Clinical trial NCT05685732
Conditions: Attention Deficit/Hyperactivity Disorder
Sponsor: Corium, Inc.
Start date: 2023-03-22; Completion date: 2024-05-02
Enrollment: 246 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, dose-optimized, randomized, double-blind, placebo controlled, efficacy and safety study with Azstarys® in children 4 to 12 years of age with attention-deficit/hyperactivity disorder (ADHD). Azstarys® contains dexmethylphenidate (d-MPH) and serdexmethylphenidate (SDX), a prodrug of d-MPH and is orally administered. The primary objective is to determine the efficacy of Azstarys® compared to placebo in treating children ages 4 to 12 years old with ADHD. The study will consist of two randomized and blinded treatment cohorts ages 4 to 5 years of age and 6 to 12 years of age. Randomization will be applied separately with a starting dose up-titration at different dose levels for each cohort. 130 and 100 subjects will be enrolled, respectively. Approximately 20 sites will participate.

Detailed description:
* Screening Period (Visit 1) Subjects will undergo a screening period up to 30 days prior to entering the Treatment Period.
* Double-Blind Treatment Period (Visit 2 through Visit 6, approx. 28 days) Eligible subjects will be randomized in a blinded fashion to Azstarys® or placebo at the start of the Treatment Period. Randomization will be applied separately in each cohort and stratified by gender.

  * Cohort 1: Subjects 4 and 5 years (\<6 years) will start at 13.1 mg/2.6 mg or matching placebo and may be titrated up or down to doses of 13.1 mg/2.6 mg, 26.1 mg/5.2 mg, or 39.2 mg/7.8 mg Azstarys® or matching placebo approximately each week through Visit 5 (Day 21)
  * Cohort 2: Subjects 6-12 years (\<13 years) will start at 39.2 mg/7.8 mg or matching placebo and may be titrated up or down to doses of 26.1 mg/5.2 mg, 39.2 mg/7.8 mg, or 52.3 mg/10.4 mg Azstarys® or matching placebo approximately each week through Visit 5 (Day 21) Subjects who participate in Cohort 1 and successfully complete the Treatment Period will have the option to participate in a 12-month open-label safety study with Azstarys®.

Arms: arm 1: 13.1 mg/2.6 mg SDX/d-MPH, 26.1 mg/5.2 mg SDX/d-MPH, 39.2 mg/7.8 mg SDX/d-MPH arm 2: matching placebo arm 3: 26.1 mg/5.2 mg SDX/d-MPH, 39.2 mg/7.8 mg SDX/d-MPH, 52.3 mg/10.4 mg SDX/d-MPH arm 4: matching placebo
Interventions: intervention 1: Serdexmethylphenidate (SDX) and dexmethylphenidate (d-MPH) intervention 2: placebo
Intervention descriptions: intervention 1: Serdexmethylphenidate (SDX) and dexmethylphenidate (d-MPH) intervention 2: matching placebo

Protocol documents:
Prot_000.pdf: 
 
 
 
NCT: NCT05685732 
Corium Protocol No. KP415.P01 
Amendment #3, Version 4.0, November 14, 2022 


 
Protocol KP415.P01 
CONFIDENTIAL 
Corium, Inc. 
 
This confidential information about the investigational product is provided for the exclusive 
use of investigators of this product and is subject to recall at any time. The information in this 
document may not be disclosed unless federal or state law or regulations require such 
disclosure. Subject to the foregoing, this information may be disclosed only to those persons 
involved in the study who have a need to know, with the obligation not to further disseminate 
this information. 
 
 
 
 
November 14, 2022 
 
 
A Multicenter, Dose-Optimized, Randomized, 
Double-Blind, Efficacy and Safety Study with Azstarys® 
in Children 4 to 12 Years of Age with 
Attention-Deficit/Hyperactivity Disorder 
 
 
Protocol No: KP415.P01 
Original Protocol (Version 1.0) dated: December 20, 2021 
Amendment #1 (Version 2.0) dated: March 23, 2022 
Amendment #2 (Version 3.0) dated: June 27, 2022 
Amendment #3 (Version 4.0) dated: November 14, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol KP415.P01 
CONFIDENTIAL 
Corium, Inc. 
 
 
Page 2 of 74 
 
November 14, 2022 
 
A Multicenter, Dose-Optimized, Randomized, Double-Blind, Efficacy and Safety Study 
with Azstarys® in Children 4 to 12 Years of Age with Attention-Deficit/Hyperactivity 
Disorder 
 
Sponsor Approval / Signature Page 
 
 
Protocol Number 
KP415.P01 
Protocol Version Date 
Amendment #3 November 14, 2022 
Version 
4.0 
Investigational Product  
Azstarys® 
IND Number 
130463 
Study Phase 
Phase 4 
Sponsor  
Corium, Inc. 
4558 50th St SE 
Grand Rapids, MI 49512 
Phone: 616-656-4563 
 
 
 
      ____________________ 
 
Date 
 
 
 
 
 


Protocol KP415.P01 
CONFIDENTIAL 
Corium, Inc. 
 
 
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November 14, 2022 
 
A Multicenter, Dose-Optimized, Randomized, Double-Blind, Efficacy and Safety Study 
with Azstarys® in Children 4 to 12 Years of Age with Attention-Deficit/Hyperactivity 
Disorder 
 
I have read the protocol and agree that it contains all necessary details for carrying out this study. 
I will conduct this study as outlined in the protocol, Master Clinical Services Agreement, 
Statement of Work, and any change orders/amendments to these documents. 
 
I understand the study protocol and will conduct the study according to the procedures therein 
and according to the principles of Good Clinical Practice and all applicable federal and local 
regulations. 
 
I will ensure that all individuals assisting with the study are adequately trained and informed 
about the protocol, investigational product(s), procedures and their study related duties and 
functions. 
 
I agree not to deviate from the protocol without prior agreement from the Sponsor except to 
eliminate an immediate safety hazard to the study subjects. 
 
I further agree that the Sponsor, Sponsor designees and federal agencies, shall have access to all 
source documents and records associated with the study for review and monitoring of the 
investigational trial. 
 
 
___________________________________________ 
Site Investigator Name (Print) 
 
 
__________________________________  
 
 
_______________________ 
Signature Site Investigator 
 
 
 
 
Date 
 
 
__________________________________ 
Name of Investigational Site 
 
 
__________________________________ 
Address of Investigational Site 
 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... 7 
PROTOCOL SYNOPSIS ............................................................................................................. 9 
1. 
SCHEDULE OF EVENTS ............................................................................................. 25 
2. 
BACKGROUND ............................................................................................................. 29 
2.1. 
Attention-Deficit/Hyperactivity Disorder (ADHD) ...................................................... 29 
2.2. 
Azstarys® Product ......................................................................................................... 29 
2.3. 
Dose Justification .......................................................................................................... 30 
3. 
CLINICAL PHARMACOLOGY OF AZSTARYS® IN SUBJECTS OF AGE ≥6 
YEARS ............................................................................................................................. 31 
4. 
STUDY RATIONALE .................................................................................................... 34 
5. 
STUDY OBJECTIVES ................................................................................................... 34 
5.1. 
Primary Objective ......................................................................................................... 34 
5.2. 
Secondary Objectives.................................................................................................... 34 
6. 
INVESTIGATIONAL PLAN ........................................................................................ 34 
6.1. 
Study Design ................................................................................................................. 34 
6.2. 
Study Duration .............................................................................................................. 35 
7. 
SUBJECT SELECTION ................................................................................................ 35 
7.1. 
Number of Subjects....................................................................................................... 35 
7.2. 
Study Population ........................................................................................................... 36 
7.2.1. 
Inclusion Criteria .................................................................................................. 36 
7.2.2. 
Exclusion Criteria ................................................................................................. 37 
8. 
STUDY TREATMENTS ................................................................................................ 39 
8.1. 
Study Treatments: ......................................................................................................... 39 
8.1.1. 
Azstarys® Capsules ............................................................................................... 40 
8.1.2. 
Placebo Capsules .................................................................................................. 40 
8.2. 
Treatment Assignment .................................................................................................. 40 
8.3. 
Drug Administration ..................................................................................................... 41 
8.4. 
Blinding......................................................................................................................... 41 
8.5. 
Compliance ................................................................................................................... 41 
9. 
STUDY PROCEDURES ................................................................................................ 42 
9.1. 
Screening Procedures .................................................................................................... 42 
9.2. 
Rescreening ................................................................................................................... 44 
9.3. 
Start of Treatment Period (Visit 2) ............................................................................... 44 
9.4. 
At Home During the Treatment Period (Non-visit Days) ............................................. 45 
9.5. 
Treatment Period (Visits 3, 4, and 5) ............................................................................ 45 
9.6. 
End of Treatment Period (Visit 6) or Early Termination Visit ..................................... 46 
9.7. 
Follow-up Phone Call ................................................................................................... 47 
9.8. 
End of Study (EOS) ...................................................................................................... 48 


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9.9. 
Unscheduled Visits ....................................................................................................... 48 
9.10. Visit and Assessment Changes Due to COVID-19....................................................... 49 
9.10.1. 
General Guidelines................................................................................................ 49 
9.10.2. 
Study-specific Guidelines ..................................................................................... 50 
10. 
CONCOMITANT MEDICATIONS AND RESTRICTIONS .................................... 50 
10.1. Concurrent Medication Restrictions ............................................................................. 50 
10.2. General Restrictions ...................................................................................................... 52 
11. 
INVESTIGATIONAL PRODUCT................................................................................ 52 
11.1. Active Pharmaceutical Ingredients ............................................................................... 52 
11.2. Packaging and Labeling ................................................................................................ 53 
11.3. Dispensing Procedures .................................................................................................. 53 
11.4. Materials Control .......................................................................................................... 54 
11.5. Storage of Study Drug .................................................................................................. 54 
11.6. Study Drug Accountability ........................................................................................... 54 
12. 
SAFETY ASSESSMENTS ............................................................................................. 54 
12.1. Medical History ............................................................................................................ 54 
12.2. Physical Examination.................................................................................................... 54 
12.3. Children’s Sleep Habits Questionnaire (CSHQ) ........................................................... 55 
12.4. Columbia-Suicide Severity Rating Scale (C-SSRS) ..................................................... 55 
12.5. Vital Signs ..................................................................................................................... 55 
12.6. 12-Lead Electrocardiogram .......................................................................................... 56 
12.7. Clinical Laboratory Measurements ............................................................................... 56 
12.8. Adverse Event Assessments ......................................................................................... 57 
13. 
EFFICACY ASSESSMENTS ........................................................................................ 57 
13.1. ADHD Diagnosis .......................................................................................................... 57 
13.2. Mini-International Neuropsychiatric Interview for Children and Adolescents (MINI 
Kid) ............................................................................................................................... 58 
13.3. Clinical Global Impressions–Severity (CGI-S) ............................................................ 58 
13.4. Clinical Global Impressions–Improvement (CGI-I) ..................................................... 58 
14. 
PHARMACODYNAMICS............................................................................................. 58 
15. 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS .............................. 58 
15.1. Withdrawal of Subjects from the Study ........................................................................ 58 
15.2. Withdrawal of Subjects Post-Dose Study Drug ............................................................ 59 
15.3. Replacement of Subjects ............................................................................................... 59 
16. 
EFFICACY ENDPOINTS.............................................................................................. 59 
16.1. Primary Efficacy Endpoint ........................................................................................... 59 
16.2. Secondary Efficacy Endpoints ...................................................................................... 59 
17. 
STATISTICAL METHODS AND REPORTING ....................................................... 59 
17.1. Sample Size Calculation ............................................................................................... 59 
17.2. Analysis Populations ..................................................................................................... 61 
17.3. Statistical Analyses ....................................................................................................... 61 
17.4. Efficacy Analyses ......................................................................................................... 62 
17.4.1. 
Primary Efficacy Endpoint Analyses .................................................................... 62 


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17.4.2. 
Analyses of Secondary Efficacy Endpoints .......................................................... 64 
17.4.3. 
Type I Error Control for Efficacy ......................................................................... 64 
17.5. Safety Analysis ............................................................................................................. 65 
17.6. Interim Analysis ............................................................................................................ 66 
18. 
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ................... 66 
18.1. Adverse Events ............................................................................................................. 66 
18.1.1. 
Recording and Monitoring of Adverse Events ..................................................... 66 
18.1.2. 
Definition .............................................................................................................. 66 
18.1.3. 
Adverse Event Grading ......................................................................................... 66 
18.1.4. 
Adverse Event Relationship to Study Drug .......................................................... 67 
18.2. Serious Adverse Events ................................................................................................ 67 
18.2.1. 
Serious Adverse Event Reporting ......................................................................... 68 
18.3. Adverse Event Treatment and Follow-up ..................................................................... 68 
18.4. Overdosage ................................................................................................................... 68 
19. 
PROTOCOL VIOLATIONS ......................................................................................... 69 
20. 
DATA MANAGEMENT AND RECORD KEEPING................................................. 69 
20.1. Data Management ......................................................................................................... 69 
20.2. Record Keeping ............................................................................................................ 69 
20.3. Access to Source Data/Documents ............................................................................... 70 
21. 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................ 70 
22. 
ETHICS AND GOOD CLINICAL PRACTICE COMPLIANCE ............................. 70 
23. 
PUBLICATION POLICY .............................................................................................. 70 
24. 
FINANCING AND INSURANCE ................................................................................. 70 
24.1. Finances ........................................................................................................................ 70 
24.2. Insurance Compensation ............................................................................................... 70 
25. 
COMPLETION OF STUDY .......................................................................................... 71 
26. 
STUDY ADMINISTRATIVE INFORMATION ......................................................... 71 
26.1. Protocol Amendments ................................................................................................... 71 
27. 
REFERENCES ................................................................................................................ 72 
Appendix A: Instructions for Oral Administration of Study Drug ....................................... 74 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
ADHD 
Attention-Deficit/Hyperactivity Disorder 
ADHD-RS-5 
ADHD Rating Scale-5 
ADHD-RS-IV 
ADHD Rating Scale-IV 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
AUC 
Area under the plasma concentration-time curve 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impressions–Improvement 
CGI-S 
Clinical Global Impressions–Severity 
CL/F 
The apparent total plasma clearance after an oral dose (L/h) 
CL/F/W 
CL/F normalized by body weight (W), in L/h/kg 
Cmax 
Maximum observed plasma concentration 
CNS 
Central nervous system 
COVID-19 
Coronavirus Disease 2019 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CSHQ 
Children’s Sleep Habits Questionnaire 
CV 
Coefficient of variation 
d-MPH 
d-methylphenidate (dexmethylphenidate) 
DEA 
Drug Enforcement Agency 
DMDD 
Disruptive Mood Dysregulation Disorder 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOS 
End of Study  
ET 
Early Termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
IR 
Immediate Release 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
LLN 
Lower Limit of Normal 
MedDRA 
Medical Dictionary of Regulatory Activities 
MAOI 
Monoamine Oxidase Inhibitor 
MINI Kid 
Mini-International Neuropsychiatric Interview for Children and Adolescents 


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Abbreviation 
Definition 
MMRM 
Mixed Model for Repeated Measures 
MPH 
Methylphenidate 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
Q1 
25th Percentile (1st Quartile) 
Q3 
75th Percentile (3rd Quartile) 
QT 
Time between the start of the Q wave and the end of the T wave (QT interval) in 
the heart’s electrical cycle 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOE 
Schedule of Events 
TEAE 
Treatment-Emergent Adverse Event 
ULN 
Upper Limit of Normal 
Tmax 
Time to achieve the maximum observed plasma concentration 
Vz/F 
Apparent volume of distribution after an oral dose (F is the oral bioavailability 
expressed as a fraction) 
 
 


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PROTOCOL SYNOPSIS 
TITLE 
A Multicenter, Dose-Optimized, Randomized, Double-Blind, 
Efficacy and Safety Study with Azstarys® in Children 4 to 12 
Years of Age with Attention-Deficit/Hyperactivity Disorder 
SPONSOR 
Corium, Inc. 
PROTOCOL NUMBER 
KP415.P01 
INVESTIGATIONAL 
PRODUCT 
Azstarys® contains dexmethylphenidate (d-MPH) and 
serdexmethylphenidate (SDX), a prodrug of d-MPH. 
NAME OF ACTIVE 
INGREDIENT 
The chemical name of SDX is 3-(((S)-1-carboxy-2-
hydroxyethyl)carbamoyl)-1-((((R)-2-((R)-2-methoxy-2-oxo-1-
phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridine-1-ium 
chloride. 
ROUTE 
Oral 
NUMBER OF SITES 
Approximately 20 sites in the United States of America 
STUDY DESIGN 
This is a multicenter, dose-optimized, randomized, double-blind, 
efficacy and safety study with Azstarys® in children 4 to 12 years 
of age with attention-deficit/hyperactivity disorder (ADHD). 
The phases of the study are as follows: 
• Screening Period (Visit 1) 
Subjects will undergo a Screening Period up to 30 days prior 
to entering the Treatment Period. 
• Double-Blind Treatment Period (Visit 2 through Visit 6) 
Eligible subjects will be randomized in a blinded fashion to 
Azstarys® or placebo at the start of the Treatment Period. 
Randomization will be applied separately in each cohort and 
stratified by gender.  
o Cohort 1: Subjects 4 and 5 years (<6 years) will start 
at 13.1 mg/2.6 mg or matching placebo and may be 
titrated up or down to doses of 13.1 mg/2.6 mg, 
26.1 mg/5.2 mg, or 39.2 mg/7.8 mg Azstarys® or 
matching placebo approximately each week through 
Visit 5 
o Cohort 2: Subjects 6 to 12 years (<13 years) will start 
at 39.2 mg/7.8 mg or matching placebo and may be 
titrated up or down to doses of 26.1 mg/5.2 mg, 
39.2 mg/7.8 mg, or 52.3 mg/10.4 mg Azstarys® or 
matching placebo approximately each week  through 
Visit 5 
• Roll-over into Study KP415.P02 


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Subjects of Cohort 1 (ages 4 and 5 years) who successfully 
complete the treatment phase have the option to participate in 
a 12-month open-label safety study with Azstarys® 
(Study KP415.P02). At Visit 6 of the current study, all entry 
criteria to enroll in Study KP415.P02 (see protocol for 
Study KP415.P02) will be evaluated (Visit 6 for the current 
study is also Visit 2 of Study KP415.P02). 
• Follow-up Phone Call: 
Subjects who will not be rolled over into Study KP415.P02 
will receive a Follow-up Phone Call, at 5 ±2 days after 
administration of the last dose of the Treatment Period. 
Subjects who elect to use another ADHD treatment will be 
discontinued from study treatment and from the study (Early 
Termination [ET]).  
Subjects who discontinue study treatment prior to the end of the 
Treatment Period (Visit 6) because of adverse events (AEs), 
overdosage, or use of a prohibited treatment other than an ADHD 
treatment will be followed (unless consent is withdrawn) with 
scheduled assessments until the end of the Treatment Period 
(Visit 6). If, during the remaining time on study, an ADHD 
treatment is used, the subject will be discontinued from the study 
(ET). 
PRIMARY OBJECTIVE 
• To determine the efficacy of Azstarys® compared to placebo 
in treating children ages 4 to 12 years old with ADHD. 
SECONDARY 
OBJECTIVE 
• To determine the safety and tolerability of Azstarys® 
compared to placebo in treating children 4 to 12 years old 
with ADHD. The safety objective includes evaluation of 
changes in body weight and height, and sleep behavior. 
SAMPLE SIZE 
CALCULATION 
Based on data from a previous study (efficacy study with 
Azstarys® in subjects 6- to 12-years of age), the power and 
proposed sample size in each age cohort was calculated based on 
a two-sample t-test as follows (with no multiplicity correction for 
the two age cohorts): 
• 90% power to detect a 6-point treatment difference with an 
SD of 10-points using two-sided α=0.05 in Cohort 1 (4- to 
5-years-of-age) yields N=60 per treatment group in a 1:1 
ratio for active and placebo for a total sample size of 120 
younger subjects 
• 80% power to detect a 6-point treatment difference with an 
SD of 10-points using two-sided α=0.05 in Cohort 2 (6- to 
12-years of age) yields N=45 per treatment group in a 1:1 
ratio for active and placebo for a total sample size of 
90 older subjects. A lower power was selected for this cohort 


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because efficacy in this age group was previously 
established. 
Combining the two age cohorts for a total of 105 subjects per 
treatment group yields 99% overall study power to detect a 
between-treatment difference of 6 points with a SD of 10 points 
using two-sided α=0.05 for a total sample size in the study of 
210  subjects. 
A blinded sample size re-estimation will be conducted to 
recalculate the SD when approximately 50% of subjects  in 
Cohort 1 have completed Visit 6.  
NUMBER OF SUBJECTS In each age cohort, an appropriate number of subjects will enter 
the Screening Period to randomize approximately the following 
number of subjects in the Treatment Period. 
Randomization between Azstarys® and placebo will be applied 
within each of two age cohorts: 
• Cohort 1 (4 and 5 years of age): 130 subjects (65 per arm) 
with the intention to complete with approximately 120 
subjects. 
• Cohort 2 (6 to 12 years of age): 100 subjects (50 per arm) 
with the intention to complete with approximately 
90 subjects. 
The additional number of subjects enrolled is based on an 
approximate 10% early discontinuation rate. Subjects who 
terminate early in the Treatment Period will not be replaced. 
In accordance with a male-to female distribution ratio of 3:1 of 
children diagnosed with ADHD in clinical practice, it is 
anticipated that approximately 75% males and 25% females will 
be enrolled. 
SUBJECT SELECTION 
CRITERIA 
Inclusion Criteria 
1. 
In Cohort 1, subjects must be at least 4 years old and less 
than 5 years and 10 months at Screening; in Cohort 2, 
subjects must be at least 6 years old and less than 
12 years and 10 months at Screening. 
2. 
Subjects must have a body weight within the 5th and 
95th percentile according to the gender-specific weight-
for-age percentile charts from the Centers for Disease 
Control and Prevention (CDC). See calculator at 
https://www.infantchart.com/child/. 
3. 
Female subjects must agree, if they are of childbearing 
potential at Screening or when they become of 
childbearing potential during the study, to remain 
abstinent or agree to use an effective and medically 
acceptable form of birth control from the time of written 


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or verbal assent to at least 14 days after the last dose of 
study drug. Childbearing potential is defined as follows: 
Girls under the age of 12 who have not had their first 
period will be considered “not of child-bearing 
potential.” Girls 12 years of age will be considered “of 
child-bearing potential,” even if they have not yet had 
their first period. Irrespective of age, girls who have had 
their first period, will be considered “of child-bearing 
potential.” 
4. 
Subjects must be in general good health defined as the 
absence of any clinically relevant abnormalities as 
determined by the Investigator based on physical 
examinations, vital signs, electrocardiograms (ECGs), 
medical history, and clinical laboratory values 
(chemistry, hematology, urinalysis) at Screening. If any 
of the chemistry or hematology tests are not within the 
laboratory's reference range, then the subject can be 
included only if the Investigator determines the 
deviations to be not clinically relevant. 
5. 
At least one parent/legal guardian of the subject must 
voluntarily give written permission for him/her to 
participate in the study. 
6. 
Subjects in Cohort 2 must give written or verbal assent 
prior to study participation. For verbal assent, the 
procedure will be documented and signed by a witness. 
A parent or guardian may not be the witness for a child’s 
verbal assent document. 
7. 
Subject must meet Diagnostic and Statistical Manual of 
Mental Disorders – Fifth Edition (DSM-5) criteria for a 
primary diagnosis of ADHD (combined, inattentive, or 
hyperactive/impulsive presentation) per clinical 
evaluation and confirmed by  Mini-International 
Neuropsychiatric Interview for Children and Adolescents 
(MINI Kid). 
8. 
Subject has had ADHD symptoms present for at least 
6 months prior to the Screening Visit. 
9. 
Subject must be able and willing to wash out current 
stimulant ADHD medications, including herbal 
medications, from 5 days prior to the start of the 
Treatment Period, and abstain from taking these to the 
end of Visit 6 or ET; and wash out non-stimulant ADHD 
medications from 14 days prior to the start of the 
Treatment Period, and abstain from taking these to the 
end of Visit 6 or ET. 


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10. 
Subject must have a score of ≥4 (Moderately Ill) on the 
clinician-administered Clinical Global Impressions–
Severity (CGI-S) scale. For subjects requiring washout of 
ADHD medications, this criterion refers to a score 
following washout. 
11. 
Subjects must have age and sex adjusted ratings of 
≥90th percentile Total Score on the ADHD-Rating Scale 
(ADHD-RS) rated over the past 6 months (for 4- and 5-
year old children, use Preschool Version of ADHD-RS-
IV; for 6-12 years old children, use ADHD-RS-5). 
12. 
Subject functions at an age-appropriate level 
intellectually, as determined by the Investigator. 
13. 
Subject must have a systolic and diastolic blood pressure 
below the 95th percentile for age and gender according to 
the 2017 AAP guidelines (Flynn 2017) based on the 
average of 3 measurements 2-5 minutes apart. 
14. 
Subject, subject’s parent/legal guardian, and caregiver (if 
applicable) must understand and be willing and able to 
comply with all study procedures and visit schedule. 
15. 
Subject, parent/legal guardian, and caregiver (if 
applicable) must be able to speak and understand English 
or Spanish and be able to communicate satisfactorily 
with the Investigator and study coordinator. 
 
