g., Selegiline, isocarboxazid, phenelzine, 
tranylcypromine) 
 
Tricyclic Antidepressants (e.g. Desipramine, protriptyline 
 
Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid 
HCl, ascorbic acid) 
 
Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, 
methenamine salts) 
To:  
5. Use of the following medications within 30 days of Baseline Visit: 
 
MAOI - monoamine oxidase inhibitors (e.g., Selegiline, isocarboxazid, phenelzine, 
tranylcypromine) 
 
Tricyclic Antidepressants (e.g. Desipramine, protriptyline) 
6. Use of the following medications within 3 days of Baseline Visit 
 
Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid 
HCl, ascorbic acid) 
 
Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, 
methenamine salts) 


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List or Abbreviations has been updated to correct grammatical errors. Some abbreviations were 
deleted as they were not applicable to this study 
 
Section 3.1. Design: This section has been updated to give more clarify on the study design 
Table 1 has been up dated to reflect the time-frame Open Label Dyanavel will be 
administrated 
Section 3.2.2: Added 
 
Change from pre-dose in PERMP scores at 30 minutes and 3 hours post-dose 
 
Subscales of these measures will also be assessed 
Section 5 Study Schedule and Procedures: updated to provide more clarify on the study design 
5.2. Efficacy: and Safety Assessments: updated for clarity purposes 
5.3.1 Study: duration updated to 6-8 weeks 
5.3.1.1 Screening: assent required only in children aged 10 – 12 years, no washout 
needed. The section has been updated accordingly 
5.3.1.2 Baseline: This section has been updated to allow the PI to customize titration 
according to each child’s condition 
5.3.1.3. Practice Laboratory School Day (Visit 2): This section has been updated to 
provide more clarity regarding this visit 
5.3.1.4 Randomized, Double-blind, Placebo-Controlled Treatment Period (Visits 3 and 
4): This section has been updated to provide more clarity regarding this visit 
6.4 Investigational Drug Dispensing / Table 3: 5 mL (12.5 mg) was added 
 
7.2.1 Prohibited Concomitant Medications:  the following items have been added to be in line 
with Dyanavel XR Package Insert: 
 
Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid) 
 
Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts) 
 
9 Adverse and Serious Adverse Events: 
 
9.1.4 Unanticipated Adverse Reaction (UAR): Adderall IR was replaced with Dyanavel 
XR 
 
9.2 Severity of AEs/SAEs: updated to current practice 
9.3 Relationship to Investigational Drug Treatment: updated to current practice 
9.4.1 Period of Collection - the following has been added: AEs that occur after at least 
one dose of study medication has been administered will be considered treatment-
emergent AEs. 
10.3.2.1 Primary Efficacy analysis: The primary efficacy outcome is change from pre-dose in the model-
adjusted average of SKAMP-Combined score at 4 hours 30 minutes post-dose. 
Appendix A has been revised to reflect the current study design.  
 
Note: multiple edits have been applied to correct grammatical and typographical errors.  
 


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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
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Version Date: 13MAR2017
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
Dyanavel® XR Extended-Release Oral Suspension in the Treatment of 
Children with ADHD:  A Laboratory School Study. 
 
Study No. TRI102-ADD-300 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Authorization Signatures 
 
Dyanavel® XR Extended-Release Oral Suspension in the Treatment of Children with ADHD:  A 
Laboratory School Study 
 
Study No. TRI102-ADD-300 
 
 
 
Author: 
 
 
 
 
 
 
 
 
 
 
Gino Colavita, M.Sc. 
 
Date 
Manager, Statistical Programming 
 
 
QuintilesIMS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Zhe Tian, M.Sc. 
 
Date 
Biostatistician I 
 
 
QuintilesIMS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
Antonio Pardo, MD 
 