Exclusion Criteria  
1. 
If female, must not be pregnant or breastfeeding, and if 
of childbearing potential, must have a negative urine 
pregnancy test at the start of the Screening Period. In 
addition, a positive pregnancy test before the last dose of 
study drug will result in early termination from the study. 
2. 
Subject with any clinically significant chronic medical 
condition that, in the judgment of the Investigator, may 
interfere with the subject’s ability to participate in the 
study. 
3. 
Subject has any diagnosis of bipolar I or II disorder, 
major depressive disorder, conduct disorder, obsessive-
compulsive disorder, any history of psychosis, autism 
spectrum disorder, disruptive mood dysregulation 
disorder (DMDD), intellectual disability, Tourette’s 
Syndrome, confirmed genetic disorder with cognitive 
and/or behavioral disturbances. Subjects with 
oppositional defiant disorder (ODD) are permitted to 
enroll in the study as long as ODD is not the primary 
focus of treatment, and, in the opinion of the 


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Investigator, the ODD is mild to moderate, and eligible 
subjects with ODD are appropriate and cooperative 
during Screening. 
4. 
Subject has generalized anxiety disorder or panic 
disorder that has been the primary focus of treatment at 
any time during the 12 months prior to Screening or that 
has required pharmacotherapy any time during the 
6 months prior to Screening. 
5. 
Subject has evidence of any chronic disease of the central 
nervous system (CNS) such as tumors, inflammation, 
seizure disorder, depression, vascular disorder, potential 
CNS-related disorders that might occur in childhood 
(e.g., Duchenne muscular dystrophy, myasthenia gravis, 
or other neurologic or serious neuromuscular disorders), 
or history of persistent neurological symptoms 
attributable to serious head injury. 
6. 
Subject taking anticonvulsants for seizure control or 
antidepressants currently or within the past 2 years 
before Screening are not eligible for study participation. 
A past history of febrile seizure or drug-induced seizure 
is allowed. 
7. 
Subject has a current (last month) psychiatric diagnosis 
other than specific phobia, motor skills disorders, ODD, 
sleep disorders, elimination disorders, adjustment 
disorders, learning disorders, or communication 
disorders. Subjects allowed to enroll with any of these 
DSM disorders will require written justification from the 
Investigator documenting why the conditions will not 
interfere with participation and to emphasize that ADHD 
is the primary indication. 
8. 
In the opinion of the Investigator, subject has clinically 
significant suicidal ideation/behavior, based on history of 
attempted suicide and the  Columbia-Suicide Severity 
Rating Scale (C-SSRS) assessment at Screening. 
9. 
Subject has any clinically significant unstable medical 
abnormality, chronic disease (including asthma or 
diabetes), or a history of a clinically significant 
abnormality of the cardiovascular (including 
cardiomyopathy, serious arrhythmias, structural cardiac 
disorders, or severe hypertension), gastrointestinal, 
respiratory, hepatic, or renal systems, or a disorder or 
history of a condition (e.g., malabsorption, 
gastrointestinal surgery) that may interfere with 
absorption, distribution, metabolism, or excretion of 
study drug. In cases in which the impact of the condition 


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upon risk to the subject or study results is unclear, the 
Medical Monitor should be consulted. Any subject with a 
known cardiovascular disease or condition (even if 
controlled) must be discussed with the Medical Monitor 
during Screening. 
10. 
Subject has a history or presence of abnormal ECGs, 
which in the Investigator’s opinion is clinically 
significant. 
11. 
Subject has a history of, or currently has, a malignancy. 
12. 
Subject has uncontrolled thyroid disorder as evidenced 
by thyroid stimulating hormone (TSH) ≤0.8 x the lower 
limit of normal (LLN) or ≥1.25 x the upper limit of 
normal (ULN) for the reference laboratory at Screening. 
13. 
Subject has greater than trace proteinuria in the urinalysis 
at Screening. Subjects with greater than trace proteinuria 
in the urinalysis at Screening but with a urine protein to 
creatinine (UP/C) ratio <0.2 in a first morning void urine 
sample will not be excluded from enrollment. 
14. 
Subjects has a current or recent (past 12 months) history 
of drug abuse; or current or recent history of drug abuse 
in someone living in the subject’s home, or are using or 
planning to use prohibited drugs during the trial as 
specified in the protocol. 
15. 
Subject has a positive urine drug screen at Screening. 
Subjects with a positive methylphenidate (MPH) urine 
drug screen may be allowed to continue in the study, 
provided that the Investigator determines that the positive 
test is a result of taking prescribed medications and 
subject is willing to wash out the current medication as 
required. 
16. 
Subject has participated in any other clinical study with an 
investigational drug/product within 30 days or at least 
5 half-lives, whichever is longer, prior to Screening. 
17. 
Subject has taken ADHD medications from more than one 
class within 30 days prior to Screening. Subjects on a 
stable dose of one ADHD medication with occasional use 
of ADHD medications from another class are eligible at 
the discretion of the Investigator. 
18. 
Subjects with demonstrated lack of response or 
intolerability to adequate dose and duration of treatment 
with MPH products. Judgment of adequate dose and 
duration is at the discretion of the Investigator.  
19. 
Subject has a positive urine MPH screen by dipstick 
(e.g., NarcoCheck®) at Visit 2. 


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20. 
Subject is planning to initiate psychotherapy during the 
study (subjects participating in psychotherapy beginning 
at least 4 weeks before study initiation are permitted to 
continue). 
21. 
Subject has a history of severe allergies or adverse drug 
reactions to more than one class of medications. 
22. 
Subject has a history of allergic reaction or a known or 
suspected sensitivity to MPH or any substance that is 
contained in the study drug. 
23. 
Subject, parent/legal guardian, and caregiver (if 
applicable, at the Investigator’s discretion) has 
commitments during the study that would interfere with 
attending study visits. 
24. 
Subject or subject’s family anticipates a move outside the 
geographic range of the investigative site during the 
study period, or plans extended travel inconsistent with 
the recommended visit interval during study duration. 
25. 
Subject has one or more siblings living in the same 
household who are enrolled in this or another clinical 
drug trial. 
26. 
Subject shows evidence of current physical, sexual, or 
emotional abuse. 
27. 
Subject is, in the opinion of the Investigator, unsuitable 
in any other way to participate in this study. 
 
Rescreening 
Subjects who require extension of the screening window and 
remain eligible for the study may be rescreened upon approval by 
the Medical Monitor. Subjects who screen fail will not be 
rescreened. 
TEST PRODUCT, DOSE, 
AND ROUTE OF 
ADMINISTRATION 
The Azstarys® capsules contain two active pharmaceutical 
ingredients: d-methylphenidate (dexmethylphenidate; d-MPH) 
hydrochloride, and serdexmethylphenidate (SDX; a prodrug of 
d-MPH). In terms of total d-MPH dose amounts, all capsule 
strengths contain 30% of d-MPH and 70% of d-MPH in form of 
the prodrug. The total equivalent amount of d-MPH in each 
capsule strength (used as daily doses in this study), and the 
amounts of both APIs are listed in the following table. 
d-MPH 
(mg) 
SDX (d-MPH) 1 
(mg) 
Total 
d-MPH dose 2 
(mg) 
Equimolar 
d-MPH HCl dose 
(mg) 
2.6 
13.1 (6.1) 
8.6 
10 
5.2 
26.1 (12.2) 
17.3 
20 
7.8 
39.2 (18.3) 
25.9 
30 


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10.4 
52.3 (24.4) 
34.6 
40 
1. This is dose of SDX. The amount of d-MPH equimolar to each SDX dose 
is listed in parentheses. 
2. The total dose of d-MPH expressed in terms of free base. 
Azstarys® is a Schedule II product under the Controlled 
Substances Act. Therefore, study sites are required to have the 
appropriate permit from the Drug Enforcement Agency (DEA) to 
receive, store, ship and dispense Azstarys® according to all local, 
state, and federal regulations for Schedule II controlled 
substances. 
All subjects will receive study drug, as follows: 
o At Visit 2, subjects will be randomized in a blinded 
fashion to either Azstarys® or placebo. 
Randomization will be applied to each cohort 
separately and will be stratified by gender 
During the Treatment Period, daily treatments of double-blind 
study drug will be administered. 
o Cohort 1: Subjects 4 and 5 years (<6 years): will start 
at 13.1 mg/2.6 mg  Azstarys® or matching placebo and 
may be titrated up or down to doses of 
13.1 mg/2.6 mg, 26.1 mg/5.2 mg, 39.2 mg/7.8 mg 
Azstarys® or matching placebo at Visits 3, 4, and/or 5 
o Cohort 2: Subjects 6-12 years (<13 years): will start 
with at 39.2 mg/7.8 mg  Azstarys® or matching 
placebo and may be titrated up or down to doses of 
26.1 mg/5.2 mg 39.2 mg/7.8 mg, 52.3 mg/10.4 mg 
Azstarys® or matching placebo  at Visits 3, 4, and/or 5 
The daily dose may be changed at Visits 3, 4 and 5 based on a 
combination of individual tolerability and effect assessed by the 
Investigator. If a lack of tolerability should occur between visits, 
the dose may be lowered at any time. 
The optimized daily dose will be determined at Visit 5 and will 
be kept the same for the remainder of the Treatment Period, with 
the following exception: if a lack of tolerability should occur, the 
dose may be lowered at any time. 
Study drug will be taken orally in the morning within 20 minutes 
after consuming breakfast. Study drug will be swallowed whole 
(without crushing, cutting, chewing, opening, or dissolving) or 
may be taken by sprinkling the contents of the capsule over a 
small amount of applesauce. 
On each day at home (no scheduled visits to the study site) during 
the Treatment Period, the assigned study drug will be taken under 
the supervision of the subject’s parent or caregiver. 


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On days with scheduled visits to the study site, subjects will take 
the assigned study drug either at home under the supervision of 
the subject’s parent or caregiver before coming to the study site 
for their scheduled visit, or, if their visit occurs in the morning, 
subjects may take the assigned study drug at the study site under 
the supervision of site staff. 
ADHD SEVERITY/ 
EFFICACY 
EVALUATION 
CRITERIA 
The following scales will be used to assess the changes in 
ADHD severity: 
• ADHD-Rating Scale (ADHD-RS): The Preschool Version 
of ADHD-RS-IV (McGoey 2007) will be used for 4- and 
5-year-old subjects (Cohort 1), and ADHD-RS-5 will be 
used in 6- to 12-year-old subjects (Cohort 2). The 
ADHD-RS is an 18-item scale (DuPaul 1998, DuPaul 2016) 
based on Diagnostic and Statistical Manual of Mental 
Disorders (American Psychiatric Association 2013) criteria 
of ADHD that rates symptoms on a 4-point scale. Each item 
is scored using a combination of severity and frequency 
ratings from a range of 0 (reflecting no symptoms or a 
frequency of never or rarely) to 3 (reflecting severe 
symptoms or a frequency of very often), so that the total 
ADHD-RS scores range from 0 to 54. The 18 items can be 
divided into two 9-item subscales: One for 
hyperactivity/impulsivity and the other for inattention. 
Scores will be obtained during a clinician-directed interview 
with the parent/guardian/ caregiver at each visit.  
• Mini-International Neuropsychiatric Interview for Children 
and Adolescents (MINI Kid; Sheehan 2010). Will be used to 
conﬁrm the diagnosis of ADHD and identify comorbid 
psychiatric conditions. 
• Clinical Global Impressions–Severity (CGI-S): The CGI-S 
is a clinician-rated scale that evaluates the severity of 
psychopathology (ADHD symptoms in the study) on a scale 
from 1 (not at all ill) to 7 (among the most severely ill) 
(Busner and Targum 2007). 
• Clinical Global Impressions–Improvement (CGI-I): The 
CGI-I is a clinician-rated scale that evaluates the 
improvement of psychopathology (ADHD symptoms in the 
study) on a scale from 1 (very much improved) to 7 (very 
much worse). 
During the Treatment Period, the ADHD-RS, CGI-I and CGI-S 
scale assessments are the main efficacy response variables (in 
conjunction with tolerability and safety) to guide dose 
optimization.  


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DURATION OF 
SUBJECT 
PARTICIPATION AND 
DURATION OF STUDY 
Subjects will participate in the study as outpatients for up to 
65 days including up to 30 days of Screening, up to 28 days in 
the Treatment Period, and a Follow-up Phone Call up to 7 days 
(5 ±2 days) after the administration of the last dose of the 
Treatment Period. 
MEDICATION 
RESTRICTIONS 
Subjects will be prohibited/limited to receive certain medications 
in the trial, as follows: 
• Stimulant ADHD medications (with the exception of study 
drug), including herbal medications, are prohibited from 
5 days prior to the start of the Treatment Period to the end of 
the Treatment Period (Visit 6) or ET Visit. These include: 
MPH, amphetamine, Ritalin®, Ritalin® SR, Metadate® ER, 
Concerta®, d-MPH, Focalin®, dextroamphetamine, 
Dexedrine®, Adderall®, Vyvanse®, lisdexamfetamine, and 
prescription Azstarys®. 
• 
Non-Stimulant ADHD medications are prohibited from 
14 days prior to the start of the Treatment Period to the end 
of the Treatment Period (Visit 6) or ET Visit. These include: 
atomoxetine, guanfacine, clonidine. 
• 
The following medications are prohibited from 14 days prior 
to the start of the Treatment Period to the end of the 
Treatment Period (Visit 6) or ET Visit: 
o Monoamine oxidase inhibitors (MAOIs). 
o Norepinephrine reuptake inhibitors (NRIs) and 
selective serotonin reuptake inhibitors (SSRIs) such as 
fluoxetine, paroxetine, and viloxazine. 
o Mood stabilizers (e.g., lithium, valproate, quetiapine). 
o Antipsychotics (e.g., risperidone, olanzapine). 
o Coumarin anticoagulants. 
o Anticonvulsants. 
o Halogenated anesthetics. 
o Phenylbutazone 
o Sedative hypnotics/sleep enhancers (with the exception 
of melatonin, which is allowed if subjects have taken it 
for more than 30 days before Screening) 
• 
Tricyclic antidepressants as well as Bupropion are prohibited 
from 30 days prior to the start of the Treatment Period to the 
end of the Treatment Period (Visit 6) or ET Visit. 
• 
Cough and cold medications containing stimulants and/or 
sedating antihistamines are prohibited from 30 days prior to 
the start of the Treatment Period to the end of the Treatment 
Period (Visit 6) or ET Visit. 


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All other concomitant medications will be allowed if 
necessary. 
Note: Subjects who are rolled over into Study KP415.P02 after 
the end of the Treatment Period in the current study will need 
to continue to abstain from prohibited medications as explained 
in the protocol for Study KP415.P02. 
SAFETY ASSESSMENTS • The occurrence of treatment emergent adverse events 
(TEAEs) will be assessed following the first dose of study 
drug and ending with the Follow-up Phone Call or ET Visit. 
• Physical examinations will be performed at Screening, before 
the first dose of study drug (Visit 2), and at the end of the 
Treatment Period (Visit 6) or at ET. 
• Clinical laboratory tests will be performed at Screening and at 
the end of the Treatment Period (Visit 6) or at ET. Urinalysis 
will also be performed at Screening, before the first dose of 
study drug and at the end of the Treatment Period or at ET. 
• ECG parameters will be collected at Screening and at the end 
of the Treatment Period (Visit 6) or at ET. 
• Vital signs, height and body weight will be collected at each 
visit. Blood pressure data will be analyzed using the 2017 
AAP guidelines based on the average of 3 blood pressure 
measurements 2-5 minutes apart. 
• Height will be measured at Screening, Visit 2, and at the End 
of the Treatment Period. 
• A C-SSRS will be performed at each study visit. 
• Ratings from the modified, abbreviated Children’s Sleep 
Habits Questionnaire (CSHQ) will be collected at Screening, 
and at each visit of the Treatment Period, or at ET. 
EFFICACY 
ASSESSMENTS 
During the Treatment Period (Visits 2-6): 
• ADHD-RS-IV (Preschool Version, Cohort 1) or ADHD-
RS-5 (Cohort 2) will be assessed at each visit. 
• CGI-S will be assessed at each visit (Visits 2-6) 
• CGI-I will be assessed at Visits 3, 4, 5, and 6. 
ANALYSIS 
POPULATIONS 
• Safety Population: Overall and for each cohort separately, 
all randomized subjects who received at least one dose of 
study medication and who have at least one post-dose 
safety assessment. Safety endpoints will be analyzed using 
the Safety Population. Demographics and baseline 
characteristics will be summarized for the Safety 
Population. 
• Intent-to-Treat (ITT) Population: Overall and for each 
cohort separately, all subjects who received at least one 


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dose of study medication and have at least one post-
randomization ADHD-RS Total Score. Demographics and 
baseline characteristics will be summarized for the ITT 
Population. All efficacy analyses will be conducted in the 
ITT Population. 
• Per-Protocol (PP) Population: Overall and for each cohort 
separately, all randomized subjects who received at least 
one dose of study medication and have the baseline and at 
least one post-randomization ADHD-RS Total Score, and 
who did not miss more than 2 days of therapy and did not 
use prohibited medications deemed to impact efficacy. The 
primary efficacy analyses will be conducted in the PP 
Population as sensitivity analyses. 
STATISTICAL 
METHODS 
Descriptive statistics will be presented for baseline, all post 
baseline measurements, and changes from baseline to all post-
baseline measurements, where applicable, for continuous efficacy 
endpoints by treatment group, overall and separately for each age 
cohort.  
For the primary endpoint of change from baseline in ADHD 
Rating Scale (ADHD-RS) total score, a mixed model repeated 
measures (MMRM) analysis of covariance (ANCOVA) model 
will be fitted using all data as observed. The model will include 
fixed effects for treatment, age cohort, gender (stratification 
factor for randomization), baseline ADHD-RS total score, visit 
and visit-by-treatment interaction as well as a random effect for 
the subject.  
The primary efficacy analysis will be based on comparisons of 
Azstarys® and placebo at Visit 6.  From the MMRM model, the 
Visit 6 difference between least square (LS) means of Azstarys® 
and placebo will be presented along with the corresponding 95% 
CI and two-sided p-value. The above analyses will be repeated 
for each age cohort separately. 
The primary estimand for this study is the difference in LS means 
of Azstarys® and placebo with respect to change from baseline in 
ADHD-RS total score at Visit 6, based on the primary endpoint 
MMRM model fitted to the Intent-to-Treat population. There will 
be no adjustments made for the use of prohibited therapies or 
other intercurrent events. The p-value associated with the primary 
estimand will be used to test the primary hypothesis of this study, 
that mean change from baseline to Visit 6 ADHD-RS total score 
for Azstarys® is different from that of placebo. If Azstarys® is 
shown to be statistically superior to placebo, then the superiority 
of Azstarys® to placebo will be tested for each cohort separately.   
As a sensitivity analysis of the primary endpoint, change from 
baseline in ADHD-RS total scores, the above analyses will be 


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repeated in their entirety using multiple imputation methods to 
impute the missing data.  If the primary analysis renders a 
significant treatment difference, a tipping point analysis will be 
performed in order to examine the sensitivity of inferences to 
departures from the missing at random (MAR) assumption. The 
imputed values for Azstarys® subjects’ visits post discontinuation 
will be made worse by a delta defined as k times the treatment 
difference between Azstarys® and placebo obtained from the MI 
MAR analysis, where k is a shift parameter that is incremented in 
order to identify the point at which the primary analysis result 
becomes non-significant (the tipping point). Consideration will 
then be given to how plausible the imputed values are at the 
tipping point. If not plausible, then the conclusion for the primary 
analysis under the MAR assumption is supported. 
The secondary efficacy endpoints, change from baseline to post-
baseline timepoints in ADHD-RS for hyperactivity/impulsivity 
and the ADHD-RS for inattention as well as change from 
baseline CGI-S will be analyzed using the same methods as the 
primary efficacy endpoint. For each endpoint, MMRM 
ANCOVA models will be fitted using all data as observed. The 
model will include fixed effects for treatment, age cohort, gender, 
baseline, visit, and visit-by-treatment interaction as well as a 
random effect for the subject. From the MMRM models, the Visit 
6 difference between LS means of Azstarys® and placebo will be 
presented along with the corresponding 95% CI and two-sided p-
value. The analyses will be repeated for each age cohort 
separately. 
For the CGI-I, an MMRM ANOVA model will be fitted using all 
data as observed. The model will include fixed effects for 
treatment, age cohort, gender, visit and visit-by-treatment 
interaction as well as a random effect for the subject. From the 
MMRM model, the Visit 6 difference between LS means of 
Azstarys® and placebo will be presented along with the 
corresponding 95% CI and two-sided p-value. The analyses will 
be repeated for each age cohort separately. 
Visit 6 CGI-I will also be compared between treatment groups 
using a Cochran-Mantel-Haenszel (CMH) chi square test within 
each age cohort stratified by gender. An overall CMH test will 
also be conducted stratified by gender and age (4 strata). 
Type I Error Control for Efficacy 
For the primary endpoint, the hypothesis of superiority of 
Azstarys® to placebo will be tested at a two-sided alpha of 0.05 
for the two age cohorts combined.  If significant, the same 
hypothesis will be tested for each age cohort at a two-sided 0.05 
level of significance.   


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If the primary endpoint comparison is significant for Cohort 1, 
the superiority of Azstarys® to placebo with respect to the 
secondary efficacy endpoints, ADHD-RS for 
hyperactivity/impulsivity and ADHD-RS for inattention, will be 
tested for Cohort 1 only using a fixed sequence testing procedure 
in that order. 
Safety Analysis 
Descriptive statistics will be presented for baseline, all post-
baseline measurements, and changes from baseline to all post-
baseline measurements, where applicable, for continuous safety 
endpoints by treatment group, overall and separately for each age 
cohort. Laboratory shift tables from baseline to each post-
baseline time-point will be presented. The incidence of clinically 
notable vital signs will be summarized. Physical examination 
findings will be presented in subject listings.  
Adverse events will be mapped to preferred term and system 
organ class using the Medical Dictionary for Regulatory 
Activities (MedDRA). The number and percentage of subjects 
reporting TEAEs will be summarized by MedDRA system organ 
class and preferred term, by severity, and by relationship to study 
treatment. The number and percentage of subjects with SAEs and 
TEAEs leading to treatment discontinuation will also be 
summarized by MedDRA system organ class and preferred term. 
Descriptive statistics will be presented by visit for body weight 
(in kg), change and percent change from baseline in body weight, 
height (in cm), change and percent change from baseline in 
height, weight and height z-scores, and weight and height 
percentiles by treatment group, separately for each age cohort. In 
addition, descriptive statistics will be tabulated by sex and 
optimized dose. 
An MMRM ANCOVA model will be fitted to change from 
baseline CSHQ total Sleep score. The model will include fixed 
effects for treatment, age cohort, gender, baseline CSHQ, visit, 
and visit-by-treatment interaction as well as a random effect for 
the subject. From the MMRM model, the Visit 6 difference 
between LS means of Azstarys® and placebo will be presented 
along with the corresponding 95% CI. The MMRM analysis of 
the change from baseline CSHQ scores will also be conducted 
separately for each age cohort. 
An MMRM ANCOVA model will be fitted to change from 
baseline C-SSRS score. The model will include fixed effects for 
treatment,  age cohort, gender, baseline C-SSRS, visit and visit-
by-treatment interaction as well as a random effect for the 
subject. From the MMRM model, the Visit 6 difference between 
LS means of Azstarys® and placebo will be presented along with 


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the corresponding 95% CI. The MMRM analysis of the change 
from baseline C-SSRS scores will also be conducted separately 
for each age cohort. 
Interim Analysis 
An interim analysis will be conducted for potential sample size 
increase in subjects 4 and 5 years of age (Cohort 1). When 
approximately 50% of the Cohort 1 subjects complete their 
Visit 6 assessments, a blinded sample size re-estimation will be 
conducted. Subjects will not be identified by treatment group.  
The within-group standard deviation (σ) will be estimated for 
change from baseline to Visit 6 ADHD-RS total score using the 
blinded methodology of Gould and Shih. The blinded analyses 
will be conducted by a firewalled independent statistician. An 
exact sample size will not be disclosed to the sponsor. Instead, 
ranges of sample size will be pre-specified in the interim analysis 
plan and the upper limit of the applicable range will be 
recommended instead of the exact sample size. Since the study 
will remain blinded for the sample size re-assessment, no alpha 
penalty for the final analysis will be incurred. 
STUDY PROCEDURES 
The study procedures are outlined in the Schedule of Events 
SOE) (Section 1).  