 
Manager, Clinical Affairs 
 
 
TRIS Pharma, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
 
1 
MODIFICATION HISTORY ............................................................................................................... 5 
2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................. 6 
3 
INTRODUCTION ............................................................................................................................... 7 
4 
STUDY OBJECTIVES ....................................................................................................................... 7 
5 
STUDY DESIGN ............................................................................................................................... 7 
5.1 
General Description ............................................................................................................. 7 
5.2 
Discussion of Study Design ................................................................................................. 8 
5.3 
Method of Assigning Subjects to Treatment Groups ........................................................... 8 
5.4 
Treatment ............................................................................................................................. 9 
5.5 
Blinding ................................................................................................................................ 9 
5.6 
Determination of Sample Size ............................................................................................. 9 
5.7 
Changes in the Conduct of the Study or Planned Analyses .............................................. 10 
6 
EFFICACY AND SAFETY VARIABLES .......................................................................................... 10 
6.1 
Schedule of Evaluations .................................................................................................... 10 
6.2 
Efficacy Outcome ............................................................................................................... 11 
6.2.1 
Primary Efficacy Outcome ................................................................................ 11 
6.2.2 
Secondary Efficacy Outcomes ......................................................................... 11 
6.3 
Baseline Characteristics .................................................................................................... 12 
6.3.1 
Demographic and Baseline Disease Characteristics ....................................... 12 
6.4 
Safety Variables ................................................................................................................. 12 
6.4.1 
Adverse Events ................................................................................................ 12 
6.4.2 
Clinical Laboratory Assessments ..................................................................... 12 
6.4.3 
Electrocardiogram ............................................................................................ 12 
6.4.4 
Physical Examinations and Vital Signs ............................................................ 13 
6.4.5 
Columbia Suicide Severity Rating Scale (C-SSRS) ......................................... 13 
7 
STATISTICAL METHODS .............................................................................................................. 14 
7.1 
General Methodology ........................................................................................................ 14 
7.2 
Adjustments for Covariates ................................................................................................ 14 
7.3 
Handling of Drop-outs or Missing Data .............................................................................. 14 
7.4 
Interim Analyses and Data Monitoring ............................................................................... 15 
8 
STATISTICAL ANALYSIS ............................................................................................................... 15 
8.1 
Disposition of Subjects ...................................................................................................... 15 
8.2 
Protocol Deviations ............................................................................................................ 15 
8.3 
Analysis Populations .......................................................................................................... 16 
8.3.1 
Enrolled Safety Population ............................................................................... 16 
8.3.2 
Randomized Safety Population ........................................................................ 16 
8.3.3 
Intent-to-Treat (ITT) Population ........................................................................ 16 
8.3.4 
Clinically Evaluable population (CE) Population .............................................. 16 
8.4 
Demographics and Baseline Characteristics ..................................................................... 16 
8.5 
Analysis of Efficacy ............................................................................................................ 17 
8.5.1 
Primary Efficacy Analysis ................................................................................. 17 
8.5.2 
Secondary Efficacy Analyses ........................................................................... 18 
8.6 
Analysis of Safety .............................................................................................................. 18 
8.6.1 
Adverse Events ................................................................................................ 18 


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8.6.2 
Vital Signs......................................................................................................... 19 
8.6.3 
Columbia Suicide Severity Rating Scale (C-SSRS) ......................................... 20 
8.6.4 
Concomitant Medications and Concomitant TherapiesError! Bookmark not 
defined. 
9 
REFERENCES ................................................................................................................................ 21 
 


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1 
MODIFICATION HISTORY 
Unique Identifier 
for this Version 
Date of the 
Document 
Version 
Significant Changes from  
Previous Authorized Version 
Version 1.0 
(Final) 
13MAR2017 
Not applicable – First version 


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2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Commonly used abbreviations such as units (ml, mmHg, h) and abbreviations used for 
electrocardiogram assessments are not included in this list. 
 
ADHD 
Attention Deficit Hyperactivity Disorder 
ADHD-RS-5 
ADHD-Rating Scale-5 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CBC 
Complete Blood Count 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
Electrocardiogram 
EROS 
Extended-Release Oral Suspension 
ITT 
Intent-to-Treat 
IQ 
Intelligence Quotient 
LS Mean  
Least-Squares Mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSE 
Mean Square Error 
PCS 
Potentially Clinically Significant 
PERMP 
Permanent Product Measure of Performance 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SKAMP 
Swanson, Kotin, Agler, M-Flynn, and Pelham rating scale 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
USA 
United States of America 
WASI 
Wechsler Abbreviated Scale of Intelligence 
WHO-DD 
World Health Organization - Drug Dictionary 


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3 
INTRODUCTION 
Amphetamine has been a well-established therapeutic agent for the treatment of Attention-
Deficit/Hyperactivity Disorder (ADHD) for decades.  Since the original amphetamine approval, various 
dosage forms have been approved for use: 
• 
immediate release (IR) dosage forms, oral solution and tablets.  
• 
extended release (ER) dosage forms, capsules, and tablets with various release 
technologies 
Dyanavel XR is an extended-release oral suspension (EROS) that contains 2.5mg/mL amphetamine 
base.  Drug-resin complexation is formed with the amphetamine and Sodium Polystyrene Sulfonate 
USP, an ion exchange resin. The extended release feature of the product is achieved by coating some 
drug/resin complexes with an extended-release coating. Dyanavel XR contains approximately a 3:1 ratio 
of d-amphetamine compared to l-amphetamine. 
 
The efficacy of Dyanavel XR in the treatment of ADHD has been established for pediatric subjects aged 
6 to 12 years old in a Phase 3 placebo-controlled laboratory classroom study TRI102-ADD-001. The 
ADHD symptoms were significantly lower in children on an individually optimized dose of amphetamine 
(range 10-20 mg/day), and the symptom control was demonstrated 1 hour after dosing with efficacy 
observed through 13 hours beyond dosing. The single-dose pharmacokinetics of orally administered 
Dyanavel XR were evaluated in Study TRI102-PPK-200 in pediatric subjects aged 6 to 12 years old with 
ADHD (10 mg oral dose) and in Study 2014-3401 in healthy adult subjects (18.8 mg oral dose).    
 
This statistical analysis plan (SAP) provides detailed descriptions of the statistical analysis needed for a 
study manuscript. The information and methodology described and to be presented in the tables in this 
SAP is intended to be sufficient to produce a manuscript appropriate for submission to a peer-reviewed 
medical journal and for the purpose of a producing an abbreviated clinical study report. 
4 
STUDY OBJECTIVES 
The efficacy objective is to demonstrate that Dyanavel XR has an onset of action as early as 30 minutes 
post-dose as determined by change from pre-dose in Swanson, Kotin, Agler, M-Flynn, and Pelham 
rating scale (SKAMP)-Combined scores at 30 minutes post-dose during the laboratory school days 
(Visits 3 and 4), relative to placebo.  
 
The safety objective is to assess the safety and tolerability of Dyanavel XR in pediatric subjects with 
ADHD. 
5 
STUDY DESIGN 
5.1 
General Description 
This randomized, double-blind, two treatment, two sequence, placebo-controlled crossover study 
assesses the efficacy and safety of Dyanavel XR in reducing signs and symptoms of ADHD compared 
with placebo in pediatric subjects aged 6 to 12 years with ADHD utilizing a laboratory classroom design. 
Safety parameters will be evaluated throughout the study.   


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5.2 
Discussion of Study Design 
This study will be conducted at one investigational site in the United States with approximately 18 
pediatric subjects enrolled. The study duration is 6-8 weeks consisting of the following visits: 
 
 Screening: Up to 4 weeks to determine eligibility. 
 Baseline (Visit 1): Once the subject is determined to be initially eligible at Screening, the Baseline 
evaluations will be performed. If the subject continues to meet eligibility criteria, the subject will be 
enrolled and take open-label Dyanavel XR orally once daily in the morning beginning the day after 
the Baseline Visit. The dose may be increased as tolerated as often as daily up to a maximum dose 
of 20 mg daily or until an optimal dose reached.  
 Practice classroom (Visit 2): Visit 2 will occur on the same day for all subjects. The date of the visit 
will be determined to permit the last enrolled subject to have at least 3 days of exposure to Dyanavel 
XR prior to Visit 2. The maximum length of exposure to Dyanavel XR prior to Visit 2 shall be limited to 
5 weeks. All subjects will be administered 15 mg, 17.5 mg or 20 mg of open-label Dyanavel XR by 
the study staff at the Practice classroom (Visit 2). The subjects will be randomized at Visit 2 to 
double-blind treatment sequence to be administered at Visits 3 and 4.  The sequences are Dyanavel 
XR (Visit 3) followed by Placebo (Visit 4), or, Placebo (Visit 3) followed by Dyanavel XR (Visit 4). 
 Double blind classroom (Visits 3 and 4): Visit 3 will be scheduled the day following Visit 2. Visit 4 
will be scheduled the weekend following Visit 3. The subjects will take double-blinded drugs (15 mg, 
17.5 mg or 20 mg of Dyanavel XR or Placebo) in the randomized treatment sequence. The efficacy 
assessments for ADHD symptoms will be measured by SKAMP and Permanent Product 
Measurement of Performance (PERMP) at pre-dose and at 30 minutes and 3 hours post-dose. The 
open-label Dyanavel XR will be dispensed to subjects between Visits 3 and 4 which may be adjusted 
as often as daily up to a maximum of 20 mg daily. 
 
A schematic of the overall study design is shown in Figure 5.2-1. 
 
FIGURE 5.2-1: STUDY DESIGN 
 
5.3 
Method of Assigning Subjects to Treatment Groups 
Approximately 18 pediatric subjects (male or female) with a diagnosis of ADHD per DSM-5 criteria will 


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be enrolled. Subjects must be aged 6-12 years at the time of screening, inclusive.  
 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria at Screening and 
Baseline (Visit 1), sign the assent form (subjects aged 10 to 12 years only) and whose parent/guardian 
sign the informed consent form will be enrolled to take open-label Dyanavel XR. 
 
At Visit 2 subjects will be randomized in a 1:1 ratio to treatment sequence: Dyanavel XR followed by 
Placebo or Placebo followed by Dyanavel XR.   
 
5.4 
Treatment 
Open-label Dyanavel XR will be dispensed to enrolled subjects. Subjects who are stimulant naive will 
take Dyanavel XR beginning at 2 mL daily. Subjects who have a history of stimulant treatment may be 
initiated on Dyanavel XR at whole mL doses between 2 and 6 mL per day, inclusive, as selected by the 
investigator. The previous stimulant medication must be discontinued prior to starting study medication.  
 
The dose of study medication for all subjects may be increased as tolerated as often as daily up to a 
maximum dose of 8 mL (20 mg) daily or until an optimal dose is reached as determined by the study 
doctor. The Investigator may decrease a subject’s dose at any time during the open-label period to 
ensure tolerability. Subjects who find the maximum study dose of 8 mL (20 mg)/day is insufficient to treat 
their symptoms of ADHD and thus are not adequately controlled will be discontinued from the study.   
 
Following randomization, during Visits 3 and 4, subjects will receive Dyanavel XR 6 ml (15 mg), 7 mL 
(17.5 mg) or 8 mL (20 mg) or Placebo 6 mL, 7 mL or 8 mL once. 
 
Study drug will be administered orally, once daily before 10 am with or without food.  Subjects will be 
instructed to take each study drug dose by swallowing.  The medication must always be administered to 
the child by the parent/caregiver or by another responsible adult. 
5.5 
Blinding 
Except for Visits 3 and 4, dosing will be conducted in an open-label fashion.   
 