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1. SCHEDULE OF EVENTS 
ASSESSMENTS 
SCREENING 
PERIOD 
DOUBLE BLIND 
TREATMENT PERIOD 
EARLY 
TERMINATION 
19 
FOLLOW-UP 
PHONE  
CALL 
Study Day 
-30 to -1 
0 
7 
(±3 
days 
14 
(±3 
days) 
21 
(±3  
days) 
28 
(±3  
days) 
 
- 
 
33 
(± 2  
days) 
Visit Number 
1 
2  
3 
4 
5 
6 
 
- 
 
- 
Parental Permission (Informed 
Consent)/Written or Verbal Assent 
(Cohort 2) 
X 
 
 
 
 
 
 
 
ADHD Diagnosis and  
Confirmation 1 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 2 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 3 
X 
X 
 
 
 
 
 
 
Physical Examination 4 
X 
 
 
 
 
X 
X 
 
Body Weight & Height 5 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs 6 
X 
X 
X 
X 
X 
X 
X 
 
12-Lead ECG 7 
X 
 
 
 
 
X 
X 
 
Chemistry/Hematology/Urinalysis 
X 
 
 
 
 
X 
X 
 
Drugs of Abuse Screen 8 
X 
 
 
 
 
 
 
 
Urine MPH Screen 9 
X 
X 
 
 
 
 
 
 
Urine Pregnancy Test 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 10 
X 
X 
X 
X 
X 
X 
X 
 
Washout ADHD Meds 11 
X 
X 
 
 
 
 
 
 
Study Drug Dispensing 
 
X 
X 
X 
X 
 
 
 
Study Drug Dosing 12 
 
 
X 
X 
X 
X 
 
 
Dose Titration Evaluation 
 
 
X 
X 
X 
 
 
 


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ASSESSMENTS 
SCREENING 
PERIOD 
DOUBLE BLIND 
TREATMENT PERIOD 
EARLY 
TERMINATION 
19 
FOLLOW-UP 
PHONE  
CALL 
Study Day 
-30 to -1 
0 
7 
(±3 
days 
14 
(±3 
days) 
21 
(±3  
days) 
28 
(±3  
days) 
 
- 
 
33 
(± 2  
days) 
Visit Number 
1 
2  
3 
4 
5 
6 
 
- 
 
- 
Drug Accountability & 
Compliance Assessment 13 
 
 
X 
X 
X 
X 
X 
 
Double-Blind Randomization 14 
 
X 
 
 
 
 
 
 
ADHD-RS-IV or ADHD-RS-5 15 
X 
X 
X 
X 
X 
X 
X 
 
MINI Kid 
X 
 
 
 
 
 
 
 
CGI-S  
X 
X 
X 
X 
X 
X 
X 
 
CGI-I  
 
 
X 
X 
X 
X 
X 
 
CSHQ  
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 16 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 17 
X 
X 
X 
X 
X 
X 
X 
X 
Rollover to Study KP415.P02 18 
 
 
 
 
 
X 
 
 
 
ADHD = Attention-Deficit/Hyperactivity Disorder; CGI-S/I = Clinical Global Impressions – Severity/Improvement; CHSQ = Children’s Sleep 
Habits Questionnaire ET = Early Termination; ECG = electrocardiogram; MPH = methylphenidate; see footnotes for other abbreviations. 
1. ADHD Diagnosis based on the Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) criteria for a primary diagnosis of ADHD 
(combined, inattentive, or hyperactive/impulsive presentation) and by the Mini-International Neuropsychiatric Interview for Children and 
Adolescents (MINI Kid). 
2. Study inclusion/exclusion criteria will be evaluated at Screening and Visit 2. 
3. Medical History: A complete medical history including chronic conditions, relevant surgical procedures (with start date), and history of drug use. 
4. Physical Examination: at Screening and at the end of the Treatment Period or ET (if possible). 
5. Height will be recorded in centimeters (cm) using a stadiometer with the subject’s shoes removed. Height will be recorded at Screening, Visit 2, 
and at the end of the Treatment Period. Body weight will be measured in kilograms (kg) using a calibrated scale; subjects will remain in their 
normal clothing with shoes and jacket (and/or outer clothing) removed. Weight will be recorded at every visit. 


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6. Vital signs will be collected at each visit. Vital sign measurements will be obtained after the subject has been seated for at least 3 minutes. Vital 
signs will include sitting blood pressure (systolic and diastolic measurements), pulse rate (beats per minute), respiratory rate (breaths per minute), 
and oral temperature. Three (3) blood pressure measurements will be taken 2-5 minutes apart. Only the average of the 3 blood pressure 
measurements will be entered into the electronic case report form (eCRF). 
7. ECG: A 12-lead ECG will be obtained after the subject has been in the supine position for at least 3 minutes. Abnormal ECGs may be repeated for 
confirmation in which case only the repeated ECG will be recorded. 
8. Urine Screen for Drugs of Abuse: Urine samples will be tested for drugs of abuse (amphetamines, methamphetamines, benzodiazepines, 
barbiturates, cannabinoids, cocaine, opioids including oxycodone) at the Screening visit. If the urine test is positive for any of the analytes at 
Screening, the subject will be excluded from study participation. 
9. Urine Screen for Methylphenidate (MPH): Urine samples will be tested for MPH by the clinical laboratory in a sample collected at the Screening 
Visit. A urine dipstick (e.g., NarcoCheck®) will be used to screen for the presence of MPH in the urine at Visit 2. If a subject’s current ADHD 
medication at Screening contains MPH, the urine screen at Screening may test positive for MPH. All ADHD medications must be washed out by 
Visit 2 and the MPH urine screen must test negative. 
10. Columbia Suicide Severity Rating Scale (C-SSRS): The “Children’s Baseline/Screening” version will be assessed at Screening, and the 
“Children’s Since Last Visit” version will be assessed at all other visits. For subjects too young to comprehend the concept of suicidal ideation, the 
C-SSRS questionnaire will be filled in by the parent/guardian/caregiver. Subjects who have, in the opinion of the Investigator, clinically 
significant suicidal ideation/behavior, based on history of attempted suicide and the C-SSRS assessment at Screening or at any time before the last 
dose of study drug, will be excluded from further participation in the study. The follow-up C-SSRS will be obtained via phone. 
11. Subjects must wash out ADHD medications prior to Visit 2. Stimulant ADHD medications (with the exception of study drug), including herbal 
medications, are prohibited from 5 days prior to Visit 2 to the end of the Treatment Period (Visit 6) or ET Visit. Non-Stimulant ADHD 
medications are prohibited from 14 days prior to the start of the Dose Optimization Phase (Visit 2) to the end of the Treatment Period (Visit 6) or 
ET Visit. Before or on the day during the Screening Period that the subject will need to start the washout of their ADHD medications (for example, 
5 days before Visit 2 for stimulants), study site staff will contact the subject’s parent/guardian by phone to remind them of the washout (“Washout 
Phone Call”). Other prohibited medications and the windows of prohibition are listed in the protocol. 
12. Dose Optimization/Treatment Period: Subjects will begin taking study drug at home the morning following Visit 2. The starting dose will be 
13.1 mg/2.6 mg day or matching placebo in Cohort 1 and 39.2 mg/7.8 mg or matching placebo in Cohort 2. Dose adjustments, if needed, will be 
performed at approximately weekly intervals. Actual visit dates may deviate from exactly 7 days apart such that the total duration is 3 weeks 
(21 ±3 days). The daily doses of study drug used will be 13.1 mg/2.6 mg, 26.1 mg/5.2 mg, 39.2 mg/7.8 mg, or 52.3 mg/10.4 mg Azstarys® or 
matching placebo. At Visits 3, 4, and 5 based on the CGI scores, interview with the parent/guardian/caregiver, and safety data, the Investigator 
will evaluate the subject’s therapeutic responses and tolerability to treatment and decide whether the current dose should be increased, decreased, 
or remain the same for the next week of dosing. If a subject experiences symptoms of intolerance during at-home treatment, they must contact the 
clinical site, and, at the discretion of the Investigator, their dose may be adjusted before the next scheduled visit. Unscheduled visits between Visits 
2, 3, 4, and 5 are allowed as needed, at the discretion of the Investigator. 
13. Drug Accountability & Compliance Assessment: Study drug receipt, dispensing, and return will be recorded by each site’s pharmacy staff or 
Investigator-delegated employee. A record of the study drug accountability will be prepared and kept by the clinical site. 
14. Randomization: Subjects will be randomized to Azstarys® or matching placebo within each cohort. Randomization will be stratified by gender. 


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15. ADHD-Rating Scale (ADHD-RS)-IV or ADHD-RS-5: (Preschool Version of ADHD-RS-IV for Cohort 1; ADHD-RS-5 for Cohort 2): 1 
assessment at the indicated visits. 
16. Adverse Events: To be assessed and recorded in the eCRF following the first dose of study drug, through either ET or the Follow-up Phone Call. 
Subject’s parent/guardian will be instructed to contact the study site for the reporting of adverse events (AEs) during at-home periods. 
17. Concomitant Medications: new and/or changed medications and dose, medical treatments, and/or therapies will be recorded at Screening through 
either the Follow-up Phone Call or ET. 
18. Subjects of Cohort 1 (ages 4 and 5 years), who qualify, have the option to participate in a 12-month open-label safety study with Azstarys® (Study 
KP415.P02). At Visit 6 of the current study, all entry criteria to enroll in Study KP415.P02 (see protocol for Study KP415.P02) will be evaluated. 
Visit 6 for the current study is also Visit 2 of Study KP415.P02. Roll-over Subjects will not receive the Follow-up Phone Call in 
Study KP415.P01. 
19. Early Termination: Subjects who meet withdrawal criteria post-dose during the Treatment Period (after at least one dose of study drug is 
administered) will complete ET procedures. At the discretion of the Investigator, ensuring the safety of the subjects, any Early Termination 
procedures that were already performed on the same day as part of the procedures of the Treatment Period, do not need to be repeated. Subjects 
who elect to use another ADHD treatment will be discontinued from study treatment and from the study (ET). Subjects who discontinue study 
treatment prior to the end of the Treatment Period because of AEs, overdosage, or use of a prohibited treatment other than an ADHD treatment 
will be followed (unless consent is withdrawn) with scheduled assessments until the end of the Treatment Period (Visit 6). If, during the 
remaining time on study, an ADHD treatment is used, the subject will be discontinued from the study (ET). 
20. Assessment changes due to Coronavirus Disease 2019 (COVID-19): If a subject is not able to attend the site for a scheduled visit due to COVID-
19 restrictions, sites will be instructed to collect data for select safety assessments (vital signs, labs, ECG, physical exam) when the subject is next 
able to safely return to an on-site visit, even if those assessments would not normally be done at that visit. These assessments will be mapped to 
the nearest scheduled visit. Changes in scheduled visits and corresponding assessments due to COVID-19 restrictions will be captured in the 
eCRF. Assessments that do not require the subject’s presence at the site (e.g., AEs, C-SSRS, ADHD-RS-IV, ADHD-RS-5; CGI-S, CGI-I, CSHQ) 
will be collected by phone at the scheduled visit times. If needed, alternate measures to dispense study drug to the subject during their COVID-19 
isolation period will be implemented (e.g., study drug directly delivered to the subject’s residence or dispensed to another family member). 
 


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2. BACKGROUND 
2.1. Attention-Deficit/Hyperactivity Disorder (ADHD) 
Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurobehavioral disorder that 
occurs in 6% to 8% of children and 4% to 5% of adults worldwide (Wilens 2008). The 3 main 
symptoms of ADHD include inattention, hyperactivity, and impulsivity. ADHD is theorized to 
result from a deficiency of neurotransmission of dopamine and norepinephrine either through the 
insufficient sensitivity of the receptors or amount of dopamine produced. The most common and 
effective therapeutics for the treatment of ADHD are central nervous system (CNS) stimulants, 
which contain amphetamine or methylphenidate (MPH). Amphetamine-containing products 
include brand names such as Adderall®, Dexedrine®, Dextrostat®, and Vyvanse®. Methylphenidate 
containing products include Metadate CD®, Concerta®, Daytrana®, Ritalin®, Methylin®, Quillivant 
XR®, and Focalin®. Positive effects on behavior and academic productivity are well established for 
stimulant medications such as MPH (Wilens and Biederman 1992). Several studies have shown 
that, in children with ADHD, MPH improves classroom functioning, notably by decreasing 
disruptive behavior and increasing academic productivity, accuracy and improvement in teacher 
ratings. In addition, MPH has been shown to improve performance in children for several cognitive 
tasks, including measures of attention and memory. 
According to the American Academy of Pediatrics Clinical Practice Guideline for the Evaluation 
and Treatment of Attention-Deficit/Hyperactivity Disorder, MPH may be considered if behavior 
therapy is not available or does not provide significant improvement, and there is moderate-to-
severe continued disturbance in the 4- through 5-year-old child’s functioning (Wolraich 2019). 
These guidelines go on to state that many young children with ADHD might still require medication 
to achieve maximum improvement. There are limited clinical studies in this age group with 
stimulants (MPH and amphetamines) and non-stimulants, although most of the evidence-based data 
is with MPH medications (Greenhill 2006). 
2.2. Azstarys® Product 
An extended-duration d-methylphenidate (d-MPH) product has been developed that contains 
immediate-release (IR) serdexmethylphenidate (SDX), a prodrug of d-MPH, co-formulated with IR 
d-MPH. SDX is an inactive prodrug until converted to d-MPH in vivo and thus SDX provides a 
molecular delivery system for d-MPH. The drug product is formulated in a fixed molar dose ratio 
of 70% SDX Cl:30% d-MPH HCl. Chemically, SDX consists of a single d-MPH molecule 
covalently attached via a carbamate bond to a methylene oxide linker, which in turn is connected 
to the nitrogen of the pyridine ring of a nicotinoyl-serine moiety. 
The three dosage strengths of the approved formulation, for the treatment of ADHD in subjects 
ages 6 years and older, are as follows: 
• 26.1 mg/5.2 mg Azstarys®  
• 39.2 mg/7.8 mg Azstarys®  
• 52.3 mg/10.4 mg Azstarys® 
To accommodate the lowest dose in children of ages 4 and 5 years, capsules with 13.1 mg/2.6 mg 
Azstarys® have been developed. 




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Table 1: Predicted Total Systemic Exposure (AUCinf) of d-MPH in Children 4 and 5 Years of Age 
Utilizing Allometric Scaling of d-MPH Clearance from Observed Data in Children 6 to 
12 Years of Age (Study KP415.105) 
SDX/d-MPH 
Dose (mg) 
 
Equimolar 
d-MPH HCl 
dose (mg) 
Age 
(years) 
Body Weight a  
(kg) 
CL/F b  
(L/h) 
AUCinf e  
(h*ng/mL) 
 
Observed in Study KP415.105 
26.1/5.2 
 
20 
6-8 
29.3 
96.9 
328 
52.3/10.4 
 
40 
9-12 
39.8 
97.4 
443 
 
Predicted for current study from Study KP415.105 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a. For subjects 4-5 years of age, this is the approximate median body weight from the CDC weight-for-age 
percentile charts. 
b. For subjects 4-5 years of age, CL/F was estimated utilizing the allometric scaling equation established with 
observed CL/F and weight (W) values for subjects 6-17 years of age (Study KP415.105): CL/F = 179 x 
(W/70)0.86 where the coefficient (179) is CL/F for a weight of 70 kg and the exponent (0.86) is the allometric 
scaling factor. 
c. For subjects 4-5 years of age, AUCinf was calculated as follows: equimolar d-MPH HCl dose divided by 
predicted CL/F. 
3. CLINICAL PHARMACOLOGY OF AZSTARYS® IN SUBJECTS OF AGE ≥6 YEARS 
As part of the clinical development program of Azstarys®, 10 studies were conducted to examine 
the PK of SDX and SDX-derived d-MPH after oral administration of clinical doses of single-entity 
SDX Cl or Azstarys®. Of these, 5 studies were conducted after single oral doses of single-entity 
SDX Cl in healthy adult volunteers, 4 studies were conducted after single or multiple oral doses of 
Azstarys® in healthy adult volunteers, and 1 study was conducted after a single oral dose of 
Azstarys® in children (6- to12-years-of-age) and adolescents (13- to 17-years-of-age) with ADHD. 
Studies were conducted with oral solutions of SDX Cl and Azstarys®, an early capsule formulation 
of single-entity SDX Cl, or with the final, marketed Azstarys® capsules. 
The key findings of the clinical pharmacology program are as follows: 
• The PK profile of Azstarys® capsules is a composite of the underlying d-MPH exposure 
derived from the d-MPH HCl and SDX Cl components (Figure 1). After oral 
administration, early d-MPH exposure is governed by the d-MPH HCl component and 
mid- to late-day exposure is governed by gradual, intra-intestinal conversion of inactive 
SDX to active d-MPH. Similar and predictable d-MPH PK profiles were observed in 
children (6 to 12 years old), adolescents, and adults, and as a result, the efficacy profiles 
are also expected to be similar in all 3 age groups. 


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Figure 1: Plasma Concentration-Time Profiles of d-MPH Predicted for 12 mg immediate-release 
(IR) d-MPH HCl Component (Based on Dose-Adjusted Focalin Data), 56 mg SDX Cl 
Component (Dose-Adjusted Data from KP415.108), and 56/12 mg Azstarys® Capsule 
(Study KP415.107) 
 
PK profile for IR d-MPH HCl, 12 mg component approximated using dose-adjusted data for 2×10 mg Focalin 
administered orally under fasted condition in Celgene-sponsored study PK-00-001 as reported in the Focalin 
NDA 21-278 Summary Basis of Approval. 
PK profile for SDX Cl, 56 mg component predicted with dose-adjusted data for 60 mg SDX Cl administered 
orally under fasted condition in study KP415.108 (Treatment A). 
PK profile for Azstarys® capsule under fasted conditions, 56/12 mg based on data from study KP415.107 
(Treatment B). 
 
• Azstarys® capsules were not bioequivalent to the Reference Listed Drug, Focalin XR 
(Focalin XR label 2019), with respect to d-MPH exposure. The long-term safety of 
Azstarys® capsules was established in a clinical trial in patients with ADHD 6- to 12-years-
of-age. The efficacy of Azstarys® was evaluated in a laboratory classroom study in children 
(ages 6 to 12 years) with ADHD. A bridge of the efficacy findings to older age groups is 
based on PK data with Azstarys® in adolescents and adults, and by relying on the overall 
efficacy of d-MPH as established by Focalin XR for children, adolescents, and adults. 
• Since the systemic exposure of d-MPH after oral administration of a 56/12 mg Azstarys® 
capsule is not higher than after 40 mg Focalin XR, prior findings of efficacy and safety for 
Focalin XR (Focalin XR label 2019) can be referenced to support, at least in part, efficacy 
and safety of Azstarys® capsules. 


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• Administration of Azstarys® capsule under fed condition (high fat/high calorie meal) and 
administration of capsule contents sprinkled on applesauce increased peak d-MPH plasma 
exposure (Cmax) by 24% and 34%, respectively, and delayed median Tmax by 1.75 and 
2.00 h, respectively, with no significant increase in overall exposure (AUC0-inf). 
Administration of Azstarys® capsule contents mixed in water under fasted condition was 
bioequivalent when compared to administration of intact Azstarys® capsule under the 
fasted condition. Based on these results, Azstarys® capsules can be administered without 
regard to food. Mixing the capsule contents in water or sprinkling on applesauce are 
acceptable alternative modes of oral drug administration. 
• Following administration of 28/6 mg, 46/9 mg, and 56/12 mg Azstarys® capsules, d-MPH 
Cmax and AUC values increased proportionally with an increase in Azstarys® dose over the 
dose range studied. 
• Following multiple doses of 56/12 mg Azstarys® capsules, steady-state of d-MPH was 
reached after the second dose, with minimal accumulation of d-MPH when comparing 
Dose 4 to Dose 1. No accumulation of intact SDX was observed with repeat-dosing. 
• Following oral administration of 60 mg [14C]-SDX Cl: 
o The mean combined total recoveries of radioactivity in feces and urine over 168 h 
was 98.9%. The mean total radioactivity recovered in urine and feces were 62.1% 
and 36.8%, respectively. 
o No SDX-unique metabolites were identified in plasma. 
o Ritalinic acid was the most abundant metabolite in all matrices (i.e., plasma, urine, 
feces). SDX was only found at trace levels in urine (0.43% of total dose) but was 
the second most abundant species in the feces, accounting for 10.8% of the total 
dose. Recovery of d-MPH was generally low in urine and feces, accounting for 
2.74% of total dose observed in both excreta. 
• Following oral administration, the pharmacologically inactive SDX is largely confined to 
the intestinal tract until it is converted in the lower intestine to active d-MPH or excreted 
unchanged in feces. Due to the charged nature of SDX and lack of substrate activity at 
common transporters, it has poor permeability across cellular membranes, resulting in both 
minimal systemic absorption and poor tissue penetration. The small fraction of oral SDX 
that is absorbed (mean oral bioavailability [F]< 3%) remains largely in the intravascular 
fluid where it remains mostly unmetabolized until excreted unchanged in urine (0.43% of 
an oral dose of SDX Cl is excreted unchanged). 
• The collective nonclinical and clinical safety package have indicated no unique biological 
effects or toxicities related to SDX as the intact prodrug. Thus, the only role of SDX is to 
provide a molecular mechanism to gradually and consistently deliver active d-MPH to the 
patient. 


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• Following Azstarys® administration (after adjusting for dose), systemic exposure to 
d-MPH was higher in younger children because CL/F increased with age due to intrinsic 
body weight differences between younger children and adolescents. As a result, when 
normalized for body weight, CL/F values of d-MPH were comparable across age groups. 
Similarly, Vz/F increased with age but when normalized for body weight, Vz/F values of 
d-MPH were more comparable across age groups. Body weight is thus an appropriate 
scaling factor between adolescents and children (6 to 12 years old) for exposure of d-MPH 
after oral Azstarys® dosing. 
4. STUDY RATIONALE 
The current study will investigate the efficacy and safety of Azstarys® compared to placebo in 
children with ADHD ages 4 to 12 years. 
5. STUDY OBJECTIVES 
5.1. Primary Objective 
• To determine the efficacy of Azstarys® compared to placebo in treating children ages 4 to 
12 years old with ADHD. 
5.2. Secondary Objectives 
• To determine the safety and tolerability of Azstarys® compared to placebo in treating 
children 4 to 12 years old with ADHD. The safety objective includes changes in weight and 
height, and sleep behavior. 
6. INVESTIGATIONAL PLAN 
6.1. Study Design 
This is a multicenter, dose-optimized, randomized, double-blind, efficacy and safety study with 
Azstarys® in children 4 to 12 years of age with ADHD. 
The phases of the study are as follows: 
• Screening Period (Visit 1):  
Subjects will undergo a Screening Period up to 30 days prior to entering the Treatment 
Period. 
• Double-Blind Treatment Period (Day after Visit 2 through Visit 6):  
Eligible subjects will be randomized to Azstarys® or placebo at the start of the Treatment 
Period. Randomization will be applied to each cohort separately and will be stratified by 
gender. 
o Cohort 1: 4 and 5 years old 
o Cohort 2: 6 to 12 years old 


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During the Treatment Period: 
o Cohort 1: Subjects 4 and 5 years (<6 years): will start at 13.1 mg/2.6 mg 
Azstarys® or matching placebo and may be titrated to doses of 26.1 mg/5.2 mg, 
39.2 mg/7.8 mg Azstarys® or matching placebo through Visit 5 
o Cohort 2: Subjects 6 to 12 years (<13 years): will start at 39.2 mg/7.8 mg or 
matching placebo and may be titrated to doses of 26.1 mg/5.2 mg, 
52.3 mg/10.4 mg Azstarys® or matching placebo through Visit 5 
• Roll-over into Study KP415.P02: 
Subjects of Cohort 1 (ages 4 and 5 years), who qualify, have the option to participate in 
a 12-month open-label safety study with Azstarys® (Study KP415.P02). At Visit 6 of 
the current study, all entry criteria to enroll in Study KP415.P02 (see protocol for 
Study KP415.P02) will be evaluated (Visit 6 for the current study is also Visit 2 of 
Study KP415.P02). 
• Follow-up Phone Call: 
Subjects who will not be rolled over into Study KP415.P02 will receive a Follow-up 
Phone Call, at 5 ±2 days after administration of the last dose of the Treatment Period. 
Subjects who elect to use another ADHD treatment will be discontinued from study treatment and 
from the study (Early Termination [ET]).  
Subjects who discontinue study treatment prior to the end of the Treatment Period because of 
adverse events (AEs), overdosage, or use of a prohibited treatment other than an ADHD treatment 
will be followed (unless consent is withdrawn) with scheduled assessments until the end of the 
Treatment Period (Visit 6). If, during the remaining time on study, an ADHD treatment is used, the 
subject will be discontinued from the study (ET). 
6.2. Study Duration 
Subjects will participate in the study as out-patients for up to 65 days, including up to 30 days of 
Screening, up to 28 days in the Treatment Period, and a Follow-up Phone Call up to 7 days (5 ±2 
days) after the administration of the last dose of the Treatment Period. 
7. SUBJECT SELECTION 
7.1. Number of Subjects 
In each age cohort, an appropriate number of subjects will enter the Screening Period to enroll 
approximately the following number of subjects in the Treatment Period: 
• Cohort 1 (4 and 5 years of age): 130 subjects (65 per arm) with the intention to complete 
with approximately 120 subjects. 
• Cohort 2 (6 to 12 years of age): 100 subjects (50 per arm) with the intention to complete 
with approximately 90 subjects. 
The additional number of subjects enrolled is based on an approximate 10% early discontinuation 
rate. Subjects who terminate early in the Treatment Period will not be replaced. 


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A blinded sample size re-estimation will be conducted when approximately 50% of subjects in 
Cohort 1 have completed Visit 6.  The sample size may be increased based on that analysis.  Details 
are provided in the Interim Analysis section below (Section 17.6). 
In accordance with a male-to female distribution ratio of 3:1 of children diagnosed with ADHD in 
clinical practice (Barkley 2006; Gaub 1997), it is anticipated that approximately 75% males and 
25% females will be enrolled. 
7.2. Study Population 
Children 4 and 5 years old (Cohort 1) and 6 to 12 years old (Cohort 2) with ADHD who meet the 
inclusion/exclusion criteria listed below. 
7.2.1. Inclusion Criteria 
A subject will be eligible for inclusion in the study if all the following criteria apply: 
1. In Cohort 1, subjects must be at least 4 years old and less than 5 years and 10 months at 
Screening; in Cohort 2, subjects must be at least 6 years old and less than 12 years and 
10 months at Screening. 
2. Subjects must have a body weight within the 5th and 95th percentile according to the 
gender-specific weight-for-age percentile charts from the CDC. See calculator at 
https://www.infantchart.com/child/. 
3. Female subjects must agree, if they are of childbearing potential at Screening or when 
they become of childbearing potential during the study, to remain abstinent or agree to 
use an effective and medically acceptable form of birth control from the time of written 
or verbal assent to at least 14 days after the last dose of study drug has been taken. 
Childbearing potential is defined as follows: Girls under the age of 12 who have not had 
their first period will be considered “not of child-bearing potential.” Girls 12 years of 
age will be considered “of child-bearing potential,” even if they have not yet had their 
first period. Irrespective of age, girls who have had their first period, will be considered 
“of child-bearing potential.” 
4. Subjects must be in general good health defined as the absence of any clinically relevant 
abnormalities as determined by the Investigator based on physical examinations, vital 
signs, electrocardiograms (ECGs), medical history, and clinical laboratory values 
(chemistry, hematology, urinalysis) at Screening. If any of the chemistry or hematology 
tests are not within the laboratory's reference range, then the subject can be included 
only if the Investigator determines the deviations to be not clinically relevant. 
5. At least one parent/legal guardian of the subject must voluntarily give written 
permission for him/her to participate in the study. 
6. Subjects in Cohort 2 must give written or verbal assent prior to study participation. For 
verbal assent, the procedure will be documented and signed by a witness. A parent or 
guardian may not be the witness for a child’s verbal assent document. 
7. Subject must meet Diagnostic and Statistical Manual of Mental Disorders – Fifth 
Edition (DSM-5) criteria for a primary diagnosis of ADHD (combined, inattentive, or 
hyperactive/impulsive presentation) per clinical evaluation and confirmed by  Mini-
International Neuropsychiatric Interview for Children and Adolescents (MINI Kid). 


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8. Subject has had ADHD symptoms present for at least 6 months prior to the Screening 
Visit. 
9. Subject must be able and willing to wash out current stimulant ADHD medications, 
including herbal medications, from 5 days prior to the start of the Treatment Period, and 
abstain from taking these to the end of Visit 6 or ET; and wash out non-stimulant ADHD 
medications from 14 days prior to the start of the Treatment Period, and abstain from 
taking these to the end of Visit 6 or ET. 
10. Subject must have a score of ≥4 (Moderately Ill) on the clinician-administered Clinical 
Global Impressions–Severity (CGI-S) scale. For subjects requiring washout of ADHD 
medications, this criterion refers to a score following washout. 
11. Subjects must have age and sex adjusted ratings of ≥90th percentile Total Score on the 
ADHD-Rating Scale (ADHD-RS) rated over the past 6 months (for 4- and 5-year-old 
children, use Preschool Version of ADHD-RS-IV; for 6-12 years old children, use 
ADHD-RS-5). 
12. Subject functions at an age-appropriate level intellectually, as determined by the 
Investigator. 
13. Subject must have a systolic and diastolic blood pressure below the 95th percentile for 
age and gender according to the 2017 AAP guidelines (Flynn 2017) based on the average 
of 3 measurements 2-5 minutes apart. 
14. Subject, subject’s parent/legal guardian, and caregiver (if applicable) must understand 
and be willing and able to comply with all study procedures and visit schedule. 
15. Subject, parent/legal guardian, and caregiver (if applicable) must be able to speak and 
understand English or Spanish and be able to communicate satisfactorily with the 
Investigator and study coordinator.  
7.2.2. Exclusion Criteria 
A subject who meets any of the following exclusion criteria will not be enrolled into the study: 
1. If female, must not be pregnant or breastfeeding, and, if of childbearing potential, must 
have a negative urine pregnancy test at the start of the Screening Period. In addition, a 
positive pregnancy test before the last dose of study drug will result in early termination 
from the study. 
2. Subject with any clinically significant chronic medical condition that, in the judgment 
of the Investigator, may interfere with the participant’s ability to participate in the study. 
3. Subject has any diagnosis of bipolar I or II disorder, major depressive disorder, conduct 
disorder, obsessive-compulsive disorder, any history of psychosis, autism spectrum 
disorder, disruptive mood dysregulation disorder (DMDD), intellectual disability, 
Tourette’s Syndrome, confirmed genetic disorder with cognitive and/or behavioral 
disturbances. Subjects with oppositional defiant disorder (ODD) are permitted to enroll 
in the study as long as ODD is not the primary focus of treatment, and, in the opinion of 
the Investigator, the ODD is mild to moderate, and eligible subjects with ODD are 
appropriate and cooperative during Screening. 


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4. Subject has generalized anxiety disorder or panic disorder that has been the primary 
focus of treatment at any time during the 12 months prior to Screening or that has 
required pharmacotherapy any time during the 6 months prior to Screening. 
5. Subject has evidence of any chronic disease of the CNS such as tumors, inflammation, 
seizure disorder, depression, vascular disorder, potential CNS related disorders that 
might occur in childhood (e.g., Duchenne muscular dystrophy, myasthenia gravis, or 
other neurologic or serious neuromuscular disorders), or history of persistent 
neurological symptoms attributable to serious head injury. 
6. Subject taking anticonvulsants for seizure control or antidepressants currently or within 
the past 2 years before Screening are not eligible for study participation. A past history 
of febrile seizure or drug-induced seizure is allowed. 
7. Subject has a current (last month) psychiatric diagnosis other than specific phobia, 
motor skills disorders, ODD, sleep disorders, elimination disorders, adjustment 
disorders, learning disorders, or communication disorders. Subjects allowed to enroll 
with any of these DSM disorders will require written justification from the Investigator 
documenting why the conditions will not interfere with participation and to emphasize 
that ADHD is the primary indication. 
8. In the opinion of the Investigator, subject has clinically significant suicidal 
ideation/behavior, based on history of attempted suicide and the Columbia-Suicide 
Severity Rating Scale (C-SSRS) assessment at Screening. 
9. Subject has any clinically significant unstable medical abnormality, chronic disease 
(including asthma or diabetes), or a history of a clinically significant abnormality of the 
cardiovascular (including cardiomyopathy, serious arrhythmias, structural cardiac 
disorders, or severe hypertension), gastrointestinal, respiratory, hepatic, or renal 
systems, or a disorder or history of a condition (e.g., malabsorption, gastrointestinal 
surgery) that may interfere with absorption, distribution, metabolism, or excretion of 
study drug. In cases in which the impact of the condition upon risk to the subject or 
study results is unclear, the medical monitor should be consulted. Any subject with a 
known cardiovascular disease or condition (even if controlled) must be discussed with 
the Medical Monitor during Screening. 
10. Subject has a history or presence of abnormal ECGs, which in the Investigator’s opinion 
is clinically significant. 
11. Subject has a history of, or currently has, a malignancy. 
12. Subject has uncontrolled thyroid disorder as evidenced by thyroid stimulating hormone 
(TSH) ≤0.8 x the lower limit of normal (LLN) or ≥1.25 x the upper limit of normal 
(ULN) for the reference laboratory at Screening. 
13. Subject has greater than trace proteinuria in the urinalysis at Screening. Subjects with 
greater than trace proteinuria in the urinalysis at Screening but with a urine protein to 
creatinine (UP/C) ratio <0.2 in a first morning void urine sample will not be excluded 
from enrollment. 


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14. Subjects has a current or recent (past 12 months) history of drug abuse; or current or 
recent history of drug abuse in someone living in the subject’s home or are using or 
planning to use prohibited drugs during the trial as specified in the protocol. 
15. Subject has a positive urine drug screen at Screening. Subjects with a positive MPH 
urine drug screen may be allowed to continue in the study, provided that the Investigator 
determines that the positive test is a result of taking prescribed medications and subject 
is willing to wash out the current medication as required. 
16. Subject has participated in any other clinical study with an investigational drug/product 
within 30 days or at least 5 half-lives, whichever is longer, prior to Screening. 
17. Subject has taken ADHD medications from more than one class within 30 days prior to 
Screening. Subjects on a stable dose of one ADHD medication with occasional use of 
ADHD medications from another class are eligible at the discretion of the Investigator. 
18. Subjects with demonstrated lack of response or intolerability to adequate dose and 
duration of treatment with MPH products. Judgment of adequate dose and duration is at 
the discretion of the Investigator.  
19. Subject has a positive urine MPH screen by dipstick (e.g., NarcoCheck®) at Visit 2. 
20. Subject is planning to initiate psychotherapy during the study (subjects participating in 
psychotherapy beginning at least 4 weeks before study initiation are permitted to 
continue). 
21. Subject has a history of severe allergies or adverse drug reactions to more than one class 
of medications. 
22. Subject has a history of allergic reaction or a known or suspected sensitivity to MPH or 
any substance that is contained in the study drug. 
23. Subject, parent/legal guardian, and caregiver (if applicable at the Investigator’s 
discretion) has commitments during the study that would interfere with attending study 
visits. 
24. Subject or subject’s family anticipates a move outside the geographic range of the 
investigative site during the study period or plans extended travel inconsistent with the 
recommended visit interval during study duration. 
25. Subject has one or more siblings living in the same household who are enrolled in this 
or another clinical drug trial. 
26. Subject shows evidence of current physical, sexual, or emotional abuse. 
27. Subject is, in the opinion of the Investigator, unsuitable in any other way to participate 
in this study. 
8. STUDY TREATMENTS 
8.1. Study Treatments: 
Blinded study drug (Azstarys® or placebo capsules) will be used in the Treatment Period. 


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8.1.1. Azstarys® Capsules 
Azstarys® capsules contain two active pharmaceutical ingredients: d-methylphenidate 
(dexmethylphenidate; d-MPH) hydrochloride, and serdexmethylphenidate (SDX; a prodrug of d-
MPH). In terms of total d-MPH dose amounts, all capsule strengths contain 30% d-MPH and 70% 
d-MPH in the form of the prodrug. The total equivalent amount of d-MPH in each capsule strength 
(used as daily doses in this study), and the amounts of both APIs are listed in the following table. 
d-MPH 
(mg) 
SDX (d-MPH) 1 
(mg) 
Total 
d-MPH dose 2 
(mg) 
Equimolar 
d-MPH HCl dose 
(mg) 
2.6 
13.1 (6.1) 
8.6 
10 
5.2 
26.1 (12.2) 
17.3 
20 
7.8 
39.2 (18.3) 
25.9 
30 
10.4 
52.3 (24.4) 
34.6 
40 
1. This is the dose of SDX. The amount of d-MPH equimolar to each SDX dose is listed in parentheses. 
2. The total dose of d-MPH expressed in terms of free base. 
The inactive ingredients in Azstarys® capsules include:  colloidal silicon dioxide, crospovidone, 
hypromellose, magnesium stearate, microcrystalline cellulose, and talc. 
Azstarys® is a Schedule II controlled substance. Therefore, study sites are required to have the 
appropriate permit from the Drug Enforcement Agency (DEA) to receive, store, ship and dispense 
Azstarys® according to all local, state, and federal regulations for Schedule II controlled substances. 
8.1.2. Placebo Capsules 
Placebo capsules will visually match the Azstarys® capsules and will contain the following inactive 
ingredients only:  colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, 
microcrystalline cellulose, and talc. 
8.2. Treatment Assignment 
All subjects will receive study drug, as follows: 
At Visit 2, subjects will be randomized in a blinded fashion to either Azstarys® or placebo. 
Randomization will be applied to each cohort separately and will be stratified by gender. 
During the Treatment Period, daily treatments of double-blind study drug (one capsule per day) will 
be administered for titration to an optimal daily dose. Subjects randomized to placebo will receive 
the dose-associated matching placebo capsules. 
o Cohort 1: Subjects 4 and 5 years (<6 years): will start at 13.1 mg/2.6 mg Azstarys® 
or matching placebo and may be titrated to doses of 26.1 mg/5.2 mg, 
39.2 mg/7.8 mg Azstarys® or matching placebo at Visits 3, 4, and/or 5. 
o Cohort 2: Subjects 6-12 years (<13 years): will start with at 39.2 mg/7.8 mg or 
matching placebo and may be titrated to doses of 26.1 mg/5.2 mg, 52.3 mg/10.4 mg 
Azstarys® or matching placebo at Visits 3, 4, and/or 5. 


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The daily dose may be changed at Visits 3, 4 and 5 based on a combination of individual tolerability 
and effect assessed by the Investigator. If a lack of tolerability should occur between visits, the dose 
may be lowered at any time.  
The optimized daily dose will be determined at Visit 5 and will be kept the same for the remainder 
of the Treatment Period, with the following exception: if a lack of tolerability should occur, the 
dose may be lowered at any time. 
8.3. Drug Administration 
All study drug will be taken orally within 20 minutes after consuming breakfast, at approximately 
the same time in the morning of each day. 
Study drug will be swallowed whole (without crushing, cutting, chewing, opening, or dissolving) 
or may be taken by sprinkling the contents of the capsule over a small amount of applesauce. See 
Appendix A for detailed instructions of the oral administration of study drug. 
On each day at home (no scheduled visits to the study site) during the Treatment Period, the 
assigned study drug will be taken under the supervision of the subject’s parent or caregiver. 
On days with scheduled visits to the study site, subjects will take the assigned study drug either at 
home under the supervision of the subject’s parent or caregiver before coming to the study site for 
their scheduled visit, or if their visit occurs in the morning, subjects may take the assigned study 
drug at the study site under the supervision of site staff. 
8.4. Blinding 
Study drug will be blinded during the Treatment Period. Neither the subject, the Investigator, nor 
the Sponsor will know the subject’s treatment assignment. Upon completion of the study and after 
the database is locked according to the Sponsor (or designee) operating procedures, the 
randomization codes will be provided to the statistician to unblind the study. 
Emergency unblinding of patients: Under normal circumstances, the blind will not be broken until 
all subjects have completed treatment. The blind for individual subjects can be broken before study 
unblinding at the request of the Investigator only if a specific emergency treatment would be 
dictated by knowing the treatment status of a subject. When knowledge of the subject’s treatment 
assignment is essential for the clinical management or welfare of the subject, the Investigator should 
contact the Medical Monitor (or designee). Prior to unblinding the subject’s treatment assignment, 
the Investigator should assess the relationship of an AE to the administration of the study drug (Yes 
or No). The Investigator must then contact the Medical Monitor to unblind an individual subject’s 
treatment assignment. If the blind is broken for any reason, the Investigator must record the date 
and reason for breaking the blind on the appropriate electronic case report form (eCRF) and source 
documents. If a serious adverse event (SAE) is reported, the Medical Monitor (or designee) may 
unblind the treatment assignment for an individual subject for expedited regulatory reporting 
requirements. 
8.5. Compliance 
Study drug receipt, dispensing, and return will be recorded by each site’s pharmacy staff or Investigator-
delegated employee. A record of the study drug accountability will be prepared and kept by the clinical site. 
Drug accountability and compliance will be evaluated at each visit in the Treatment Period and will 
be based on the number of dispensed and returned capsules for each subject. Subjects will be asked 


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to bring their unused medication to the clinical site at each visit. 
Acceptable compliance is defined as 80-100% (inclusive). If compliance between subsequent 
scheduled visits is outside this acceptance range, or cannot be determined (when, for example, the 
subject did not return unused study drug), the Investigator or designee will counsel the parent/legal 
guardian. If a subject is noncompliant more than once, the Investigator will discuss the subject’s 
noncompliance with the Medical Monitor, to decide whether the subject should be terminated early 
from further participation in the study. 
9. STUDY PROCEDURES 
The study will consist of a Screening Period, a Double-Blind Treatment Period, and a Follow-up 
Phone Call. A table with the Schedule of Events (SOE) representing the required testing procedures 
to be performed is included in Section 1. Following is a list of these procedures and assessments. 
For instructions on procedures to follow if a subject is unable to attend a visit due to Coronavirus 
Disease 2019 (COVID-19) restrictions, see Section 9.10.2. 
9.1. Screening Procedures 
Subjects will complete the Screening Visit within 30 days (Day -30 to Visit 2) prior to starting the 
Treatment Period. Prior to conducting any study-related activities, including screening procedures, 
written Informed Consent and the Health Insurance Portability and Accountability Act (HIPAA) 
authorization must be signed and dated by the parent/legal guardian. For subjects 6 to 12 years old, 
the Informed Assent must be completed. 
The following information collection/assessments will be performed at the Screening Visit: 
1. Informed Consent and HIPAA authorization by one parent/legal guardian of the subject. 
2. Informed Assent by the subject (Cohort 2, 6 years and older). 
3. Subject demographics including date of birth, sex, race, and ethnicity. 
4. Review of inclusion/exclusion criteria to determine study eligibility. 
5. Record (with start date and stop date [if applicable]) medical history, including chronic 
conditions, relevant surgical procedures, and medications, including treatments and 
therapies for ADHD. 
6. A complete physical examination. 
7. Body weight and height. 
8. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood 
pressure, and oral temperature). Three (3) blood pressure measurements will be 
collected 2-5 minutes apart. The average of the three measurements will be entered into 
the eCRF. 
9. Perform the clinician-administered CGI-S scale assessment. Subjects must have a 
CGI-S score of ≥4 (Moderately Ill) for further study participation. For subjects requiring 
washout of ADHD medications, this criterion refers to a score following washout. 
10. Perform the ADHD-RS-5 for Cohort 2 and the ADHD-RS-IV assessment for Cohort 1 
subjects. Scores will be obtained during a clinician-directed interview with the 


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parent/guardian/caregiver present. The ADHD subtype in each subject (combined 
subtype, impulsive/hyperactive subtype, etc.) will be recorded. 
11. Perform the MINI Kid. 
12. Perform the Children’s Sleep Habits Questionnaire (CSHQ) assessment. 
13. Perform the C-SSRS assessment, “Children’s Baseline/Screening” version. For subjects 
too young to comprehend the concept of suicidal ideation, the C-SSRS questionnaire 
will be completed by the parent/guardian/caregiver. Subjects with clinically significant 
suicidal ideation/behavior, in the opinion of the Investigator, based on a history of 
attempted suicide and the C-SSRS assessment, will be excluded from enrollment in the 
study, and further evaluation and/or preventive intervention steps for suicidal behavior 
will be taken, at the discretion of the Investigator. 
14. 12-lead ECG after subject has been in supine position for a minimum of 3 minutes. 
Abnormal ECGs may be repeated for confirmation in which case only the repeated ECG 
will be recorded. 
15. Clinical laboratory tests (chemistry, hematology, and urinalysis) will be obtained under 
fasted or non-fasted conditions (fasted/non-fasted state will be recorded). Clinical 
laboratory measurements may be repeated at the discretion of the Investigator. Subjects 
with a greater than trace proteinuria will be asked to provide the study site a morning 
void urine sample (unscheduled urine sample) to rule out orthostatic proteinuria. This 
urine sample will be sent to the clinical laboratory where urine protein and creatinine 
will be quantified and the UP/C ratio will be calculated to rule out “false positive” 
proteinuria. The morning void urine sample will be collected by the 
parent/guardian/caregiver under direction of the study site, and will be dropped off at 
the study site. 
16. Urine pregnancy test for female subjects of childbearing potential. A positive pregnancy 
test will exclude a subject from further participation in the study. 
17. Perform urine screen for drugs of abuse (amphetamines, methamphetamines, 
benzodiazepines, barbiturates, cannabinoids, cocaine, opioids including oxycodone). If the urine 
test is positive for any of the analytes at Screening, the subject will be excluded from study 
participation. 
18. Urine samples will be tested for MPH in a clinical laboratory. If the urine test is positive 
for MPH at Screening, the subject will be excluded from study participation, with the 
exception of the following: Depending on a subject’s current ADHD medication at 
Screening, the urine screen may test positive for MPH. All ADHD medications must 
be washed out by Visit 2. Subjects with a positive MPH urine screen by dipstick (e.g., 
NarcoCheck®) at Visit 2 will be excluded from further participation in the study or may 
be retested at a later date, and may be enrolled if the MPH urine screen retest is 
negative, as long as the Screening window has not expired. 
19. Before or on the day during the Screening Period that the subject will need to start the 
washout of their ADHD medications (for example, 5 days before Visit 2 for stimulants), 
study site staff will contact the subject’s parent/guardian by phone to remind them of 
current ADHD medication washout (“Washout Phone Call”). Stimulant ADHD 
medications, including herbal medications, are prohibited from 5 days prior to Visit 2 


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to the end of the Treatment Period (Visit 6) or ET Visit. Non-Stimulant ADHD 
medications are prohibited from 14 days prior to the start of the Treatment Period (Visit 
2) to the end of the Treatment Period (Visit 6) or ET Visit. Other prohibited medications 
and the windows of prohibition are listed in the protocol. 
After a subject completes the screening procedures and is considered eligible to take part in the 
clinical study, they will be instructed when to return to the site to begin the Treatment Period 
(Visit 2). 
9.2. Rescreening 
Subjects who require extension of the screening window and remain eligible for the study may be 
rescreened upon written approval of the Medical Monitor. Subjects who screen fail will not be 
rescreened. 
9.3. Start of Treatment Period (Visit 2) 
After a subject complete the screening procedures and is considered eligible to take part in the 
clinical study, they will be instructed when to begin washout of disallowed medications/treatments 
and when to return to the clinic at Visit 2 to begin the Treatment Period. 
1. Review of inclusion/exclusion criteria to determine whether subject continues to meet 
study eligibility. 
2. Update medical history. 
3. Review of concomitant medications, treatment and/or therapies, with special attention 
to whether the subject has washed out of disallowed medications/treatments in the 
appropriate time frames before Visit 2. 
4. Body weight and height. 
5. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood 
pressure, and oral temperature). Three (3) blood pressure measurements will be 
collected 2-5 minutes apart. The average of the three measurements will be entered into 
the eCRF. 
6. Perform the ADHD-RS-5 for Cohort 2 and the ADHD-RS-IV assessment for Cohort 1 
subjects. Scores will be obtained during a clinician-directed interview with the 
parent/guardian/caregiver present. 
7. Perform the clinician-administered CGI-S scale assessment. Subjects must have a 
CGI-S score of ≥4 (Moderately Ill) for further study participation. 
8. Perform the CSHQ assessment. 
9. Perform the C-SSRS assessment, “Children’s Baseline/Screening” version. For subjects 
too young to comprehend the concept of suicidal ideation, the C-SSRS questionnaire 
will be completed by the parent/guardian/caregiver. Subjects with clinically significant 
suicidal ideation/behavior, in the opinion of the Investigator, based on a history of 
attempted suicide and the C-SSRS assessment, will be excluded from further 
participation in the study, and further evaluation and/or preventive intervention steps 
for suicidal behavior will be taken, at the discretion of the Investigator. 