The laboratory school days (Visits 3 and 4) and associated classroom testing will be performed in a 
double-blind manner. Subjects will receive Dyanavel XR 6 ml (15 mg), 7 mL (17.5 mg) or 8 mL (20 mg) 
or Placebo 6 mL, 7 mL or 8 mL once. Dyanavel XR and Placebo will be supplied as a liquid suspension 
in identical bottles and will be similar in physical characteristics (color, smell, and appearance), thereby 
enabling double-blind conditions. 
5.6 
Determination of Sample Size 
The primary efficacy outcome is change from pre-dose in the model-adjusted SKAMP-Combined score 
at 30 minutes post-dose as measured during the laboratory school days (Visits 3 and 4). Assuming an 
effect size of 1.00 between Dyanavel XR and Placebo and approximately 15 subjects completing the 
double-blind treatment, this study will have greater than 90% power at the level of alpha = 0.05 (2-sided) 
to detect a treatment  effect. To allow for an estimated 15% potential drop-out rate, this study plans to 
enroll approximately 18 subjects. 
 
The assumed effect size is based on differences measured between active and placebo in previous 
laboratory school studies conducted with similar drug formulations at the earliest measured time point 
and reducing that by 20%. The power calculations are based on an assumed 15% dropout rate. 


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5.7 
Changes in the Conduct of the Study or Planned Analyses 
There are none at this time. 
6 
EFFICACY AND SAFETY VARIABLES 
6.1 
Schedule of Evaluations 
A detailed visit schedule is shown in Table 6.1-1. 
 
TABLE 6.1-1: SCHEDULE OF ASSESSMENTS 
 
Procedure 
 
Screening Visit  
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Early 
Termination 
Parent/Guardian IC 
x 
 
 
 
 
 
Pediatric Subject Assent 
x 
 
 
 
 
 
Eligibility Assessment 
x 
x 
 
 
 
 
Previous  
Medications 
x 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
Medication History 
x 
 
 
 
 
 
Physical Examination 
x 
 
 
 
 
 
Height & Weight c 
x 
 
 
 
x 
x 
Screening Laboratory f 
x 
 
 
 
 
 
ADHD-RS-5 Score 
x 
x 
 
 
 
 
Pregnancy test d 
x e 
x 
 
 
 
 
Cognitive Functioning a 
x 
 
 
 
 
 
Demographics  
x 
 
 
 
 
 
Vital Signs b  
x 
x 
x 
x 
x 
x 
12-Lead ECG 
x 
 
 
 
 
 
PERMP g,  
x j 
x j 
x 
x 
x 
 
SKAMP g 
 
 
x 
x 
x 
 
CSSRS i 
x 
x 
x 
x 
x 
x 
Open Label medication 
dispensed l 
 
x 
  
x k 
 
 
Randomization 
 
 
x 
 
 
 
Double Blind Medication 
Administration h 
 
 
 
x 
x 
 
Drug Accountability 
 
x 
x 
x 
x 
x 
Concomitant Medications 
x 
x 
x 
x 
x 
x 
Adverse Events i 
x 
x 
x 
x 
x 
x 
a. 
When cognitive functioning level is not clear by clinical signs and symptoms, a Wechsler Abbreviated Scale of Intelligence (WASI) may be 
administered to estimate IQ.   
b. 
At Screening, vital signs will include respiratory rate and temperature.   
c. 
Height measurement required only at Screening. 
d. 
Females of child bearing potential only. 
e. 
Serum pregnancy test will be performed at Screening; Urine dipstick pregnancy test will be performed at Baseline (Visit 2); pregnancy testing 
will also occur in the event of a suspected pregnancy.   
f. 
Laboratory tests will include: hematology (WBC, RBC, Hemoglobin, Hematocrit, MCV, MCH, MCHV, RDW, and platelet count) and Chemistry 
(glucose, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase) 
g. 
Assessments will occur pre-dose, 30 minutes and 3 hours post-dose  
h. 
To be dosed in clinic 
i. 
Different versions of the C-SSRS will be used a Baseline and subsequent visits (Since Last Visit) 
j. 
PERMP math pre-test (PERMP placement test may be conducted at screening or baseline) 
k. 
After the completion of visit 3, open label study medication will be dispensed to each subject 
 


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6.2 
Efficacy Outcome 
6.2.1 Primary Efficacy Outcome 
 
The primary efficacy endpoint is the change from pre-dose in model-adjusted SKAMP-Combined scores 
at 30 minutes post-dose measured during the double-blind laboratory school days (Visits 3 and 4). 
 
The SKAMP scale is a 13-item independent observer rating of subject impairment of classroom 
observed behaviors. The following SKAMP scores will be assessed at each time point during each of the 
laboratory school days (Visits 2, 3, 4): 
  
 SKAMP-Combined scores (items 1-13). 
 SKAMP-Attention subscale scores (items 1-4). 
 SKAMP-Deportment subscale scores (items 5-8). 
 SKAMP-Quality of Work subscale scores (items 9-11). 
 SKAMP-Compliance subscale scores (items 12-13). 
 
Each item is rated on a 7-point impairment scale (0=normal to 6=maximal impairment). Items are 
specific to place (classroom setting) and time (during a typical classroom period), and the scale can be 
used to assess multiple ratings taken within a day. The SKAMP scale is collected during each laboratory 
classroom day at pre-dose, 30 minutes, and 3 hours post-dose.  The combined scores and subscale 
scores for the SKAMP are obtained by summing the values of corresponding items in the assessment. 
 
Missing or invalid data will be handled in the following manner:  
 
 If 3 or more individual items in the SKAMP have missing or invalid data, the SKAMP-Combined score 
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 rounded up to the nearest integer.  
 If any item within a SKAMP subscale is missing or invalid, the entire subscale score will be set to 
missing.  
 
6.2.2 Secondary Efficacy Outcomes 
Secondary efficacy endpoints include change from pre-dose in the following measures at 30 minutes 
and 3 hours post-dose during the double-blind laboratory school day (Visits 3 and 4): 
 
 SKAMP-Combined scores (3 hours post-dose only). 
 SKAMP-Attention subscale scores. 
 SKAMP-Deportment subscale scores. 
 SKAMP-Quality of Work subscale scores. 
 SKAMP-Compliance subscale scores. 
 PERMP scores. 
 
Refer to Section 6.2.1 for specifications on the SKAMP scale. 
 
PERMP scores will be obtained at pre-dose and each post-dose (30 minutes and 3 hours) time points 
during each laboratory classroom day (Visits 2, 3, 4).  The PERMP is a 10-minute written test performed 


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as seatwork in the classroom. Subjects are given five pages of 80 math problems, and are instructed to 
work at their desks and to complete as many problems as possible in 10 minutes. The number of 
problems correct plus the number of problems attempted will be used to measure a subject’s 
performance. Different versions are used among the subjects to adjust for ability as determined by the 
math pretest done at the Baseline Visit. In addition, different versions are used across classroom cycles, 
so that a subject does not take the same test more than once during a day.  
 
Due to the nature of the PERMP, no imputation will be done. If a subject came into the study late and 
the subject completed the next available scheduled assessment, no imputation will be done for missing 
classroom assessments. 
 
The following PERMP scores will be assessed at each individual time point of each laboratory classroom 
day (Visits 2, 3, 4): 
 
 Number of math problems attempted. 
 Number of math problems correct. 
6.3 
Baseline Characteristics  
6.3.1 Demographic and Baseline Disease Characteristics 
Demographic and baseline disease characteristics will be recorded at Screening, and these 
characteristics will be summarized and presented in a table for the randomized safety study population. 
6.4 
Safety Variables 
6.4.1 Adverse Events 
The occurrence of adverse events (AEs) will be assessed at all visits. The C-SSRS will be assessed at 
each visit. 
 
For the purpose of this study, data related to this will summarized as described in section 8.6.1. 
6.4.2 Clinical Laboratory Assessments 
Clinical laboratory assessments, including serum chemistry panel, hematology complete blood count 
(CBC), and a serum pregnancy test (where applicable) will be performed at Screening. 
 
The purpose of these screening laboratories is to assist the physician in determining if potential subjects 
have medical issues which would preclude their participation in the clinical study. 
 
Subjects may not be eligible for participation in the clinical study if any screening laboratory test is 
outside of the reference range and is considered clinically significant.  
 
For the purpose of this study, data related to clinical laboratory assessments will be incorporated into the 
CRFs for each subject, but will not be included in the electronic database and therefore not summarized. 
6.4.3 Electrocardiogram  
A 12-lead electrocardiogram (ECG) will be collected at Screening in order to exclude subjects with 


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cardiac abnormalities.  
 
For the purpose of this study, ECG tracing results will be part of the CRF for each subject.  The 
electronic database will include whether each ECG was assessed as normal, abnormal not clinically 
significant or abnormal clinically significant at screening.  This data will not be summarized. 
6.4.4 Physical Examinations and Vital Signs  
Blood pressure (systolic and diastolic) and pulse rate will be measured at all visits in triplicate.   
 
Respiratory rate and temperature will be measured only in conjunction with the physical examinations at 
Screening.  Focused examinations may be performed if needed at all other visits. 
 
Height and weight will be measured at Screening and Visit 4 (or Early Termination Visit). Body mass 
index (BMI) will be calculated as Weight (kg) / Height (m)2. 
 
For the purpose of this study, only potentially clinically significant vital sign values will be summarized in 
a table as described in section 8.6.2. Data related to physical examination will be collected and stored in 
the electronic database. 
6.4.5 Columbia Suicide Severity Rating Scale (C-SSRS)  
The Columbia Suicide Severity Rating Scale (C-SSRS) will be administered to assess emergent suicidal 
thoughts or behaviors. The “Baseline” version of the C-SSRS will be administered to all subjects at 
Screening. The “Since Last Visit” version is to be used at all subsequent visits. 
 