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10. Subjects with a positive MPH urine screen by dipstick (e.g., NarcoCheck®) at Visit 2 
will be excluded from further participation in the study. Subjects must have washed out 
ADHD medications from 5 days prior to Visit 2 and must not use ADHD medications, 
other than study drug, to the end of the Treatment Period (Visit 6). 
11. Urine pregnancy test for female subjects of childbearing potential. A positive pregnancy 
test will exclude a subject from further participation in the study. 
12. Assessment and review of AEs. Subject’s parent/guardian will be instructed to contact 
the study site for the reporting of AEs during the dosing periods at home. 
13. Randomize subjects, by cohort, on a 1:1 basis to double-blinded treatment (Azstarys® 
or placebo) according to the randomization schedule. Randomization will be stratified 
by gender within each cohort. The assigned treatment group will be maintained during 
the Treatment Period; although, the dose may change during dose optimization. 
14. Provide subject with double-blind study drug for daily oral administration at home until 
the next visit. See Section 8 for further details on study treatment and administration. 
9.4. At Home During the Treatment Period (Non-visit Days) 
While at home during the Treatment Period, subjects will receive study drug according to the 
procedures detailed in Section 8.3 and Appendix A. 
9.5. Treatment Period (Visits 3, 4, and 5) 
The following procedures will be performed at Visits 3, 4, and 5: 
1. Subjects will take the assigned study drug either at home under the supervision of the 
subject’s parent or caregiver before coming to the study site for their scheduled visit, or 
if their visit occurs in the morning, subjects will take the assigned study drug at the study 
site under the supervision of site staff. 
2. Record the number of returned and administered capsules of study drug for drug 
accountability and compliance. Unused study drug will remain at the site. 
3. Body weight. 
4. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood 
pressure, and oral temperature). Three (3) blood pressure measurements will be 
collected 2 -5 minutes apart. The average of the three measurements will be entered into 
the eCRF. 
5. Perform the ADHD-RS-5 for Cohort 2 and the ADHD-RS-IV assessment for Cohort 1 
subjects. Scores will be obtained during a clinician-directed interview with the 
parent/guardian/caregiver present. 
6. Perform the clinician-administered CGI-S scale assessment. 
7. Perform the Clinical Global Impressions–Improvement (CGI-I) scale assessment. 
8. Perform the CSHQ assessment. 
9. Perform the C-SSRS assessment, “Children’s Baseline/Screening” version. For subjects 
too young to comprehend the concept of suicidal ideation, the C-SSRS questionnaire 


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will be completed by the parent/guardian/caregiver. Subjects with clinically significant 
suicidal ideation/behavior, in the opinion of the Investigator, based on a history of 
attempted suicide and the C-SSRS assessment, will be excluded from further 
participation in the study, and further evaluation and/or preventive intervention steps 
for suicidal behavior will be taken, at the discretion of the Investigator. 
10. Urine pregnancy test for female subjects of childbearing potential. A positive pregnancy 
test will exclude a subject from further participation in the study. 
11. Review of concomitant medications, treatment and/or therapies. 
12. Assessment and review of AEs. Subject’s parent/guardian will be instructed to contact 
the study site for the reporting of AEs during the dosing periods at home. 
13. Study drug dose adjustments. The Investigator will evaluate the subject’s therapeutic 
responses and tolerability to treatment, and decide whether the current dose should be 
increased, decreased, or remain the same for the next week. 
14. Provide subject with double-blind study drug for daily oral administration at home until 
the next visit. See Section 8 for further details on study treatment and administration. 
Dose adjustments from the previous visit will be performed if needed based on the 
Investigator’s assessment. 
9.6. End of Treatment Period (Visit 6) or Early Termination Visit 
At Visit 6, the last day of the Treatment Period, the final dose of double-blind study drug will be 
administered. 
ET procedures are not required for subjects who fail Screening prior to receiving study drug. 
At the discretion of the Investigator, ensuring the safety of the subjects, ET procedures that were 
already performed on the same day as part of the visit on which the subject enters ET do not need 
to be repeated. 
Subjects who withdraw early from the study and complete the ET procedures will not have a 
Follow-up Phone Call. Therefore, the ET Visit is the end of study (EOS) for these subjects. 
The following procedures will occur during Visit 6 of the study or at the ET Visit, unless otherwise 
specified. 
1. Subjects will take the assigned study drug either at home under the supervision of the 
subject’s parent or caregiver before coming to the study site for their scheduled visit, or 
if their visit occurs in the morning, subjects may take the assigned study drug at the 
study site under the supervision of site staff. May not be applicable for the ET Visit. 
2. Record the number of returned and administered capsules of blinded study drug for drug 
accountability and compliance. Unused study drug will remain at the site. 
3. Body weight and height. 
4. Vital signs (respiratory rate, pulse rate, blood pressure, and oral temperature) after 
subject has been sitting for a minimum of 3 minutes. Three (3) blood pressure 
measurements will be collected 2-5 minutes apart. The average of the three 
measurements will be entered into the eCRF. 


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5. Perform the C-SSRS assessment, “Children’s Since Last Visit” version. For subjects too 
young to comprehend the concept of suicidal ideation, the C-SSRS questionnaire will 
be filled in by the parent/guardian/caregiver. Subjects with clinically significant suicidal 
ideation/behavior, in the opinion of the Investigator, based on a history of attempted 
suicide and the C-SSRS assessment, will be referred for further evaluation and/or 
preventive intervention steps for suicidal behavior will be taken, at the discretion of the 
Investigator. 
6. Perform the ADHD-RS-5 for Cohort 2 and the ADHD-RS-IV assessment for Cohort 1 
subjects. Scores will be obtained during a clinician-directed interview with the 
parent/guardian/caregiver present. 
7. Perform the clinician-administered CGI-S scale assessment. 
8. Perform the Clinical Global Impressions–Improvement (CGI-I) scale assessment. 
9. Perform the CSHQ assessment. 
10. A complete physical examination. 
11. Clinical laboratory tests (chemistry, hematology, and urinalysis) will be obtained under 
fasted or non-fasted conditions (fasted/non-fasted state will be recorded). Clinical 
laboratory measurements may be repeated at the discretion of the Investigator. Subjects 
with a greater than trace proteinuria will be asked to provide the study site a morning 
void urine sample (unscheduled urine sample) to rule out orthostatic proteinuria. This 
urine sample will be sent to the clinical laboratory where urine protein and creatinine 
will be quantified and the UP/C ratio will be calculated to rule out “false positive” 
proteinuria. The morning void urine sample will be collected by the 
parent/guardian/caregiver under direction of the study site, and will be dropped off at 
the study site. 
12. Urine pregnancy test for female subjects of childbearing potential. 
13. 12-lead ECG after subject has been in supine position for a minimum of 3 minutes. 
Abnormal ECGs may be repeated for confirmation in which case only the repeated ECG 
will be recorded. 
14. Review of concomitant medications, treatment and/or therapies. 
15. Assessment of AEs. 
16. Subjects in Cohort 1, who have completed the Treatment Period and who qualify, have 
the option to participate in a 12-month open-label safety study with Azstarys® (Study 
KP415.P02). At Visit 6 of the current study, all entry criteria to enroll in Study 
KP415.P02 (see protocol for Study KP415.P02) will be evaluated. Visit 6 for the current 
study is also Visit 2 of Study KP415.P02. Roll-over Subjects will not receive the Follow-
up Phone Call of Study KP415.P01. Subjects who terminate early may not roll over to 
Study KP415.P02. 
9.7. Follow-up Phone Call 
Subjects who will not be rolled over into Study KP415.P02 will receive a Follow-up Phone Call at 
5 ±2 days after administration of the last dose of the Treatment Period for the evaluation of safety 
parameters. 


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The following will be completed during the Follow-up Phone Call: 
1. Review of concomitant medications, treatment and/or therapies. 
2. Assessment of AEs. 
The Follow-up Phone Call is the EOS for subjects who receive the call. 
9.8. End of Study (EOS) 
The EOS is one of the following: 
• The Follow-up Phone Call for subjects who complete the Treatment Period and are not 
rolled over into Study KP415.P02. 
• Visit 6 for subjects who complete the Treatment Period and are rolled over into 
Study KP415.P02. 
• The ET Visit for subjects who withdraw early from the study. 
9.9. Unscheduled Visits 
At the discretion of the Investigator, subjects may be asked to come to the clinical site for an 
unscheduled visit. Subjects will need to bring their unused study drug to the visit. 
Unscheduled visits can occur at any time during the study. Examples of reasons to conduct an 
unscheduled visit: 
• If a subject experiences an AE during at-home treatment, they must contact the clinical site, 
and, at the discretion of the Investigator, further in-person medical evaluation and review 
may be performed. 
• If a subject experiences symptoms of intolerance during at-home treatment or have 
complaints about increases in ADHD symptoms, they must contact the clinical site, and, at 
the discretion of the Investigator, their dose may be adjusted before the next scheduled visit. 
The following procedures will occur at the Unscheduled Visit: 
1. Record the number of administered capsules of unblinded study drug for drug 
accountability and compliance. For this purpose, subjects will be asked to bring their 
unused medication to the clinical site. 
2. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood 
pressure, and oral temperature). Three (3) blood pressure measurements will be 
collected approximately 2-5 minutes apart. The average of the three measurements will 
be entered into the eCRF. 
3. Assessment and review of AEs. 
4. Review of concomitant medications, treatment and/or therapies.  
The following procedures will occur at the Unscheduled Visit, each at the discretion of the 
Investigator: 
1. Evaluations for safety, as needed (for example, to evaluate and review AEs): 
a. Physical examination. 


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b. 12-lead ECG after subject has been in supine position for a minimum of 3 
minutes. Abnormal ECGs may be repeated for confirmation in which case only 
the repeated ECG will be recorded. 
c. C-SSRS, “Children’s Since Last Visit” version. The C-SSRS questionnaire will 
be filled in by the parent/guardian/caregiver. Subjects with clinically significant 
suicidal ideation/behavior, in the opinion of the Investigator, based on the 
C-SSRS assessment, will be excluded from further participation in the study, and 
further evaluation and/or preventive intervention steps for suicidal behavior will 
be taken, at the discretion of the Investigator. 
d. Clinical laboratory assessments (under fasted or non-fasted conditions). 
2. If, at the discretion of the Investigator, an unscheduled evaluation of the changes in 
ADHD symptoms is needed, for a potential unscheduled dose level change of study 
drug: 
a. If needed, perform an assessment of ADHD severity. This may include an 
ADHD-RS, CGI-S, and/or CGI-I scale assessment. 
b. If needed, perform a dose adjustment: based on the ADHD severity assessment, 
interview with the parent/guardian/caregiver, and safety data, the Investigator 
will evaluate the subject’s therapeutic response and tolerability to treatment, and 
decide whether the current dose should be increased, decreased, or remain the 
same. On any day during the study, the daily dose will be either 13.1 mg/2.6 mg, 
26.1 mg/5.2 mg, 39.2 mg/7.8 mg, or 52.3 mg/10.4 mg Azstarys® or matching 
placebo capsules. 
If a subject meets any of the withdrawal criteria during the Unscheduled Visit, the subject will be 
withdrawn, and ET procedures will be completed. 
9.10. Visit and Assessment Changes Due to COVID-19 
9.10.1. General Guidelines 
Due to the COVID-19 public health emergency and in alignment with the Food and Drug 
Administration (FDA) Guidance for Industry, Investigators, and Institutional Review Boards 
entitled FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public 
Health Emergency (March 2020; updated August 30, 2021), alternative measures will be 
implemented for some subjects and/or sites participating in the study. Measures will be 
implemented on an “as needed” basis, to maintain trial continuity, sustain subjects’ access to study 
drug and ensure the continued safety of subjects and the integrity of the study data. Where it is 
possible, the study will be conducted in accordance with the protocol. However, for some study 
subjects and sites, the COVID-19 public health emergency and resulting “stay at home” orders, site 
closures, and travel limitations may lead to difficulties in meeting protocol-specified procedures, 
including on-site delivery of investigational product and adhering to protocol-mandated on-site 
visits and laboratory/diagnostic testing for the study. In these circumstances, alternative measures 
will be employed and documented as protocol deviations that will be summarized within the CSR. 
These alternative measures are intended to remain in effect only for the duration of the public health 
emergency related to COVID-19, and are applied only if an on-site study visit cannot occur. The 


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measures include the delivery of study drug directly to subject’s residence and replacing on-site 
study visits with remote study visits, which may include: 
• Adaptation of efficacy assessments 
• Alternative methods for safety assessments 
A listing of all subjects affected by the COVID-19 related study disruption by subject number and 
by investigational site, and a description of how the individual’s participation was altered will be 
generated. Specifically, the listing will include, but is not limited to, the following: 
• Subjects who had on-site visits converted into remote visits 
• Subjects who had visits and/or assessments not performed/missing along with the reason 
• Subjects who had efficacy and safety data collected out of window 
All of the above study changes will be captured as protocol deviations. Additionally, these data will 
be captured in the eCRF. 
9.10.2. Study-specific Guidelines 
If a subject is not able to attend the site for a scheduled visit due to COVID-19 restrictions, sites 
will be instructed to collect data for select safety assessments (vital signs, labs, ECG, physical exam) 
when the subject is next able to safely return to an on-site visit, even if those assessments would 
not normally be done at that visit. These assessments will be mapped to the nearest scheduled visit. 
Changes in scheduled visits and corresponding assessments due to COVID-19 restrictions will be 
captured in the eCRF. Instructions will be included in the eCRF completion guidelines for capturing 
visits and/or assessments that were missed (not performed), delayed, or performed remotely. The 
following visit and assessment changes will be included in submission datasets:  
• All on-site visits that were converted to remote visits due to COVID-19 restrictions will be 
flagged. This information will be captured in the eCRF and protocol deviation log. 
• Missed visits and assessments are flagged if the “not done” field is indicated and the 
comment field indicates “COVID-19.” 
Assessments that do not require the subject’s presence at the site (e.g., AEs, C-SSRS, ADHD-RS, 
CGI-S, CGI-I, CSHQ) will be collected by phone at the scheduled visit times. 
If needed, alternate measures to dispense study drug to the subjects during their COVID-19 isolation 
period will be implemented (e.g., study drug directly delivered to the subject’s residence or 
dispensed to another family member). 
10. CONCOMITANT MEDICATIONS AND RESTRICTIONS 
Subjects will be instructed not to consume any of the below products; however, allowance for an 
isolated incidences will be evaluated and approved by the study Investigator based on the potential 
for interaction with the study drug, and impact on subject safety and the validity of the study results. 
10.1. Concurrent Medication Restrictions 
Permitted and must be reported at Screening: 
• ADHD medications, current at Screening and during the 6 months prior to Screening. 


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• Melatonin, which is allowed if subjects have taken it for more than 30 days before 
Screening. 
Restricted Medications: 
Subjects will be prohibited/limited to receive certain medications in the trial, as follows: 
• Stimulant ADHD medications (with the exception of study drug), including herbal 
medications, are prohibited from 5 days prior to the start of the Treatment Period to the 
end of the Treatment Period or ET Visit. These include: MPH, amphetamine, Ritalin®, 
Ritalin® SR, Metadate® ER, Concerta®, d-MPH, Focalin®, dextroamphetamine, 
Dexedrine®, Adderall®, Vyvanse ® and prescription Azstarys®. 
• Non-stimulant ADHD medications are prohibited from 14 days prior to the start of the 
Treatment Period to the end of the Treatment Period or ET Visit. These include: 
Atomoxetine, guanfacine, and clonidine. 
The following medications are prohibited from 14 days prior to the start of the Treatment Period to 
the end of the Treatment Period or ET Visit: 
• Monoamine oxidase inhibitors (MAOIs). 
• NRIs and SSRIs such as fluoxetine, paroxetine, and viloxazine. 
• Mood stabilizers (e.g., lithium, valproate, quetiapine). 
• Antipsychotics (e.g., risperidone, olanzapine). 
• Coumarin anticoagulants. 
• Anticonvulsants. 
• Halogenated anesthetics. 
• Phenylbutazone 
• Sedative hypnotics/sleep enhancers (with the exception of melatonin, which is allowed 
if subjects have taken it for more than 30 days before Screening). 
• Tricyclic antidepressants as well as Bupropion are prohibited from 30 days prior to the 
start of the Treatment Period to the end of the Treatment Period (Visit 6) or ET Visit. 
• Cough and cold medications containing stimulants and/or sedating antihistamines are 
prohibited from 30 days prior to the start of the Treatment Period to the end of the 
Treatment Period (Visit 6) or ET Visit. 
All other concomitant medications will be allowed if necessary. Concomitant use of prescription or 
nonprescription medications, including reasons for use, will be reviewed, and recorded on the eCRF 
from the Screening Period through the Follow-up Phone Call. 
Note: Subjects who are rolled over into Study KP415.P02 after the end of the Treatment Period in 
the current study will need to continue to abstain from prohibited medications as explained in the 
protocol for Study KP415.P02. 


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10.2. General Restrictions 
Female subjects must agree, if they are of childbearing potential at Screening or when they become 
of childbearing potential during the study, to remain abstinent or agree to use an effective and 
medically acceptable form of birth control from the time of written or verbal assent to at least 
14 days after the last dose of study drug. 
Male subjects with female partners must agree, when their partners are of childbearing potential at 
Screening or when their partners become of childbearing potential during the study, to remain 
abstinent or agree to use an effective and medically acceptable form of birth control from the time 
of written or verbal assent to at least the Follow-up Phone Call. 
Childbearing potential is defined as follows: Girls under the age of 12 who have not had their first 
period will be considered “not of child-bearing potential.” Girls 12 years of age (including girls who 
will become 13 years during the study) will be considered “of child-bearing potential,” even if they 
have not yet had their first period. Irrespective of age, girls who have had their first period, will be 
considered “of child-bearing potential.” 
11. INVESTIGATIONAL PRODUCT 
11.1. Active Pharmaceutical Ingredients 
The Azstarys® capsules contain two active pharmaceutical ingredients: d-methylphenidate 
(dexmethylphenidate; d-MPH) hydrochloride, and serdexmethylphenidate (SDX; a prodrug of d-
MPH). In terms of total d-MPH dose amounts, all capsule strengths contain 30% of d-MPH and 
70% of d-MPH in form of the prodrug. The total equivalent amount of d-MPH in each capsule 
strength (used as daily doses in this study), and the amounts of both APIs are listed in the following 
table). 
d-MPH 
(mg) 
SDX (d-MPH) 1 
(mg) 
Total 
d-MPH dose 2 
(mg) 
Equimolar 
d-MPH HCl dose 
(mg) 
2.6 
13.1 (6.1) 
8.6 
10 
5.2 
26.1 (12.2) 
17.3 
20 
7.8 
39.2 (18.3) 
25.9 
30 
10.4 
52.3 (24.4) 
34.6 
40 
1. This is the dose of SDX. The amount of d-MPH equimolar to each SDX dose is listed in 
parentheses. 
2. The total dose of d-MPH expressed in terms of free base. 
Blinded capsules of 13.1 mg/2.6 mg, 26.1 mg/5.2 mg, 39.2 mg/7.8 mg, and 52.3 mg/10.4 mg 
Azstarys® and matching placebo capsules will be used in the Treatment Period. All study drug will 
be supplied by the Sponsor (or designee). The Sponsor (or designee) will supply sufficient 
quantities of Azstarys® and placebo to allow for completion of the study. The study drug 
shipment(s) will be shipped to each site after site activation (i.e., after all required regulatory 
documentation has been received by the Sponsor or designee and a contract has been executed). 
The lot numbers of study drug supplied will be recorded in the study report. 


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11.2. Packaging and Labeling 
The Azstarys® capsules and placebo capsules for the Treatment Period will be packaged and labeled 
appropriately. 
All study medication will be blinded throughout the study. Blinded study medication will be 
dispensed for each subject based on the randomization scheme. The patient randomization number 
assigned by the Interactive Response Technology (IRT) or similar system/process will correspond 
to the number on the bottle(s). 
Blinded study medication will be packaged as bottles with 10 capsules. One bottle will contain 
enough drug supply for one subject, for at least 7 days of dosing in the Treatment Period (1 
capsule/day) and 3 extra capsules to cover the potential loss of capsules or extra dosing days before 
the next visit. Each bottle will be dispensed with instructions on how to administer study drug. The 
number on the bottle will be recorded in the Electronic Data Capture (EDC) system for the study. 
11.3. Dispensing Procedures 
Blinded bottles of drug supply (Azstarys® capsules or matching placebo) will be dispensed at each 
visit as follows: 
• Visit 2: Subjects will be dispensed a blinded bottle with 10 capsules of either 
13.1 mg/2.6 mg or 39.2 mg/7.8 mg Azstarys® (starting dose for Cohort 1 and Cohort 2, 
respectively), or associated placebo capsules. 
• Visit 3: Subjects will return to the clinic after 7 ±3 days for Visit 3 with unused study drug 
and will be dispensed a bottle with 13.1 mg/2.6 mg or 39.2 mg/7.8 mg Azstarys® (same 
daily dose as Week 1 for Cohort 1 and Cohort 2, respectively), with 26.1 mg/5.2 mg 
Azstarys® (dose level increase from Week 1 for Cohort 1 subjects or decrease from Week 1 
for Cohort 2 subjects), or with 52.3 mg/10.4 mg Azstarys® (dose level increase from Week 
1 for Cohort 2 subjects), or associated placebo capsules. 
• Visit 4: Subjects will return to the research clinic after 7 ±3 days for Visit 4 with unused 
study drug, and will be dispensed a bottle with 13.1 mg/2.6 mg, 26.1 mg/5.2 mg, 
39.2 mg/7.8 mg, or 52.3 mg/10.4 mg Azstarys® (same daily dose as Week 2, or a dose level 
decrease or increase from Week 2), or associated placebo capsules.  
• Visit 5: Subjects will return to the research clinic after 7 ±3 days for Visit 5 with unused 
study drug, and will be dispensed a bottle with 13.1 mg/2.6 mg, 26.1 mg/5.2 mg, 
39.2 mg/7.8 mg, or 52.3 mg/10.4 mg Azstarys® (same daily dose as Week 3, or dose level 
decrease or increase from Week 3), or associated placebo capsules. 
At Visits 2, 3, 4 and 5, a bottle will be dispensed to the subject’s parent or legal guardian with 
instructions when and how to administer study drug while at home, under supervision of parent or 
legal guardian. At each visit, site personnel will record the number of returned and administered 
capsules of study drug for drug accountability and compliance. 
In the event that a subject experiences lost study drug during the at-home dosing periods, they will 
be instructed to contact the study site as soon as possible after the loss. Lost drug supply may be 
replaced with the appropriate new bottle after the Investigator or designee contacts the IRT or 
similar system/process. All efforts will be made to ensure subjects receive daily doses of double-
blind study drug for at least 14 days during the Treatment Period. 