The C-SSRS is a brief clinician-administered questionnaire that provides for the identification, 
quantification and standardized assessment of the occurrences and severity of suicidal ideation and 
behavior. The interview includes a few skip out questions so that participants are asked only relevant 
questions and the typical administration time is a few minutes.  
 
The results of the C-SSRS at each visit will categorize each subject as having suicidal ideation (yes/no) 
and suicidal behavior (yes/no). 
 
A subject will be defined as having suicidal ideation if they have a ‘Yes’ to any of the following questions: 
 Wish to be dead. 
 Non-specific active suicidal thoughts. 
 Active suicidal ideation with any methods (not plan) without intent to act. 
 Active suicidal ideation with some intent to act, without specific plan. 
 Active suicidal ideation with specific plan and intent. 
 
A subject will be defined as having suicidal behavior if they have a ‘Yes’ to any of the following 
questions: 
 Actual attempt. 
 Interrupted attempt. 
 Aborted attempt. 
 Preparatory acts or behavior. 
 Suicidal behavior. 
 
For the purpose of this study, data related to this will be summarized in a table by each stage of the 
study and treatment sequence when applicable as described in 8.6.3. 


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7 
STATISTICAL METHODS 
7.1 
General Methodology 
All analyses will be conducted by using SAS® for Windows, Version 9.2 (or higher), SAS Institute, Cary, 
North Carolina, USA.  
 
Descriptive summary statistics will include: 
 
 Number of observations (n), mean, standard deviation (SD), minimum, median and maximum values 
for continuous parameters.  
 
 Number of subjects (n) and relative frequencies (%) for categorical parameters.  
 
Hypothesis testing, unless otherwise indicated, will be two-sided and performed at the 5% significance 
level.  All p-values less than or equal to 0.05 will be considered statistically significant.  
   
All efficacy comparisons from the mixed-effects repeated-measures model will be based on Type III 
tests. In the case of substantial non-normality, the normality-based analyses will be carried out on the 
ranked scores instead of the actual values. The normality assumption will be assessed for the primary 
efficacy variable using residual plot. When confidence intervals are presented, they will be two-sided 
with a confidence coefficient of 95%.  
 
Data will be summarized based on the recorded visit; no visit windowing will be conducted. 
 
For summary purposes, Baseline will be defined as the last available non-missing pre-dose observation, 
which should be Visit 1. When pre-dose observations at Visit 1 are missing, the last available non-
missing pre-dose observations at Screening will be designated Baseline. Post-baseline will be defined 
as post-dose observations.  
 
The treatment periods will defined for the analysis. The open label period will include (1) The time from 
first dose of open label study medication  the start of the double blind study medication at Visit 3, and (2) 
given Visit 3 happened, the time of first dosing at home after Visit 3 to the start of double blind study 
medication at Visit 4. 
 
The double blind period will include the time from first dose of double blind medication on Visit 3 until the 
first home dose of open label medication the next morning, and the time from first dose of double blind 
medication on Visit 4 until 24 hours later. 
 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 16.1 or higher. Medications will be coded using the latest version of World Health Organization -
Drug Dictionary (WHO-DD).  
7.2 
Adjustments for Covariates 
No adjustments for covariates will be made. 
7.3 
Handling of Drop-outs or Missing Data 
In general, missing or invalid data of efficacy assessments will be handled by individual scales or 
subscales on the basis of each individual assessment, and is described in the corresponding 
sub-section of Section 6.2. No imputation will be carried out on missing combined and subscale scores 


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between the time points of the classroom days.  
 
Missing end dates for medical history findings and 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 assumptions: 
 
 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 month are known the date will be set to first day of the month.  If the year and month 
is 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.   
 
Missing end dates for prior and concomitant medication will be imputed based on the following 
assumptions: 
 
 If only the year is known, the date will be set to 31 December of that year.  If the year is the same as 
the year of the last visit, the date will be set to the last visit date. 
 
 If the year and month are known the date will be set to the end of that month. 
 
 If the end date is completely missing it will be assumed that the medication is ongoing for the duration 
of the study, and as such regarded as concomitant. 
 
 If these rules are followed and the completed end date is after the last visit date, the end date will be 
set to the last visit date. 
7.4 
Interim Analyses and Data Monitoring 
No interim analysis or official data monitoring is planned for this study. 
8 
STATISTICAL ANALYSIS 
8.1 
Disposition of Subjects 
Subject disposition, including the number and percentage of subjects who were enrolled, randomized, 
completed the study, and discontinued early during open-label and double-blind periods (including 
reasons for discontinuations), will be summarized in a table.   
8.2 
Protocol Deviations 
Protocol deviations will be discussed in the abbreviated clinical study report by the sponsor. 


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8.3 
Analysis Populations 
A review of subject disposition and relevant data will take place before unblinding to determine the 
analysis populations.   
 
The database will be hard locked (all user rights revoked) when: 
 
 The SAP is authorized. 
 There are no outstanding data issues. 
 The authorized analysis populations are imported as SAS® data sets. 
8.3.1 Enrolled Safety Population 
Enrolled Safety population is defined as all enrolled subjects who receive at least one dose of open-label 
study medication and have at least one post-dose safety assessment. 
8.3.2 Randomized Safety Population  
Randomized Safety population is defined as all randomized subjects who receive at least one dose of 
double-blind study medication. 
 