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The Investigator will not supply study drug to anyone other than those named as sub-investigators 
on FDA Form 1572, designated site staff, and subject’s parent/legal guardian in the study. 
11.4. Materials Control 
Azstarys® is a Schedule II product under the Controlled Substances Act. Therefore, the study site 
is required to have the appropriate permit from the DEA to receive, store, ship and dispense the 
Azstarys® product according to all local, state, and federal regulations for Schedule II substances. 
Once received and labeled by the onsite pharmacist or designee for use in the study, the drugs will 
be considered study drug material. The pharmacist or designee will maintain adequate records of 
the receipt, dispensing, return or other disposition of the drug, including dates, quantity, serial 
numbers, expiration dates, as appropriate. Reasons for any departure from the expected regimen 
will be documented. These documents will be made available to regulatory agency inspectors upon 
request. The Investigator will not supply study drug to anyone other than those named as sub-
investigators on FDA Form 1572, designated site staff, and subject’s parent/legal guardian in the 
study. 
11.5. Storage of Study Drug 
Study drug will be stored at controlled room temperature 20°-25°C (68°-77°F) with excursions 
allowed between 15° and 30°C (59° and 86°F). Transient spikes up to 40°C are permitted as long 
as they do not last for more than 24 hours. Study drug will be stored in a safe, secure area with 
limited, controlled access in accordance with all local, state, and federal regulations for Schedule II 
controlled substances. Investigational products must not be frozen. The Investigator will ensure that 
adequate precautions are taken, including storage of the study drug in a securely locked, 
substantially constructed cabinet, or other securely locked, substantially constructed enclosure, 
access to which is limited, to prevent theft or diversion of the substance into illegal channels of 
distribution. 
The investigational product(s) must be stored as indicated. Deviations from the storage 
requirements, including any actions taken, must be documented, and reported to the Sponsor. Once 
a deviation is identified, the investigational product must be quarantined and not used until the 
Sponsor provides documentation of permission to use the investigational product. 
11.6. Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for each subject will 
be maintained on an ongoing basis by a member of the study site staff. The number of study drug 
dispensed will be recorded on the Investigational Drug Accountability Record. The study monitor 
will verify these documents throughout the course of the study. 
12. SAFETY ASSESSMENTS 
12.1. Medical History 
12.2. Physical Examination 
A complete physical examination will be completed for all subjects at Screening and at the End-of-
Treatment (Visit 6) or ET. The complete physical examination will include a review of the subject’s 


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general appearance, skin, head and neck, musculoskeletal/extremities, heart, lungs, abdomen and a 
brief examination of the neurological system. 
Body weight and height will be determined at each visit. Height will be recorded in centimeters 
(cm) using a stadiometer with the subject’s shoes removed. Body weight will be measured in 
kilograms (kg) using a calibrated scale; subjects will remain in their normal clothing with shoes and 
jacket (and/or outer clothing) removed. 
A complete medical history will be obtained at the Screening Visit including the recording of 
demographic data (date of birth, sex, age, race, ethnicity), and collection of previous surgeries, 
medications, and chronic conditions, past or present illnesses or dysfunctions, substance/drug 
abuse, and history of allergies or idiosyncratic responses to drugs. Medical history (changes from 
Screening) will be updated at subsequent visits after the Screening Period. 
12.3. Children’s Sleep Habits Questionnaire (CSHQ) 
The modified, abbreviated CSHQ will be used to assess the sleep behavior during the Treatment 
Period. The CSHQ is a retrospective, 33-item parent questionnaire to examine sleep behavior in 
small children (Owens 2020). Items are rated on a 3-point scale of “Usually”, “Sometimes” and 
“Rarely” for occurrences in a number of key sleep domains (bedtime resistance, sleep onset delay, 
sleep duration, sleep anxiety, night wakings, parasomnias, sleep disordered breathing, and daytime 
sleepiness). Scores will be obtained during a clinician-directed interview with the 
parent/guardian/caregiver at Screening, at each visit during the Treatment Period, or at the ET Visit. 
The total Sleep Disturbance Score is the sum of the frequency ratings of the 33 items. 
CSHQ 
scores 
will 
be 
obtained 
during 
a 
clinician-directed 
interview 
with 
the 
parent/guardian/caregiver. 
12.4. Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidal ideation will be assessed by the C-SSRS, Pediatric Version (Posner 2010). The “Children’s 
Baseline/Screening” version will be assessed at Screening, and the “Children’s Since Last Visit” 
version will be assessed at all other visits. For subjects too young to comprehend the concept of 
suicidal ideation, the C-SSRS questionnaire will be filled in by the parent/guardian/caregiver. 
Subjects who, in the opinion of the Investigator, have clinically significant suicidal 
ideation/behavior, based on history of attempted suicide and the C-SSRS assessment at Screening 
or at any time before the last dose of study drug, will be excluded from further participation in the 
study, and further evaluation and/or preventive intervention steps for suicidal behavior will be 
taken, at the discretion of the Investigator. 
12.5. Vital Signs 
Vital sign measurements will be obtained at each visit after the subject has been seated for 
3 minutes. Vital signs will include sitting blood pressure (systolic and diastolic measurements), 
pulse rate (beats per minute), respiratory rate (breaths per minute), and oral temperature. Blood 
pressure data will be analyzed using the 2017 AAP guidelines (Flynn 2017) based on the average 
of 3 blood pressure measurements at least 2-5 minutes apart. The average of the three measurements 
will be entered into the eCRF 


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12.6. 12-Lead Electrocardiogram 
A 12-lead ECG will be obtained after the subject has been in a supine position for a minimum of 
3 minutes. Abnormal ECGs may be repeated for confirmation in which case only the repeated ECG 
will be recorded. ECGs will be collected at Screening, Visit 6, and at ET. 
The following ECG parameters will be recorded: 
• Heart Rate (bpm) 
• QT Interval (msec) 
• RR Interval (msec) 
• ECG Evaluation (performed at the clinical site): one of the following: Normal; Abnormal, 
not clinically significant; Abnormal, clinically significant. If Abnormal, a specific 
description of the abnormality in the ECG. 
12.7. Clinical Laboratory Measurements 
Up to 40 mL of blood will be collected for clinical chemistries and hematology from each subject 
during the study and sent to the clinical laboratory. Clinical laboratory samples will be obtained at 
the Screening Visit, at the end of the Treatment Period (Visit 6), at ET, and at Unscheduled Visits 
(if applicable). 
Urinalysis will also be performed by the clinical laboratory from samples taken at Screening 
(Visit 1), at the end of the Treatment Period (Visit 6), at ET, and at Unscheduled Visits (if 
applicable).  
Clinical laboratory measurements may be repeated at the discretion of the Investigator. 
The clinical laboratory evaluations will consist of the following: 
• Total Hematology with differential: red blood cell count, white blood cell count with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), hemoglobin, 
hematocrit and platelets. 
• Serum Chemistry: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
albumin, alkaline phosphatase, bicarbonate, total bilirubin, blood urea nitrogen, 
phosphorus (inorganic), calcium, chloride, creatine phosphokinase, creatinine, gamma 
glutamyl transferase, glucose, lactate dehydrogenase, potassium, sodium, total protein, 
and thyroid stimulating hormone (TSH). TSH will be measured at Screening only (to 
evaluate the exclusion criterion for subjects with uncontrolled thyroid disease). 
• Urinalysis: 
o Urinalysis will include, but not be limited to, the following: bilirubin, blood, 
glucose, ketones, leukocytes, nitrite, pH, protein, and urobilinogen 
o Unscheduled urine sample: Subjects with a greater than trace proteinuria on any 
visit (including Screening) with urinalysis assessments throughout the study will 
be asked to provide the study site a morning void urine sample to rule out 
orthostatic proteinuria. This urine sample will be sent to the clinical laboratory, 
where urine protein and creatinine will be quantified, and the urine protein to 


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creatinine (UP/C) ratio will be calculated to rule out “false positive” proteinuria. A 
UP/C ratio <0.2 will be considered normal. The morning void urine sample will be 
collected by the parent/guardian/caregiver under direction of the study site, and 
will be dropped off at the study site. 
• Urine Screen for Drugs of Abuse: Urine samples will be tested for drugs of abuse 
(amphetamines, methamphetamines, benzodiazepines, barbiturates, cannabinoids, 
cocaine, opioids including oxycodone) at the Screening visit. If the urine test is positive 
for any of the analytes at Screening, the subject will be excluded from study participation. 
• Urine Screen for MPH: 
o At Screening, the urine sample collected for urinalysis will also be tested for MPH 
in the clinical laboratory. Depending on a subject's current ADHD medication at 
Screening, the urine screen may test positive for MPH. Subjects must wash out 
current ADHD medications from 5 days prior to Visit 2 and not use them to the 
end of the Treatment Period (Visit 6) or ET. 
o At Visit 2, urine samples will be tested for MPH with a urine dipstick 
(e.g., NarcoCheck®) that provides immediate results. Subjects with a positive 
screen at check-in to the Treatment Period will be excluded from further study 
participation. 
12.8. Adverse Event Assessments 
Adverse events (AEs) shall be monitored continuously from the administration of the first dose of 
study drug until either the Follow-up Phone Call or ET visits as noted on the SOE. Definitions and 
details of AE reporting and documentation are listed in Section 18. 
13. EFFICACY ASSESSMENTS 
13.1. ADHD Diagnosis 
ADHD-RS: The Preschool Version of ADHD-RS-IV (McGoey 2007) will be used for 4- and 
5-year-old subjects (Cohort 1), and ADHD-RS-5 will be used in 6- to 12-year-old subjects 
(Cohort 2). Although there is a Version 5 of the ADHD-RS, the validated preschool version is 
currently Version IV. The ADHD-RS-IV and ADHD-RS-5 are 18-item scales (DuPaul 1998, 
DuPaul 2016) based on Diagnostic and Statistical Manual of Mental Disorders (American 
Psychiatric Association 2013) criteria of ADHD that rates symptoms on a 4-point scale. Each item 
is scored using a combination of severity and frequency ratings from a range of 0 (reflecting no 
symptoms or a frequency of never or rarely) to 3 (reflecting severe symptoms or a frequency of 
very often), so that the total ADHD-RS scores range from 0 to 54. The 18 items can be divided into 
two 9-item subscales, one for hyperactivity/impulsivity and the other for inattention. Scores will be 
obtained during a clinician-directed interview with the parent/guardian/caregiver at each visit. 
At Screening, the ADHD Presentation (Predominantly Inattentive, Hyperactive-Impulsive, or 
Combined) will be recorded for each subject. 


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13.2. Mini-International Neuropsychiatric Interview for Children and Adolescents (MINI 
Kid) 
The MINI Kid (Sheehan 2010) will be used to conﬁrm the diagnosis of ADHD and identify 
comorbid psychiatric conditions at the Screening Visit only. 
13.3. Clinical Global Impressions–Severity (CGI-S) 
The CGI-S is a clinician-rated scale that evaluates the severity of psychopathology (ADHD 
symptoms in the study) on a scale from 1 (not at all ill) to 7 (among the most severely ill) (Busner 
and Targum 2007). The CGI-S will be performed at Screening and at Visits 2, 3, 4, 5, and 6. 
13.4. Clinical Global Impressions–Improvement (CGI-I) 
The CGI-I is a clinician-rated scale that evaluates the improvement of psychopathology (ADHD 
symptoms in the study) on a scale from 1 (very much improved) to 7 (very much worse). The CGI-I 
will be performed at Visits 3, 4, 5, and 6. Since the CGI-I is an assessment of improvement versus 
the previous visit, there is no CGI-I assessment at baseline (Visit 2). 
14. PHARMACODYNAMICS 
This study will not include PK evaluations. Therefore, PD assessments are not applicable.  
15. DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
15.1. Withdrawal of Subjects from the Study 
A subject may be discontinued or choose to withdraw from study treatment at any time if the 
subject, the Investigator, or the Sponsor feels that it is not in the subject’s best interest to continue. 
The following is a list of possible reasons for study treatment discontinuation: 
• 
Subject withdrawal of consent. 
• 
Subject is not compliant with study procedures. 
• 
Adverse event that in the opinion of the Investigator would be in the best interest of the 
subject to discontinue study treatment. 
• 
Protocol violation requiring discontinuation of study treatment. 
• 
Lost to follow-up after a missed visit, when there is no response to two attempts by phone 
and a registered letter to the subject. After these 3 failed attempts, the subject will be 
considered lost to follow-up. 
• 
Sponsor request for early termination of the study.  
• 
Overdosage, at the discretion of the Investigator (e.g., intentional overdosage, multiple 
occurrences of overdosage). 
• 
For other reasons (reason will be recorded). 


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If a subject is withdrawn from treatment due to an AE, the subject will be followed and treated by 
the Investigator until the abnormal parameter or symptom has resolved or stabilized. 
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
15.2. Withdrawal of Subjects Post-Dose Study Drug 
If a subject meets withdrawal criteria post-dose during the Treatment Period, the subject will 
complete, if possible, all study procedures post-dose study drug before starting ET procedures. The 
subject will be withdrawn and ET procedures will be completed, prior to the subject’s discharge 
from the clinic, if possible. 
At the discretion of the Investigator, ensuring the safety of the subjects, any ET procedures that 
were already performed on the same day as part of the procedures of the Treatment Period, do not 
need to be repeated. 
The Sponsor may be contacted if clarification is required on a case-by-case basis. 
15.3. Replacement of Subjects  
Enrolled subjects who withdraw from the study early will not be replaced.  
16. EFFICACY ENDPOINTS 
The following endpoints will be used to determine efficacy: 
16.1. Primary Efficacy Endpoint 
• Change from baseline (Visit 2) through the end of treatment (Visit 6) in the ADHD  
Rating Score (total score). For Cohort 1, the ADHD-RS-IV will be used; for Cohort 2, the 
ADHD-RS-5 will be used. 
16.2. Secondary Efficacy Endpoints 
• Changes from baseline (Visit 2) to all post-baseline visits through the last evaluation (Visit 6 
or ET ) in the ADHD Rating Score for hyperactivity/impulsivity.  
• Changes from baseline (Visit 2) to all post-baseline visits through the last evaluation (Visit 6 
or ET) in the ADHD Rating Score for inattention.  
• Changes from baseline (Visit 2) to all post-baseline visits through the last evaluation (Visit 6 
or ET) in the CGI-S. 
• CGI-I from Visit 3 to all post-baseline visits through the last evaluation (Visit 6 or ET). 
17. STATISTICAL METHODS AND REPORTING 
17.1. Sample Size Calculation 
Based on data from a previous study (efficacy study with Azstarys® in subjects 6- to 12-years of 


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age), the power and proposed sample size in each age cohort was calculated based on a 
two-sample t-test for the comparison of change from baseline to 28 days post-baseline in ADHD 
Rating Scale total score as follows (with no multiplicity correction for the two age cohorts): 
   
− 90% power to detect a 6-point treatment difference with an SD of 10-points using two-
sided α=0.05 in the Younger Cohort (4- to 5-years of age) yields N=60 per treatment 
group in a 1:1 ratio for Active and Placebo for a total sample size of 120 younger subjects 
− 80% power to detect a 6-point treatment difference with an SD of 10-points using two-
sided α=0.05 in the Older Cohort (6- to 12-years of age) yields N=45 per treatment group 
in a 1:1 ratio for Active and Placebo for a total sample size of 90 older subjects. A lower 
power was selected for this cohort because efficacy in this age group was previously 
established. 
 
Combining the two age cohorts for a total of 105 subjects per treatment group yields 99% overall 
study power to detect a between-treatment difference of 6 points with a SD of 10 points using 
two-sided α=0.05 for a total sample size in the study of 210 subjects. 
 
A blinded sample size re-estimation will be conducted when approximately 50% of subjects in 
Cohort 1 have completed Visit 6.  The sample size may be increased based on that analysis.  
Details are presented in the Interim Analysis section below. 
 
Supporting Material for the Assumed Mean Treatment Difference and SD: 
The estimation of the point estimate of 6 points and a SD of 10 points is based on the following 
data: 
• No clinical studies with MPH have been published that used a parallel design with active vs 
placebo throughout the study. Dose titration with active investigational drug followed by 
randomized withdrawal in part of the population to a placebo arm was typical. Therefore, 
the mean ADHD-RS-5 (total score) change from baseline (CFB) in the titration phases of 
the Phase 3 studies conducted with Azstarys® were used (Table 2 and Table 3). 
• Point Estimate: Based on the range of CFB seen in E01 (-25.6) and S01 (-28.2) during 
4 weeks of treatment, a treatment difference of active vs placebo of 6 is a conservative 
treatment effect that accounts for a potentially large placebo effect. 
• Variability: The SD (10 points) was estimated as approximately the overall mean of the SD 
values of CFB at each visit across both studies (E01 and S01 studies, Table 2 and Table 3, 
respectively). Based on the range of coefficients of variation (CVs) seen in E01 (16.7-
54.8%) and S01 (18.7-63.0%) during 4 weeks of treatment, a SD of 10 is equivalent to a 
CV of 10/6 = 167%, and is very conservative. 


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Table 2: Mean ADHD-RS-5 Total Scores by Visit During the Dose Optimization Phase (ITT 
Population, KP415.E01) 
 
N 
Mean (SD) 
CV (%) 
Mean Change from 
Baseline (SD) 
CV (%) 
Baseline (Visit 2) 
150 
41.8 (7.0) 
16.7 
 
 
Visit 3 
150 
22.1 (12.4) 
54.8 
-19.6 (11.7) 
59.7 
Visit 4 
150 
18.9 (9.3) 
49.2 
-22.8 (9.9) 
43.4 
Visit 5 
150 
16.2 (7.7) 
47.5 
-25.6 (8.6) 
33.6 
Source: Table 22 in Study KP415.E01 CSR 
 
Table 3: Mean ADHD-RS-5 Total Scores by Visit During the Dose Optimization Phase (Efficacy 
Population, KP415.S01) 
 
N 
Mean (SD) 
CV (%) 
Mean Change from 
Baseline (SD) 
CV (%) 
Baseline (Visit 2) 
225 
41.5 (7.7) 
18.7 
 
 
Visit 3 
159 
24.6 (13.9) 
56.6 
-18.4 (14.0) 
76.1 
Visit 4 
159 
19.4 (12.3) 
63.0 
-23.5 (12.9) 
54.9 
Visit 5 
159 
14.1 (8.3) 
59.1 
-28.8 (9.3) 
32.3 
Source: Table 11-1 in Study KP415.S01 CSR 
 
17.2. Analysis Populations 
Safety Population is defined overall and for each cohort separately.  Safety population includes all 
randomized subjects who received at least one dose of study medication and who have at least one 
post-dose safety assessment. Safety endpoints will be analyzed using the Safety Population. 
Demographics and baseline characteristics will be summarized for the Safety Population. 
Intent-to-Treat (ITT) Population is defined overall and for each cohort separately.  ITT 
population includes all subjects who received at least one dose of study medication and have at least 
one post-randomization ADHD-RS Total Score. Demographics and baseline characteristics will be 
summarized for the ITT Population. All efficacy analyses will be conducted in the ITT Population. 
Per-Protocol (PP) Population is defined overall and for each cohort separately. PP population 
includes all randomized subjects who received at least one dose of study medication and have the 
baseline and at least one post-randomization ADHD-RS Total Score, and did not use prohibited 
medications deemed to impact efficacy. The primary efficacy analyses will be conducted in the PP 
Population, as sensitivity analyses. 
17.3. Statistical Analyses 
A Statistical Analysis Plan (SAP) will be developed and finalized before database lock and will 
include detailed descriptions of all analyses to be conducted on all data collected for this study as 
well as complete details on the procedures to handle missing data. This section is a summary of the 
planned statistical analyses of the primary and secondary endpoints.  
All clinical study data will be presented in subject data listings. Descriptive statistics will be 


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presented by treatment group for all endpoints and will include number of subjects (n), mean, 
standard deviation (SD), median, minimum. and maximum for continuous variables, and frequency 
and percentage for categorical and ordinal variables. Unless otherwise specified, all tests will be 2-
tailed at 0.05 level of significance. All CIs will be two-sided 95% CIs.   
Within each cohort and overall, the numbers of subjects screened, the number of subjects 
randomized, and the number of subjects in the safety, ITT, and PP Populations will be displayed 
overall and by treatment group. For randomized subjects who discontinue from the study, the 
primary reason for discontinuation will be listed and summarized by treatment group overall and 
by age cohort. 
Demographic and baseline disease characteristic data will be summarized descriptively by 
treatment group, overall and by age cohort, including sex, age, and race as well as weight, height, 
BMI, and ADHD subtype. The study medication doses received will be analyzed descriptively and 
the optimized dose will be analyzed descriptively overall and by age cohort. Concomitant 
medications will be coded using the World Health Organization (WHO) Drug Dictionary. 
Frequencies and percentages of subjects using each concomitant medication will be presented by 
treatment group, overall and by age cohort. 
17.4. Efficacy Analyses 
17.4.1. Primary Efficacy Endpoint Analyses 
Descriptive statistics will be presented for baseline (Visit 2), all post baseline measurements (Visits 
3 to 6), and changes from baseline to all post-baseline measurements of ADHD Rating Scale 
(ADHD-RS) total score by treatment group, overall and separately for each age cohort.  
For the primary endpoint of change from baseline in ADHD Rating Scale (ADHD-RS) total score, 
a mixed model repeated measures (MMRM) analysis of covariance (ANCOVA) model will be 
fitted using all data as observed. The dependent variable will be change from baseline (Visit 2) in 
ADHD Rating Scale total score for all post-baseline assessments for each subject. The model will 
include fixed effects for treatment, age cohort, gender (stratification factor for randomization), 
baseline ADHD-RS total score, visit (Visit 3, 4, 5, and 6), and visit-by-treatment interaction as well 
as a random effect for the subject. The mixed model will utilize restricted maximum likelihood 
estimation with the Kenward-Roger method used to compute the denominator degrees of freedom 
for tests of fixed effects. The model will assume an unstructured covariance matrix. If the model 
does not converge under the unstructured covariance matrix when using the SAS PROC MIXED 
default Newton-Raphson algorithm, other numerical methods such as the Fisher scoring algorithm 
will be tried. Details regarding the alternative algorithm(s) will be provided in the study SAP. If the 
model using the unstructured covariance matrix still fails to converge, alternative covariance 
structures will be used until convergence is reached based on an ordered list of progressively more 
specific covariance structures which will be documented in the SAP. If a structured covariance is 
used, then a robust sandwich estimator will be utilized for estimating the variance of the treatment 
effect estimate. 
The primary efficacy analysis will be based on comparisons of Azstarys® and placebo at Visit 6. 
From the MMRM model, the Visit 6 difference between least square (LS) means of Azstarys® and 
placebo will be presented along with the corresponding 95% CI and two-sided p-value.  
The above analyses will be repeated for each age cohort separately. 


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The primary estimand for this study is the difference in LS means of Azstarys® and placebo with 
respect to change from baseline in ADHD-RS total score at Visit 6, based on the primary endpoint 
MMRM model fitted to the Intent-to-Treat population. There will be no adjustments made for the 
use of prohibited therapies or other intercurrent events. The p-value associated with the primary 
estimand will be used to test the primary hypothesis of this study, that mean change from baseline 
to Visit 6 ADHD-RS total score for Azstarys® is different from that of placebo. If Azstarys® is 
shown to be statistically superior to placebo, then the superiority of Azstarys® to placebo will be 
tested for each cohort separately.   
To the extent possible, attempts will be made to minimize the amount of missing data through 
measures planned in the study conduct. Subjects who discontinue treatment due to adverse events, 
overdosage, and use of prohibited medications will be followed through the end of study unless and 
until they withdraw consent or start a new ADHD medication (as treatment with a new ADHD 
medication will confound the effects of the randomized treatment). Despite these measures, it is 
expected that there would still be some missing primary endpoint data in this study. Missing primary 
endpoint data will be handled as follows: 
As a sensitivity analysis of the primary endpoint, change from baseline in ADHD-RS total scores, 
the above analyses will be repeated in their entirety using multiple imputation methods to impute 
the missing data. The following three steps will be followed:  
In step 1, missing data will be imputed with multiple imputation (MI) using SAS PROC MI. The 
SAS PROC MI will be used for imputing the change from baseline in ADHD-RS total score over 
time. Missing values at intermittent timepoints prior to the permanent discontinuation of study drug 
will be imputed using the MCMC option. Since classification variables such as treatment group 
cannot be included in the MCMC statement directly, a BY statement will be included in the PROC 
MI code to provide separate imputation models for each treatment group. Missing data following 
permanent discontinuation of study drug will be imputed by treatment group under the assumption 
of MAR using the regression option from the monotone statement of SAS PROC MI. Baseline and 
post-baseline scheduled visits will be used in the regression option to impute the missing values. 
The output from PROC MI will be a data set containing multiple repetitions of the original data set, 
along with the newly imputed values. A minimum of 30 repetitions will be performed. 
In step 2 of the primary analysis, each MI repetition will be analyzed separately to test the equality 
of the change from baseline in ADHD-RS total score means for Azstarys® and placebo.  
In step 3, the results from each separate analysis in step 2 will be pooled using SAS PROC 
MIANALYZE. The pooled results will contain the estimate for the mean difference between 
Azstarys® and placebo for the change from baseline in ADHD-RS total score at Visit 6, as well as 
the corresponding standard error, 95% CI, and p-value.  
If the primary analysis renders a significant treatment difference, a tipping point analysis will be 
performed in order to examine the sensitivity of inferences to departures from the missing at random 
(MAR) assumption. Details will be provided in the SAP and a summary is provided below: 
As missing values following early discontinuations may not be consistent with a MAR assumption, 
a sensitivity analysis using multiple imputation under a missing not at random (MNAR) assumption 
will be performed searching for a tipping point that reverses the primary analysis conclusion. The 
imputed values for Azstarys® subjects’ visits post discontinuation will be made worse by a delta 
defined as k times the treatment difference between Azstarys® and placebo obtained from the MI 


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MAR analysis, where k is a shift parameter that is incremented in order to identify the point at 
which the primary analysis result becomes non-significant (the tipping point). Consideration will 
then be given to how plausible the imputed values are at the tipping point. If not plausible, then the 
conclusion for the primary analysis under the MAR assumption is supported. 
17.4.2. Analyses of Secondary Efficacy Endpoints 
Descriptive statistics will be presented for baseline (Visit 2), all post baseline measurements (Visits 
3 to 6), and changes from baseline to all post-baseline measurements of ADHD-RS for 
hyperactivity/impulsivity and ADHD-RS for inattention by treatment group, overall and separately 
for each age cohort.   
The secondary efficacy endpoints, change from baseline to post-baseline timepoints in ADHD-RS 
for hyperactivity/impulsivity and the ADHD-RS for inattention will be analyzed using the same 
methods as the primary efficacy endpoint, change from baseline in ADHD-RS Total Score. 
Descriptive statistics will be presented for baseline (Visit 2), all post baseline measurements (Visits 
3 to 6), and changes from baseline to all post-baseline measurements of CGI-S by treatment group, 
overall and separately for each age cohort. A MMRM ANCOVA model will be fitted using all data 
as observed. The dependent variable will be change from baseline in CGI-S post-baseline 
assessments for each subject. The model will include fixed effects for treatment,  age cohort, gender 
(stratification factor for randomization), baseline CGI-S, visit (Visit 3, 4, 5, and 6), and visit-by-
treatment interaction as well as a random effect for the subject. The mixed model will be fitted in 
the same manner as described above for the primary endpoint analysis. From the MMRM model, 
the Visit 6 difference between LS means of Azstarys® and placebo will be presented along with 
the corresponding 95% CI and two-sided p-value.  
Descriptive statistics will be presented for all post baseline measurements of CGI-I by treatment 
group, overall and for each age cohort separately. A MMRM ANOVA model will be fitted using 
all data as observed. The dependent variable will be CGI-I post-baseline assessments for each 
subject. The model will include fixed effects for treatment, age cohort, gender (stratification factor 
for randomization), visit (Visit 3, 4, 5, and 6), and visit-by-treatment interaction as well as a random 
effect for the subject. The mixed model will be fitted in the same manner as described above for the 
primary endpoint analysis. From the MMRM model, the Visit 6 difference between LS means of 
Azstarys® and placebo will be presented along with the corresponding 95% CI and two-sided p-
value.  
Visit 6 CGI-I will also be compared between treatment groups using a Cochran-Mantel-Haenszel 
(CMH) chi square test within each age cohort stratified by gender. An overall CMH test will also 
be conducted stratified by gender and age (4 strata). 
17.4.3. Type I Error Control for Efficacy 
For the primary endpoint, the hypothesis of superiority of Azstarys® to placebo will be tested at a 
two-sided alpha of 0.05 for the two age cohorts combined. If significant, the same hypothesis will 
be tested for each age cohort at a two-sided 0.05 level of significance.   
If the primary endpoint comparison is significant for Cohort 1, the superiority of Azstarys® to 
placebo with respect to the secondary efficacy endpoints, ADHD-RS for hyperactivity/impulsivity 
and ADHD-RS for inattention, will be tested for Cohort 1 only using a fixed sequence testing 
procedure in that order.     