For the purpose of this study, the safety analyses will be performed on the Enrolled Safety populations. 
8.3.3 Intent-to-Treat (ITT) Population 
Intent-to-Treat (ITT) population is defined as all randomized subjects who receive at least one dose of 
double-blind study medication and have at least one post-dose assessment of the primary efficacy 
variable at both Visits 3 and 4. The ITT population will be considered as the primary population for 
efficacy analysis.    
8.3.4 Clinically Evaluable population (CE) Population 
The clinically evaluable (CE) population is defined as all ITT subjects who have no major protocol 
deviations.  This includes any subject who: 
o 
Received the morning dose of double-blind study medication at Visits 3 and 4 
o 
Completed all laboratory classroom assessments 
o 
Did not use prohibited medication during the double-blind Treatment Period. 
 
The CE population will be determined by the sponsor prior to unblinding and provided to CRO for 
statistical analysis of the secondary endpoints. 
 
8.4 
Baseline Characteristics 
8.4.1      Demographics and Baseline Characteristics 
Demographics and baseline characteristics including age (both continuous and categorized: 6-7 years, 


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8-10 years, 11-12 years), gender, race, ethnicity, height (cm), weight (kg), BMI (kg/m2), and ADHD type 
(inattentive, hyperactive/Impulsive, combined) will be summarized by treatment sequence in tables for 
the randomized safety population. 
 
8.4.2            Medical History 
Medical history findings will be summarized descriptively by system organ class (SOC) and preferred 
term (PT) on the Enrolled Safety population. 
 
8.4.3 
Prior and Concomitant Medication 
Prior medications are medications that were taken prior to the first dose of open-label study medication. 
Concomitant medications are medications that were taken during the treatment period.  The double-blind 
period will include medications that were taken during the day of Visit 3 and the day of Visit 4, whether 
the start date was before or on that day. 
 
Medications with partial start dates will be imputed as outlined in Section 7.3, and determined as 
concomitant medications based on the imputed start date. Medications with completely missing start 
dates (i.e. missing information for medication start day, month, and year) are assumed to be 
concomitant medications. 
 
The frequency of subjects using prior and concomitant medications at screening, open label and double 
blind stage of the study will be summarized according to medication name. 
8.5 
Analysis of Efficacy 
8.5.1 
Primary Efficacy Analysis  
The primary efficacy analysis will be conducted on the ITT population. The primary efficacy outcome is 
the change from pre-dose in SKAMP-Combined score at 30 minutes post-dose on the double-blind 
classroom days. Treatment comparisons for the primary efficacy outcome will be assessed using a 
mixed-effects repeated-measures model. The analysis will be repeated on the Clinically Evaluable 
population only if it differs from the ITT population.  
 
The mixed-effects repeated-measures model will include sequence (2 levels), period (2 levels), and 
treatment (2 levels) as fixed effects, and subject within sequence as a repeated effect with a compound 
symmetry correlation structure.  This two-tailed test at the 5% significance level will be carried out with 
SAS using the MIXED procedure. 
 
The sequence levels are: 
 
 Placebo / Dyanavel XR. 
 Dyanavel XR / Placebo. 
 
The period levels are: 
 
 First double-blind classroom day (Visit 3). 
 Second double-blind classroom day (Visit 4). 
 


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The treatment levels are: 
 
 Dyanavel XR. 
 Placebo. 
 
Descriptive statistics of the SKAMP-Combined scores at pre-dose, 30 minutes post-dose, and change 
from pre-dose to 30 minutes post-dose will be presented in a table for the double blind period by 
treatment. In addition, the paired differences between the treatments for each subject (Dyanavel XR - 
Placebo) will be presented for the double blind period. The difference in the change from pre-dose to 30 
minutes post-dose within each treatment will be assessed using a one-sample (paired) t-test, and the 
raw SKAMP-Combined scores at 30 minutes will be also be assessed using a one sample t-test. 
Furthermore, a graphical representation of the SKAMP-Combined scores will be presented for the 
double blind phase. 
 
The point estimate of the least-squares mean (LS Mean) and the corresponding 95% confidence interval 
of the change from pre-dose to 30 minutes post-dose scores will be presented for each treatment group. 
The point estimate, corresponding 95% confidence interval and p-value for the treatment difference in 
the LS Means, including the effect size (calculated as the LS Means difference divided by the square 
root of the mean-squared error (MSE)) will be presented.  
8.5.2 Secondary Efficacy Analyses 
The secondary efficacy outcome include the following scores: 
 
- 
Change from pre-dose to 3 hours post-dose for SKAMP-Combined scores 
- 
Difference of PERMP scores (number of math problems attempted and number of math 
problems correct) between Dyanavel XR and placebo at 30 minutes and 3 hours.  
- 
Change from pre-dose to 30 minutes and 3 hours post-dose for SKAMP subscale scores 
(Attention, Deportment, Quality of Work and Compliance). 
. Each secondary efficacy outcome will be analyzed and presented the same way as the primary 
outcome variable as described in section 8.5.1. 
 