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17.5. Safety Analysis 
Unless otherwise specified, all safety analyses will be performed on the safety population, by 
treatment group, overall and separately for the two age cohorts.  
Continuous laboratory data will be examined for trends using descriptive statistics of actual values 
and changes from baseline over time. Shift tables from baseline to each post-baseline time-point 
will be presented. Vital signs and ECG parameters will be summarized using descriptive statistics 
of actual values and changes from baseline over time. The incidence of clinically notable vital signs 
will be summarized.  Physical examination findings will be presented in subject listings.  
Adverse events will be mapped to preferred term and system organ class using the Medical 
Dictionary for Regulatory Activities (MedDRA). Treatment emergent adverse events (TEAEs) are 
AEs that begin in the time period following the first administration of study medication through 5 
days after the last dose of study medication or existing AEs that worsen in the time period following 
the first dose of study medication through 5 days after the last dose of study medication.  The 
number and percentage of subjects reporting TEAEs will be summarized by MedDRA system organ 
class and preferred term, by severity, and by relationship to study treatment.  Drug-related AEs will 
be considered those at least possibly related to study medication based on the Investigator’s 
assessment.  The number and percentage of subjects with SAEs, and the number and percentage of 
subjects with AEs leading to treatment discontinuation will also be summarized by MedDRA 
system organ class and preferred term. 
Descriptive statistics will be presented by visit for body weight (in kg), change and percent change 
from baseline in body weight, height (in cm), change and percent change from baseline in height, 
weight and height z-scores, and weight and height percentiles by treatment group, separately for 
each age cohort. The descriptive statistics will include n, mean, standard deviation (SD), median, 
1st and 3rd quartile (Q1, Q3), and range (minimum and maximum). In addition, descriptive statistics 
will be tabulated by sex and optimized dose. 
The CSHQ total Sleep Disturbance Score and the change and percent change from baseline CSHQ 
score will be analyzed descriptively by treatment overall and by age cohort. A MMRM ANCOVA 
model will be fitted using all data as observed. The dependent variable will be change from baseline 
to all post-baseline assessments of the CSHQ score for each subject. The model will include fixed 
effects for treatment,  age cohort, gender (stratification factor for randomization), baseline CSHQ, 
visit (Visit 3, 4, 5, and 6), and visit-by-treatment interaction as well as a random effect for the 
subject. The mixed model will be fitted in the same manner as described above for the primary 
endpoint analysis. From the MMRM model, the Visit 6 difference between LS means of Azstarys® 
and placebo will be presented along with the corresponding 95% CI. The MMRM analysis of the 
change from baseline CSHQ scores will also be conducted separately for each age cohort. 
Descriptive statistics by treatment group will be displayed for baseline, observed values, and 
changes from baseline in C-SSRS for all post-baseline assessments, overall and by age cohort. A 
MMRM ANCOVA model will be fitted using all data as observed. The dependent variable will be 
change from baseline to all post-baseline assessments of the C-SSRS score for each subject. The 
model will include fixed effects for treatment,  age cohort, gender (stratification factor for 
randomization), baseline C-SSRS, visit (Visit 3, 4, 5, and 6), and visit-by-treatment interaction as 
well as a random effect for the subject. The mixed model will be fitted in the same manner as 
described above for the primary endpoint analysis. From the MMRM model, the Visit 6 difference 
between LS means of Azstarys® and placebo will be presented along with the corresponding 95% 


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CI. The MMRM analysis of the change from baseline C-SSRS scores will also be conducted 
separately for each age cohort. 
17.6. Interim Analysis 
An interim analysis will be conducted for potential sample size increase in subjects 4 and 5 years 
of age (Cohort 1). When approximately 50% of the Cohort 1 subjects complete their Visit 6 
assessments, a blinded sample size re-estimation will be conducted. Subjects will not be identified 
by treatment group. The within-group standard deviation (σ) will be estimated for change from 
baseline to Visit 6 ADHD-RS total score using the blinded methodology of Gould and Shih. The 
adjusted variance estimate will be used, which was recommended by Friede and Kieser and is 
similar to the estimate proposed by Zucker. Friede and Kieser and Waksman showed this estimate 
to be superior to the one obtained from the EM algorithm which was also proposed by Gould and 
Shih. 
The blinded analyses will be conducted by a firewalled independent statistician. An exact sample 
size based on the abovementioned methodology will not be disclosed to the Sponsor.  Instead, 
ranges of sample size will be pre-specified in the interim analysis plan and the upper limit of the 
applicable range will be recommended instead of the exact sample size. Since the study will remain 
blinded for the sample size re-assessment, no alpha penalty for the final analysis will be incurred.  
18. ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
18.1. Adverse Events 
18.1.1. Recording and Monitoring of Adverse Events 
For the purpose of this clinical trial, all AEs will be recorded and monitored for all enrolled subjects 
from the moment they receive the dose of study drug until they complete the study at the EOS (the 
Follow-up Phone Call or the ET Visit). 
18.1.2. Definition 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a patient 
administered a pharmaceutical product and that does not necessarily have a causal relationship with 
the treatment. An AE is therefore any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the administration of an 
investigational product, whether or not related to that investigational product. An unexpected AE 
is one of a type not identified in nature, severity, or frequency in the current Investigator’s Brochure 
or of greater severity or frequency than expected based on the information in the Investigator’s 
Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs during each 
subject visit and record the information in the site’s source documents. Adverse events will be 
recorded in the patient eCRF. AEs will be described by duration (start and stop dates and times), 
severity, outcome, treatment and relation to study drug, or if unrelated, the cause. 
18.1.3. Adverse Event Grading  
The severity of each AE will be graded by the investigator using the following categories: 


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Mild 
Does not interfere with subject’s usual function (awareness of symptoms or signs, but 
easily tolerated [no specific medical intervention required]). 
Moderate 
Interferes to some extent with subject’s usual function (enough discomfort to interfere 
with usual activity [minimal intervention; local intervention; noninvasive 
intervention]). 
Severe 
Interferes significantly with subject’s usual function (incapacity to work or to do usual 
activities [significant symptoms requiring hospitalization or invasive intervention]). 
 
If there is a change in severity of an AE, only the maximum severity of the AE should be recorded. 
The investigator will describe the action taken in the appropriate section of the eCRF, as follows: 
• None 
• Study product stopped 
• Study product temporarily interrupted 
• Concomitant medication 
• Other, specify 
18.1.4. Adverse Event Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following: 
1. Probably - Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the drug; that follows a known or expected 
response pattern to the suspected drug; that is confirmed by stopping or reducing the dosage 
of the drug; and that is not explained by any other reasonable hypothesis. 
2. Possibly - An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but that 
could readily have been produced by a number of other factors. 
3. Unrelated - An event that can be determined with certainty to have no relationship to the 
study drug. 
18.2. Serious Adverse Events 
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
• Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention 
to prevent one of the outcomes listed. 


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18.2.1. Serious Adverse Event Reporting 
Within 24 hours after a SAE detection, observation, or report of occurrence (regardless of the 
relationship to test article), the investigator/qualified designee will complete a SAE/Overdosage 
report with required information regarding the SAE in accordance with the Safety Management 
Plan and submit the completed form to the Pharmacovigilance service provider. The event will also 
be entered into the appropriate AE module of the eCRF as soon as possible. Preliminary reports of 
SAEs must be followed by detailed descriptions later on, such as including clear and anonymized 
photocopies of hospital case reports, consultant reports, autopsy reports, and other documents when 
requested and applicable. SAE reports must be made whether or not the investigator considers the 
event to be related to the investigational drug. 
Serious adverse events considered probably or possibly related to study drug shall also be classified 
by the Sponsor as being “expected” or “unexpected.” An unexpected event is one that is not 
listed in the Investigator’s Brochure or Azstarys® Prescribing Information document. 
All serious event reporting by Sponsor will adhere to 21 Code of Federal Regulations (CFR) 312.32 
for Investigational New Drug (ND) substances (7-day or 15-day alerts) and 21 CFR 314.80 for 
marketed drugs (15-day alerts). Unexpected fatal or life-threatening SAEs considered probably or 
possibly related to the study drug by the Sponsor will be reported to the FDA by the Sponsor with 
an IND Safety report within 7 days of the receipt of the initial information. The Institutional Review 
Board (IRB) will be notified of the 7- and 15-day alert reports per FDA regulations. 
18.3. Adverse Event Treatment and Follow-up 
All AEs, including SAEs, will be followed to resolution when possible. All AEs and treatment 
administered will be recorded on the eCRF. Treatment may be rendered on site under the direction 
of the Investigator as appropriate. Events requiring diagnostic evaluation or treatment beyond the 
scope of what is available and appropriate within the clinical research unit shall be referred in a 
timely basis to other care providers. Records of diagnostic and therapeutic interventions shall be 
requested in compliance with HIPAA requirements, and those received shall be retained in the 
subject’s file. 
Serious adverse event assessment, treatment, and follow up shall be performed up to at least 30 
days after last dose for events considered definitely, probably, or possibly related to study drug, and 
continue until resolved or clinically stable. 
18.4. Overdosage 
For the purposes of this clinical trial, overdosage is defined as the administration of a 
supratherapeutic dose, a daily dose of study drug larger than the highest dose used in the study (by 
cohort), i.e., > 39.2 mg/7.8 mg Azstarys® for Cohort 1 or > 52.3 mg/10.4 mg Azstarys® for 
Cohort 2. If the overdosage has an associated AE or SAE, the site is to report and document the 
event as listed in this protocol. 
Signs and symptoms of acute MPH overdose, resulting principally from overstimulation of the CNS 
and from excessive sympathomimetic effects, may include the following: nausea, vomiting, 
diarrhea, restlessness, anxiety, agitation, tremors, hyperreflexia, muscle twitching, convulsions 
(may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, 
headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, hypotension, 


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tachypnea, mydriasis, dryness of mucous membranes, and rhabdomyolysis (Azstarys® Package 
Insert 2021). 
Notifications of known incidences of subjects taking more than one capsule of study drug per day 
(irrespective of the dose size), which is considered misuse, will be provided by each study site to 
the Sponsor or designee. 
19. PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, Investigator, or Sponsor fails to adhere to significant 
protocol requirements that materially (a) reduces the quality or completeness of the data, (b) makes 
the Informed Consent Form inaccurate, or (c) impacts a subject's safety, rights, or welfare. Examples 
of protocol violations may include the following: 
1. Inadequate or delinquent Informed Consent 
2. Inclusion/exclusion criteria not met 
3. Unreported SAEs 
4. Multiple visits missed or outside permissible windows 
5. Materially inadequate record keeping 
6. Intentional deviation from protocol, Good Clinical Practice, or regulations by study 
personnel 
7. Subject repeated non-compliance with study requirements 
It is the Investigator’s responsibility to report to the IRB of any Protocol Violation(s) according to 
the IRB’s policy. Copy of the IRB submission will be filed in the site’s regulatory binder and in the 
Sponsor’s files. 
20. DATA MANAGEMENT AND RECORD KEEPING 
20.1. Data Management 
Data will be recorded at the site on eCRFs using EDC. All entries on an eCRF are ultimately the 
responsibility of the Investigator, who is expected to review each form for completeness, accuracy 
and legibility before signing. An eCRF must be completed for each participant who has given 
informed consent. The eCRFs and source documents must be made available to Sponsor and/or its 
representatives. 
20.2. Record Keeping 
The Investigator must maintain all documents and records, originals or certified copies of original 
records, relating to the conduct of this trial, and necessary for the evaluation and reconstruction of 
the clinical trial. This documentation includes, but is not limited to protocol, eCRFs, AE reports, 
subject source data (including records of subjects, subject visit logs, clinical observations and 
findings), correspondence with health authorities and IRB, consent forms, inventory of study 
product, Investigator’s curriculum vitae, monitor visit logs, laboratory reference ranges and 
laboratory certification or quality control procedures and laboratory director curriculum vitae. 
The Investigator and affiliated Institution should maintain the trial documents as required by the 
applicable regulations. The Investigator and affiliated Institution should take measures to prevent 


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accidental or premature destruction of documents. Clinical trial documents must be kept in the 
clinical site’s archives indefinitely, unless written authorization is obtained from the Sponsor. 
20.3. Access to Source Data/Documents 
The Investigator and research Institution agree that the Sponsor, their representatives, the IRB, and 
representatives from worldwide regulatory agencies will have the right, both during and after the 
clinical trial, to review and inspect pertinent medical records related to the clinical trial. 
21. QUALITY CONTROL AND QUALITY ASSURANCE 
By signing the protocol, the Institution and the Sponsor agree to be responsible for implementing 
and maintaining quality control and quality assurance systems with written standard operating 
procedures to ensure that trials are conducted and data are generated, documented, and reported in 
compliance with the protocol, accepted standards of Good Clinical Practice. (GCP), International 
Council for Harmonisation (ICH) and other applicable regulations. 
22. ETHICS AND GOOD CLINICAL PRACTICE COMPLIANCE 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting trials that involve human subjects. Compliance with this 
standard provides public assurance that the rights, safety, and wellbeing of trial subjects are 
protected, consistent with the principles that have their origin in the Declaration of Helsinki, and 
that the clinical trial data are credible. In this study, the 2008 version of the Declaration of Helsinki 
will be adhered to. It can be found on the website of The World Medical Association: 
https://www.wma.net/wp-content/uploads/2018/07/DoH-Oct2008.pdf. 
23. PUBLICATION POLICY 
Confidentiality, presentation, and publication of manuscripts containing the study data, and patent 
applications related to unpublished study-related information and unpublished information given to 
the Investigator by the Sponsor and/or its representatives shall be handled as set forth in a mutual 
written agreement between the Sponsor and the Institution. The publication or presentation of any 
study results shall comply with all applicable privacy laws, including, but not limited to, the Health 
Insurance Portability and Accountability Act of 1996. 
24. FINANCING AND INSURANCE 
24.1. Finances 
Prior to starting the study, the Principal Investigator and/or Institution will sign an agreement with 
the Sponsor related to conducting the clinical trial. This agreement will include the financial 
information agreed upon by the parties. 
24.2. Insurance Compensation 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. The 
insurance of the Sponsor does not relieve the Investigator and the other collaborators from 


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November 14, 2022 
 
maintaining their own liability insurance policy. An insurance certificate will be provided to the 
IRB according to regulatory requirements. 
25. COMPLETION OF STUDY 
The end of the study will be at the time of the last subject, last visit. The IRB will be notified about 
the end of the study according to regulatory requirements. 
26. STUDY ADMINISTRATIVE INFORMATION 
26.1. Protocol Amendments 
Any amendments to the study protocol considered to be a substantial amendment will be 
communicated to the Investigator by the Sponsor. All substantial protocol amendments will 
undergo the same review and approval process as the original protocol and may be implemented 
after it has been approved by the IRB, unless immediate implementation of the change is necessary 
for subject safety. In this case, the situation must be documented and reported to the IRB according 
to all relevant regulatory requirements. 
A protocol amendment is considered to be a substantial amendment if it is likely to affect the safety, 
physical, or mental integrity of subjects in the study; the scientific value of the study; the conduct 
or management of the study; or the quality or safety of any Investigational Medicinal Product used 
in the study. 
Any other minor changes to the protocol not considered to be substantial amendments will not need 
prior approval of the IRB and will be communicated to the Investigator by the Sponsor. 


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November 14, 2022 
 
27. REFERENCES 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition (DSM-5). Arlington, VA, American Psychiatric Association, 2013. 
Azstarys® Package Insert, Corium, 2021. 
Barkley RA. Attention-deficit hyperactivity disorder: A handbook for diagnosis and treatment (3rd 
edition). The Guilford Press, 2006. 
Busner J, Targum SD. The Clinical Global Impressions Scale: Applying a research tool in clinical 
practice. Psychiatry 4:28–37, 2007. 
DuPaul GJ, Power TJ, Anastopoulos AD, Reid R. ADHD Rating Scale-IV (for Children and 
Adolescents): Checklists, Norms, and Clinical Interpretation. New York: Guildford, 1998. 
DuPaul GJ, Power TJ, Anastopoulos AD, Reid R. ADHD Rating Scale-5 for Children and 
Adolescents: Checklists, Norms, and Clinical Interpretation. New York: Guildford, 2016. 
Flynn JT, Kaelber DC, Baker-Smith CM, et al. Clinical Practice Guideline for Screening and 
Management of High Blood Pressure in Children and Adolescents [published correction appears 
in Pediatrics. 2017 Nov 30] [published correction appears in Pediatrics. 2018 Sep;142(3):]. 
Pediatrics. 2017;140(3):e20171904. doi:10.1542/peds.2017-1904. 
Focalin XR® [Package Insert].Novartis Pharmaceuticals Corporation. 2021. 
Food and Drug Administration (FDA) Guidance for Industry, Investigators, and Institutional 
Review Boards entitled FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Public Health Emergency. March 2020; updated August 30, 2021. 
Gaub M, Carlson CL. Gender differences in ADHD: a meta-analysis and critical review. J Am 
Acad Child Adolesc Psychiatry. 1997, 36(8):1036-1045. 
Greenhill L, Kollins S, Abikoff H, et al. Efficacy and safety of immediate-release methylphenidate 
treatment for preschoolers with ADHD. J Am Acad Child Adolesc Psychiatry. 2006;45(11):1284-
1293. Erratum in: J Am Acad Child Adolesc Psychiatry. 2007;46(1):141. 
McGoey KE, DuPaul GJ, Haley E, Shelton T. Parent and teacher ratings of attention-
deficit/hyperactivity disorder in preschool: The ADHD rating scale-IV preschool version. J 
Psychopathol Behav Assess 29:269–276, 2007. 
Owens JA, Spirito A, McGuinn M. The Children’s Sleep Habits Questionnaire (CSHQ): 
Psychometric properties of a survey instrument for school-aged children. Sleep 23:1043–1051, 
2000. 
Posner K, Brent D, Lucas C, et al. Columbia-Suicide Severity Rating Scale (C-SSRS) Pediatric 
Baseline Version. New York, NY: The Research Foundation for Mental Hygiene, Inc., 20102010. 
Sheehan DV et al. Reliability and validity of the Mini International Neuropsychiatric Interview for 
children and adolescents (MINI Kid). J Clin Psychiatry 2010;71(3):313-326. 
Wilens T, Adler LA, Adams J, et al. Misuse and diversion of stimulants prescribed for ADHD: a 
systematic review of the literature. J Am Acad Child Adolesc Psychiatry 47:21-31,2008. 
Wilens TE, Biederman J. The stimulants. Psychiatr Clin N Amer. 15:191-222,1992. 


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November 14, 2022 
 
Wolraich ML, Hagan JF, Allan C, et al; Subcommittee on Children and Adolescents with 
Attention-Deficit/Hyperactive Disorder. Clinical Practice Guideline for the Diagnosis, Evaluation, 
and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. 
Pediatrics. 2019;144(4):e20192528. Pediatrics. 2020;145(3):e20193997. doi:10.1542/peds.2019-
3997. 


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Appendix A: Instructions for Oral Administration of Study Drug 
• Instructions for taking study drug as a whole capsule 
1. Swallow capsule whole with a cup of water. The capsule needs to be swallowed whole 
(without crushing, cutting, crushing, chewing, opening, or dissolving). Do not swallow the 
capsule without water. 
2. Take more sips of water as needed, up to approximately 8 ounces (240 mL) of water in total. 
 
• Instructions for taking study drug with applesauce: 
1. Place approximately 1-2 tablespoons (~15-30 mL) of applesauce into a clean cup. 
2. Carefully open the capsule and sprinkle the powder onto the applesauce. Discard the capsule 
shell in the garbage. 
3. Swallow the applesauce with study drug right away. Do not save the applesauce with study 
drug for later use. 
4. To make sure that the entire dose is taken, add more water to the cup, swirl and swallow the 
water right away. 
5. Take more sips of water as needed, up to approximately 7 ounces (210 mL) of water in total. 
 
 

SAP_001.pdf: 
 
 
 
NCT: NCT05685732 
Corium Protocol KP415.P01 Statistical Analysis Plan 
Version 1.0 31Jan2024 


THIS DOCUMENT IS PROPRIETARY AND ITS CONTENTS ARE THE EXCLUSIVE PROPERTY OF PROMETRIKA, LLC. 
THIS DOCUMENT MAY NOT BE REPRODUCED IN ANY FORM WHATSOEVER WITHOUT PRIOR WRITTEN PERMISSION FROM 
PROMETRIKA, LLC.  Copyright © 2021 PROMETRIKA, LLC. 
Corium LLC 
STATISTICAL ANALYSIS PLAN 
A Multicenter, Dose-Optimized, Randomized, Double-Blind, Efficacy and Safety 
Study with Azstarys® in Children 4 to 12 Years of Age with Attention-
Deficit/Hyperactivity Disorder 
KP415.P01 
Version: 
Date: 
Version 1.0 
31JAN2024 


 
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SIGNATURE PAGE 
 


 
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Table of Contents 
1. 
INTRODUCTION .................................................................................................................. 6 
2. 
STUDY SUMMARY .............................................................................................................. 6 
2.1. 
Study Objectives .............................................................................................................. 6 
2.2. 
Study Design .................................................................................................................... 6 
2.2.1. 
Number of Subjects....................................................................................................7 
2.2.2. 
Randomization and Blinding Procedures...................................................................7 
2.2.3. 
Sample Size Justification ...........................................................................................7 
2.2.4. 
Efficacy Assessments.................................................................................................8 
2.2.5. 
Safety Assessments ....................................................................................................9 
3. 
STATISTICAL METHODS ................................................................................................. 15 
3.1. 
General Methods ............................................................................................................ 15 
3.1.1. 
Computing Environment ..........................................................................................15 
3.1.2. 
Reporting Numerical Values ....................................................................................15 
3.1.3. 
Baseline Value and Changes from Baseline ............................................................15 
3.1.4. 
Handling of Missing/Incomplete Values .................................................................15 
3.1.5. 
Visit Windows .........................................................................................................17 
3.1.6. 
Standard Calculations ..............................................................................................17 
3.2. 
Analysis Populations and Subgroups ............................................................................. 18 
3.2.1. 
Definition of Analysis Populations ..........................................................................18 
3.2.2. 
Definition of Subgroups ...........................................................................................18 
3.3. 
Analysis Variables.......................................................................................................... 19 
3.3.1. 
Efficacy Variables ....................................................................................................19 
3.3.2. 
Safety Variables .......................................................................................................19 
3.4. 
Subjects Disposition and Evaluability ........................................................................... 19 
3.4.1. 
Subject Disposition ..................................................................................................19 
3.4.2. 
Protocol Deviations ..................................................................................................19 
3.5. 
Demographics and Baseline Characteristics .................................................................. 20 
3.5.1. 
Demographics and Baseline Characteristics ............................................................20 
3.5.2. 
ADHD Diagnosis .....................................................................................................20 
3.5.3. 
Medical History .......................................................................................................20 
3.6. 
Concomitant Medications .............................................................................................. 20 


 
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3.6.1. 
Prior and Concomitant Medications ........................................................................20 
3.7. 
Study Drug Exposure and Compliance .......................................................................... 21 
3.7.1. 
Study Drug Exposure ...............................................................................................21 
3.7.2. 
Treatment Compliance .............................................................................................21 
3.8. 
Efficacy Analyses ........................................................................................................... 21 
3.8.1. 
Primary Efficacy Endpoint ......................................................................................21 
3.8.2. 
Secondary Efficacy Endpoints .................................................................................23 
3.9. 
Safety Analysis ............................................................................................................... 24 
3.9.1. 
Adverse Events ........................................................................................................24 
3.9.2. 
Clinical Laboratory Evaluation ................................................................................25 
3.9.3. 
Vital Signs ................................................................................................................25 
3.9.4. 
Body Weight and Height .........................................................................................25 
3.9.5. 
Physical Examinations .............................................................................................26 
3.9.6. 
ECGs ........................................................................................................................26 
3.9.7. 
CSHQ .......................................................................................................................26 
3.9.8. 
C-SSRS ....................................................................................................................26 
3.10. Interim Analysis: Blinded Sample Size Re-Estimation ................................................. 27 
3.10.1. Analysis Objective ...................................................................................................27 
3.10.2. Analysis Method ......................................................................................................27 
3.10.3. Maintaining the Treatment Masking ........................................................................27 
3.10.4. Distribution of Results .............................................................................................28 
4. 
modifications FROM STATISTICAL METHODS IN THE PROTOCOL.......................... 28 
5. 
References ............................................................................................................................. 30 
6. 
Sample SAS Codes ............................................................................................................... 31 
  
 




 
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1. INTRODUCTION 
This is a multicenter, dose-optimized, randomized, double-blind, efficacy and safety study with 
Azstarys® in children 4 to 12 years of age with attention-deficit/hyperactivity disorder (ADHD). 
The goal of the study is to evaluate the efficacy and safety and tolerability of Azstarys® in 
treating subjects with ADHD. 
 