  
8.6 
Analysis of Safety 
All safety data will be analyzed descriptively by treatment group on the Enrolled and Randomized Safety 
populations, unless otherwise stated. If the Enrolled and Randomized Safely populations are identical, 
the data will be presented only once. 
 
8.6.1 
Adverse Events 
 
An AE is considered treatment-emergent, if it started on or after the first dose of study medication. If a 
subject terminates early from the study and has an AE after his/her last dosing date, the AE will not be 
deemed as treatment-emergent. AEs with partial start dates will be imputed as outlined in Section 7.3, 
and assigned to the associated treatment phase.   
 
AEs will be presented for (1) the open-label period on the Enrolled Safety population and (2) the double-
blind cross-over period on the randomized safety population. The double-blind period will include 
adverse events that started after Visit 3 or Visit 4 dosing. The frequency of subjects reporting the 
following AEs will be presented by SOC and PT for the enrolled safety population: 
- 
TEAEs. 
- 
TEAEs by severity. 


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- 
SAEs. 
- 
AEs leading to premature discontinuation 
8.6.2 
Physical Examination and Vital Signs 
Physical examination data from the screening visit will be recorded and stored in the electronic 
database, and will be available should a discussion require this information, but it will not be 
summarized.  
 
The incidence of sponsor defined potentially clinically significant (PCS) post-treatment vital sign values  
will be presented by treatment sequence to examine the frequency and percentage of subjects that meet 
the PCS criteria outlined in Table 8.10-1a. 
 
TABLE 8.10-1A: POTENTIALLY CLINICALLY SIGNIFICANT (PCS) VITAL SIGN VALUES 
Parameter 
Observed Value 
Change from Baseline 
Systolic Blood Pressure 
> 95th percentile  
≥ 20 mmHg increase 
Diastolic Blood Pressure 
> 95th percentile 
≥ 20 mmHg increase 
Pulse 
> 110 bpm 
≥ 25 bpm increase 
Weight 
N/A 
≥ 5% decrease 
 
The systolic and diastolic percentile is determined based on the subjects’ age, gender, and height 
percentile, using the chart created by the Fourth Report on the Diagnosis, Evaluation, and Treatment of 
High Blood Pressure in Children and Adolescents[1], as outlined in Tables 8.10-1b and 8.10-1c. 
 
TABLE 8.10-1B:  SYSTOLIC BLOOD PRESSURE NORMATIVE VALUES 
 
 
95th  Percentile for Systolic Blood Pressure 
 
 
Percentile for Height 
Gender 
Age 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
Male 
6 
109 
110 
112 
114 
115 
117 
117 
 
7 
110 
111 
113 
115 
117 
118 
119 
 
8 
111 
112 
114 
116 
118 
119 
120 
 
9 
113 
114 
116 
118 
119 
121 
121 
 
10 
115 
116 
117 
119 
121 
122 
123 
 
11 
117 
118 
119 
121 
123 
124 
125 
 
12 
119 
120 
122 
123 
125 
127 
127 
Female 
6 
108 
109 
110 
111 
113 
114 
115 
 
7 
110 
111 
112 
113 
115 
116 
116 
 
8 
112 
112 
114 
115 
116 
118 
118 
 
9 
114 
114 
115 
117 
118 
119 
120 
 
10 
116 
116 
117 
119 
120 
121 
122 
 
11 
118 
118 
119 
121 
122 
123 
124 
 
12 
119 
120 
121 
123 
124 
125 
126 
 
TABLE 8.10-1C:  DIASTOLIC BLOOD PRESSURE NORMATIVE VALUES 
 
 
95th  Percentile for Systolic Blood Pressure 
 
 
Percentile for Height 
Gender 
Age 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
Male 
6 
72 
72 
73 
74 
75 
76 
76 
 
7 
74 
74 
75 
76 
77 
78 
78 
 
8 
75 
76 
77 
78 
79 
79 
80 


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76 
77 
78 
79 
80 
81 
81 
 
10 
77 
78 
79 
80 
81 
81 
82 
 
11 
78 
78 
79 
80 
81 
82 
82 
 
12 
78 
79 
80 
81 
82 
82 
83 
Female 
6 
72 
72 
73 
74 
74 
75 
76 
 
7 
73 
74 
74 
75 
76 
76 
77 
 
8 
75 
75 
75 
76 
77 
78 
78 
 
9 
76 
76 
76 
77 
78 
79 
79 
 
10 
77 
77 
77 
78 
79 
80 
80 
 
11 
78 
78 
78 
79 
80 
81 
81 
 
12 
79 
79 
79 
80 
81 
82 
82 
 
8.6.3 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The frequency of suicidality using the C-SSRS will be summarized by treatment for the Enrolled Safety 
population, for the following parameters: 
 
 Number of subjects reporting at least one occurrence of suicidal ideation or behavior. 
 
 
 


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9 
REFERENCES 
[1] High Blood Pressure Education Program Working Group on High Blood Pressure in Children and 
Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in 
children and adolescents. Pediatrics 2004;114(2 Suppl 4th Report):555-576.  
 
Version 1 of the TRI102-ADD-300 clinical study protocol dated 30JAN2017.