This statistical analysis plan (SAP) contains a detailed description of the data presentations and 
statistical analyses for Protocol KP415.P01. The statistical analyses described here are based on 
Version 4.0 of the protocol dated 14 November 2022. 
2. STUDY SUMMARY 
2.1. Study Objectives 
The primary objective is: 
• To determine the efficacy of Azstarys® compared to placebo in treating children ages 4 
to 12 years old with ADHD. 
 
The secondary objective is: 
• To determine the safety and tolerability of Azstarys® compared to placebo in treating 
children 4 to 12 years old with ADHD. This includes changes in weight, height and sleep 
behavior. 
2.2. Study Design 
This is a multicenter, dose-optimized, randomized, double-blind, efficacy and safety study with 
Azstarys (SDX/dMPH) in children 4 to 12 years of age with attention-deficit/hyperactivity 
disorder (ADHD).  
 
The study consists of 3 phases: up to 30 days in Screening Phase, 28 days in Double-Blind 
Treatment Phase, and a Follow Up Phone Call 5±2 days after administration of the last dose of 
the Treatment Phase. 
 
Approximately 230 eligible subjects will be randomized 1:1 to Azstarys or placebo stratified by 
gender. Randomization will be applied within two age cohorts: Cohort 1 (4 - <5 years and 10 
months), Cohort 2 (6 - <12 years and 10 months). For Cohort 1, 130 subjects (65 per arm) will 
start at 13.1 mg/2.6 mg or matching placebo in order to have approximately 120 completers (60 
per group). Subjects in Cohort 1 may be titrated up to doses of 26.1 mg/5.2 mg, 39.2 mg/7.8 mg 
Azstarys (SDX/dMPH), or matching placebo. For Cohort 2, 100 subjects (50 per arm) will start 
at 39.2 mg/7.8 mg or matching placebo in order to have approximately 90 completers. Subjects 
in Cohort 2 may be titrated up or down to doses of 26.1 mg/5.2 mg, 52.3 mg/10.4 mg Azstarys 
(SDX/dMPH) or matching placebo. The daily dose may be changed or remain the same 
throughout the Double-Blind Treatment Phase based on a combination of individual tolerability 
and effect assessed by the Investigator. 


 
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Subjects in Cohort 1 who are eligible will have the option to participate and roll-over into a 12-
month open-label safety study with Azstarys (SDX/dMPH) (Study KP415.P02) after the Double-
Blind Treatment Phase.  
2.2.1. Number of Subjects 
Up to 230 eligible subjects will be enrolled. Up to 130 subjects (65 per arm) will be enrolled into 
Cohort 1 (4 - <5 years and 10 months) with the intention to complete with approximately 120 
subjects, and up to 100 subjects (50 per arm) will be enrolled into Cohort 2 (6 - <12 years and 10 
months) with the intention to complete with approximately 90 subjects. Approximately 20 sites 
will participate in this study.  
2.2.2. Randomization and Blinding Procedures 
Randomization will be carried out using an interactive web response system (IWRS), with 
central randomization following a 1:1 ratio between Azstarys and placebo. Randomization will 
occur within each age cohort and will be stratified by gender. 
 
Study drug will be blinded during the Treatment Period. Neither the subject, the Investigator, nor 
the Sponsor will know the subject’s treatment assignment. Upon completion of the study and 
after the database is locked according to the Sponsor (or designee) operating procedures, the 
randomization codes will be provided to the statistician to unblind the study. The blind for 
individual subjects can be broken before study unblinding at the request of the Investigator only 
if a specific emergency treatment would be dictated by knowing the treatment status of a subject. 
2.2.3. Sample Size Justification 
Sample size calculations were based on data from a previous study (efficacy study with 
Azstarys® in subjects 6 to 12 years of age). The power and proposed sample size in each age 
cohort was calculated based on a two-sample t-test for the comparison of change from baseline 
to 28 days post-baseline in ADHD Rating Scale total score as follows (with no multiplicity 
correction for the two age cohorts): 
   
• 90% power to detect a 6-point treatment difference with a standard deviation (SD) of 10 
points using two-sided α=0.05 in the Younger Cohort (4 - <5 years and 10 months) yields 
N=60 per treatment group in a 1:1 ratio for Active and Placebo for a total sample size of 
120 younger subjects. 
 
• 80% power to detect a 6-point treatment difference with an SD of 10 points using two-
sided α=0.05 in the Older Cohort (6 - <12 years and 10 months) yields N=45 per 
treatment group in a 1:1 ratio for Active and Placebo for a total sample size of 90 older 
subjects. A lower power was selected for this cohort because efficacy in this age group 
was previously established. 
 
Combining the two age cohorts for a total of 105 subjects per treatment group yields 99% overall 
study power to detect a between-treatment difference of 6 points with a SD of 10 points using 


 
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two-sided α=0.05 for a total sample size in the study of 210 subjects. Assuming up to 10% of the 
subjects discontinue prior to completing the 28-day treatment period, up to 230 subjects will be 
randomized.  
 
A blinded sample size re-estimation will be conducted when 50% of subjects in Cohort 1 (4 - <5 
years and 10 months) have completed the Double-Blind Treatment Phase in order to check the 
between-subject variability assumption. The sample size will be increased if the estimated SD is 
larger than the assumed 10 points.  If the estimated SD is smaller than the assumed 10 points, no 
adjustments to the sample size will be made and enrollment will continue until the total 
estimated sample size of 230 subjects is accrued. Details of the blinded sample size re-estimation 
are provided in Section 3.10. 
2.2.4. Efficacy Assessments 
2.2.4.1 ADHD Diagnosis 
The ADHD-Rating Scale (ADHD-RS): The Preschool Version of ADHD-RS-IV will be used for 
Cohort 1 (4 - <5 years and 10 months) and ADHD-RS-5 will be used for Cohort 2 (6 - <12 years 
and 10 months). The ADHD-RS-IV and ADHD-RS-5 each contain 18-item scales based on 
Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association 2013) 
criteria of ADHD which rate the frequency of behaviors on a 4-point scale ranging from 0 (never 
or rarely) to 3 (very often). The ADHD-RS total score ranges from 0 to 54. The 18 behavior 
items are further divided into two 9-item subscales: hyperactivity/impulsivity and inattention. 
The ADHD-RS-5 also contains items related to the severity of the 18 behaviors that are rated 
from 0 (no problem) to 3 (severe problem). Scores will be obtained during a clinician-directed 
interview with the parent/guardian/caregiver at each visit. ADHD-RS scores should be collected 
using an ePRO device; for instances when the ePRO device is not available, ADHD-RS scores 
may be collected on paper CRFs. 
 
The ADHD Presentation (Predominantly Inattentive, Hyperactive-Impulsive, or Combined) will 
be collected for each subject at the Screening Visit only. 
2.2.4.2 Mini-International Neuropsychiatric Interview for Children and Adolescents  
(MINI Kid) 
The MINI Kid will be used to conﬁrm the diagnosis of ADHD and identify comorbid psychiatric 
conditions at the Screening Visit only. MINI Kid data will be captured on paper CRFs. 
2.2.4.3 Clinical Global Impressions–Severity (CGI-S) 
The CGI-S is a clinician-rated scale that evaluates the severity of psychopathology (ADHD 
symptoms in the study) on a scale from 1 (not at all ill) to 7 (among the most severely ill). Refer 
to Table 2 for details on the scheduled collection time points. The CGI-S rating will be collected 
using an ePRO device. 
2.2.4.4 Clinical Global Impressions–Improvement (CGI-I) 
The CGI-I is a clinician-rated scale that evaluates the improvement of psychopathology (ADHD 




 
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minutes apart. Body weight (kg) and height (cm) will also be measured and collected at each 
visit.  
2.2.5.4 Physical Examinations 
A complete physical examination will include assessments of the subject’s general appearance, 
skin, head and neck, musculoskeletal/extremities, heart, lungs, abdomen and a brief examination 
of the neurological system. Refer to Table 2 for details on the scheduled collection time points. 
2.2.5.5 Electrocardiogram (ECG) 
A 12-lead ECG will be obtained after the subject has been in a supine position for a minimum of 
3 minutes. Abnormal ECGs may be repeated for confirmation in which case only the repeated 
ECG will be recorded. ECG measurements will include: heart rate (bpm), QT Interval (msec), 
RR Interval (msec) and ECG evaluation (normal; abnormal, not clinically significant; abnormal, 
clinically significant). Refer to Table 2 for details on the scheduled collection time points. 
2.2.5.6 Children’s Sleep Habits Questionnaire (CSHQ) 
The modified, abbreviated Children’s Sleep Habits Questionnaire (CSHQ) will be used to assess 
the sleep behavior during the Treatment Phase. The CSHQ is a retrospective, 33-item 
questionnaire to examine sleep behavior in small children. Items are rated on a 3- point scale of 
“Usually”, “Sometimes” and “Rarely” for occurrences in a number of key sleep domains 
(bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night wakings, parasomnias, 
sleep disordered breathing, and daytime sleepiness). Scores will be obtained during a clinician-
directed interview with the parent/guardian/caregiver. The total Sleep Disturbance Score is the 
sum of the frequency ratings of the 33 items. Refer to Table 2 for details on the scheduled 
collection time points. 
2.2.5.7 Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale (C-SSRS, Pediatric Version) will be used to assess 
suicidal ideation. The “Children’s Baseline/Screening” version will be assessed at Screening, and 
the “Children’s Since Last Visit” version will be assessed at all other visits. For subjects too 
young to comprehend the concept of suicidal ideation, the C-SSRS questionnaire will be filled in 
by the parent/guardian/caregiver. Refer to Table 2 for details on the scheduled collection time 
points. 


 
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    Table 2 : Schedule of Events 
ASSESSMENTS 
SCREENING 
PERIOD 
DOUBLE BLIND 
TREATMENT PERIOD 
EARLY 
TERMINATION 
19 
FOLLOW-UP 
PHONE  
CALL 
Study Day 
-30 to -1 
0 
7 
(±3 
days 
14 
(±3 
days) 
21 
(±3  
days) 
28 
(±3  
days) 
 
- 
 
33 
(± 2  
days) 
Visit Number 
1 
2  
3 
4 
5 
6 
 
- 
 
- 
Parental Permission (Informed 
Consent)/Written or Verbal Assent 
(Cohort 2) 
X 
 
 
 
 
 
 
 
ADHD Diagnosis and  
Confirmation 1 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 2 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 3 
X 
X 
 
 
 
 
 
 
Physical Examination 4 
X 
 
 
 
 
X 
X 
 
Body Weight & Height 5 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs 6 
X 
X 
X 
X 
X 
X 
X 
 
12-Lead ECG 7 
X 
 
 
 
 
X 
X 
 
Chemistry/Hematology/Urinalysis 
X 
 
 
 
 
X 
X 
 
Drugs of Abuse Screen 8 
X 
 
 
 
 
 
 
 
Urine MPH Screen 9 
X 
X 
 
 
 
 
 
 
Urine Pregnancy Test 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 10 
X 
X 
X 
X 
X 
X 
X 
 
Washout ADHD Meds 11 
X 
X 
 
 
 
 
 
 
Study Drug Dispensing 
 
X 
X 
X 
X 
 
 
 
Study Drug Dosing 12 
 
 
X 
X 
X 
X 
 
 
Dose Titration Evaluation 
 
 
X 
X 
X 
 
 
 


 
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ASSESSMENTS 
SCREENING 
PERIOD 
DOUBLE BLIND 
TREATMENT PERIOD 
EARLY 
TERMINATION 
19 
FOLLOW-UP 
PHONE  
CALL 
Study Day 
-30 to -1 
0 
7 
(±3 
days 
14 
(±3 
days) 
21 
(±3  
days) 
28 
(±3  
days) 
 
- 
 
33 
(± 2  
days) 
Visit Number 
1 
2  
3 
4 
5 
6 
 
- 
 
- 
Drug Accountability & Compliance 
Assessment 13 
 
 
X 
X 
X 
X 
X 
 
Double-Blind Randomization 14 
 
X 
 
 
 
 
 
 
ADHD-RS-IV or ADHD-RS-5 15 
X 
X 
X 
X 
X 
X 
X 
 
MINI Kid 
X 
 
 
 
 
 
 
 
CGI-S  
X 
X 
X 
X 
X 
X 
X 
 
CGI-I  
 
 
X 
X 
X 
X 
X 
 
CSHQ  
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 16 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 17 
X 
X 
X 
X 
X 
X 
X 
X 
Rollover to Study KP415.P02 18 
 
 
 
 
 
X 
 
 
 
ADHD = Attention-Deficit/Hyperactivity Disorder; CGI-S/I = Clinical Global Impressions – Severity/Improvement; CHSQ = Children’s Sleep 
Habits Questionnaire ET = Early Termination; ECG = electrocardiogram; MPH = methylphenidate; see footnotes for other abbreviations. 
1. ADHD Diagnosis based on the Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) criteria for a primary diagnosis of ADHD 
(combined, inattentive, or hyperactive/impulsive presentation) and by the Mini-International Neuropsychiatric Interview for Children and 
Adolescents (MINI Kid). 
2. Study inclusion/exclusion criteria will be evaluated at Screening and Visit 2. 
3. Medical History: A complete medical history including chronic conditions, relevant surgical procedures (with start date), and history of drug use. 
4. Physical Examination: at Screening and at the end of the Treatment Period or ET (if possible). 
5. Height will be recorded in centimeters (cm) using a stadiometer with the subject’s shoes removed. Height will be recorded at Screening, Visit 2, 
and at the end of the Treatment Period. Body weight will be measured in kilograms (kg) using a calibrated scale; subjects will remain in their 
normal clothing with shoes and jacket (and/or outer clothing) removed. Weight will be recorded at every visit. 


 
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6. Vital signs will be collected at each visit. Vital sign measurements will be obtained after the subject has been seated for at least 3 minutes. Vital 
signs will include sitting blood pressure (systolic and diastolic measurements), pulse rate (beats per minute), respiratory rate (breaths per minute), 
and oral temperature. Three (3) blood pressure measurements will be taken 2-5 minutes apart. Only the average of the 3 blood pressure 
measurements will be entered into the electronic case report form (eCRF). 
7. ECG: A 12-lead ECG will be obtained after the subject has been in the supine position for at least 3 minutes. Abnormal ECGs may be repeated for 
confirmation in which case only the repeated ECG will be recorded. 
8. Urine Screen for Drugs of Abuse: Urine samples will be tested for drugs of abuse (amphetamines, methamphetamines, benzodiazepines, 
barbiturates, cannabinoids, cocaine, opioids including oxycodone) at the Screening visit. If the urine test is positive for any of the analytes at 
Screening, the subject will be excluded from study participation. 
9. Urine Screen for Methylphenidate (MPH): Urine samples will be tested for MPH by the clinical laboratory in a sample collected at the Screening 
Visit. A urine dipstick (e.g., NarcoCheck®) will be used to screen for the presence of MPH in the urine at Visit 2. If a subject’s current ADHD 
medication at Screening contains MPH, the urine screen at Screening may test positive for MPH. All ADHD medications must be washed out by 
Visit 2 and the MPH urine screen must test negative. 
10. Columbia Suicide Severity Rating Scale (C-SSRS): The “Children’s Baseline/Screening” version will be assessed at Screening, and the 
“Children’s Since Last Visit” version will be assessed at all other visits. For subjects too young to comprehend the concept of suicidal ideation, the 
C-SSRS questionnaire will be filled in by the parent/guardian/caregiver. Subjects who have, in the opinion of the Investigator, clinically 
significant suicidal ideation/behavior, based on history of attempted suicide and the C-SSRS assessment at Screening or at any time before the last 
dose of study drug, will be excluded from further participation in the study. The follow-up C-SSRS will be obtained via phone. 
11. Subjects must wash out ADHD medications prior to Visit 2. Stimulant ADHD medications (with the exception of study drug), including herbal 
medications, are prohibited from 5 days prior to Visit 2 to the end of the Treatment Period (Visit 6) or ET Visit. Non-Stimulant ADHD 
medications are prohibited from 14 days prior to the start of the Dose Optimization Phase (Visit 2) to the end of the Treatment Period (Visit 6) or 
ET Visit. Before or on the day during the Screening Period that the subject will need to start the washout of their ADHD medications (for example, 
5 days before Visit 2 for stimulants), study site staff will contact the subject’s parent/guardian by phone to remind them of the washout (“Washout 
Phone Call”). Other prohibited medications and the windows of prohibition are listed in the protocol. 
12. Dose Optimization/Treatment Period: Subjects will begin taking study drug at home the morning following Visit 2. The starting dose will be 
13.1 mg/2.6 mg day or matching placebo in Cohort 1 and 39.2 mg/7.8 mg or matching placebo in Cohort 2. Dose adjustments, if needed, will be 
performed at approximately weekly intervals. Actual visit dates may deviate from exactly 7 days apart such that the total duration is 3 weeks 
(21 ±3 days). The daily doses of study drug used will be 13.1 mg/2.6 mg, 26.1 mg/5.2 mg, 39.2 mg/7.8 mg, or 52.3 mg/10.4 mg Azstarys® or 
matching placebo. At Visits 3, 4, and 5 based on the CGI scores, interview with the parent/guardian/caregiver, and safety data, the Investigator 
will evaluate the subject’s therapeutic responses and tolerability to treatment and decide whether the current dose should be increased, decreased, 
or remain the same for the next week of dosing. If a subject experiences symptoms of intolerance during at-home treatment, they must contact the 
clinical site, and, at the discretion of the Investigator, their dose may be adjusted before the next scheduled visit. Unscheduled visits between Visits 
2, 3, 4, and 5 are allowed as needed, at the discretion of the Investigator. 
13. Drug Accountability & Compliance Assessment: Study drug receipt, dispensing, and return will be recorded by each site’s pharmacy staff or 
Investigator-delegated employee. A record of the study drug accountability will be prepared and kept by the clinical site. 


 
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14. Randomization: Subjects will be randomized to Azstarys® or matching placebo within each cohort. Randomization will be stratified by gender. 
15. ADHD-Rating Scale (ADHD-RS)-IV or ADHD-RS-5: (Preschool Version of ADHD-RS-IV for Cohort 1; ADHD-RS-5 for Cohort 2): 1 
assessment at the indicated visits. 
16. Adverse Events: To be assessed and recorded in the eCRF following the first dose of study drug, through either ET or the Follow-up Phone Call. 
Subject’s parent/guardian will be instructed to contact the study site for the reporting of adverse events (AEs) during at-home periods. 
17. Concomitant Medications: new and/or changed medications and dose, medical treatments, and/or therapies will be recorded at Screening through 
either the Follow-up Phone Call or ET. 
18. Subjects of Cohort 1 (ages 4 and 5 years), who qualify, have the option to participate in a 12-month open-label safety study with Azstarys® (Study 
KP415.P02). At Visit 6 of the current study, all entry criteria to enroll in Study KP415.P02 (see protocol for Study KP415.P02) will be evaluated. 
Visit 6 for the current study is also Visit 2 of Study KP415.P02. Roll-over Subjects will not receive the Follow-up Phone Call in 
Study KP415.P01. 
19. Early Termination: Subjects who meet withdrawal criteria post-dose during the Treatment Period (after at least one dose of study drug is 
administered) will complete ET procedures. At the discretion of the Investigator, ensuring the safety of the subjects, any Early Termination 
procedures that were already performed on the same day as part of the procedures of the Treatment Period, do not need to be repeated. Subjects 
who elect to use another ADHD treatment will be discontinued from study treatment and from the study (ET). Subjects who discontinue study 
treatment prior to the end of the Treatment Period because of AEs, overdosage, or use of a prohibited treatment other than an ADHD treatment 
will be followed (unless consent is withdrawn) with scheduled assessments until the end of the Treatment Period (Visit 6). If, during the 
remaining time on study, an ADHD treatment is used, the subject will be discontinued from the study (ET). 
20. Assessment changes due to Coronavirus Disease 2019 (COVID-19): If a subject is not able to attend the site for a scheduled visit due to COVID-
19 restrictions, sites will be instructed to collect data for select safety assessments (vital signs, labs, ECG, physical exam) when the subject is next 
able to safely return to an on-site visit, even if those assessments would not normally be done at that visit. These assessments will be mapped to 
the nearest scheduled visit. Changes in scheduled visits and corresponding assessments due to COVID-19 restrictions will be captured in the 
eCRF. Assessments that do not require the subject’s presence at the site (e.g., AEs, C-SSRS, ADHD-RS-IV, ADHD-RS-5; CGI-S, CGI-I, CSHQ) 
will be collected by phone at the scheduled visit times. If needed, alternate measures to dispense study drug to the subject during their COVID-19 
isolation period will be implemented (e.g., study drug directly delivered to the subject’s residence or dispensed to another family member). 
 
 


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3. STATISTICAL METHODS  
3.1. General Methods 
3.1.1. Computing Environment 
All statistical analyses will be performed using SAS® Version 9.4 or higher for Windows. 
3.1.2. Reporting Numerical Values 
All clinical study data will be presented in subject data listings. Relevant descriptive statistics (n, 
mean, standard deviation, median, minimum, and maximum) will be calculated for continuous 
variables. Frequencies and percentages will be presented for categorical and ordinal variables. 
Percentages will be based on the number of non-missing values. If there are missing values, the 
number missing will be presented, but without a percentage. Unless otherwise specified, all tests 
will be 2-tailed at a 0.05 level of significance. All confidence intervals (CIs) will be two-sided 
95% CIs.   
 
Means, medians, and CIs will be reported to one decimal place more than the data reported on 
the case report form (CRF) or by the laboratory/vendor up to a maximum of two decimal places. 
Standard deviations will be reported to one additional decimal place. A maximum of three 
decimal places will apply to all summary statistics. P-values will be displayed to four decimal 
places. If a p-value less than 0.0001 occurs it will be shown in tables as <0.0001. 
3.1.3. Baseline Value and Changes from Baseline 
The baseline value will be defined as the last non-missing value prior to the administration of the 
first dose of study drug. If an assessment is obtained on the same day as first dose of study drug 
and times are not available for both assessment and dosing, it will be assumed that the 
assessment is prior to dosing. Change from baseline will be calculated by subtracting the 
baseline value from the post-dose assessment for each subject (i.e., post-dose – baseline). Percent 
change from baseline will be calculated by dividing change from baseline by the baseline value 
given it is not missing or zero, and then multiplying by 100 for each subject (i.e., [change from 
baseline/baseline] x 100). 
3.1.4. Handling of Missing/Incomplete Values 
For all baseline and safety endpoints, no substitutions will be made for missing/incomplete data 
points, except for adverse event and medication dates, as described below. Handling of missing 
values for the efficacy endpoints is also described below.  
3.1.4.1 Adverse Events or Medication Missing Dates 
Partial dates for AEs and medications will be imputed for the ease of determining whether 
adverse events were treatment-emergent and whether medications were concomitant to study 
drug.  
 
Missing or partial dates for AEs and medications will be handled as follows in the safety 


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analysis: 
 
 
Start Date 
Missing day: If month and year are equal to the month and year of first dose date, 
set start date to the first dose date. Otherwise, set the day to the first of the month. 
Missing month and day: If year is equal to the year of first dose date, set start 
date to the first dose date. Otherwise, set the month and day to Jan 1. 
Missing year, month, and day: Set start date to the first dose date. 
End Date 
Missing day: set end date to the last day of the month. 
Missing month and day: set to Dec 31. 
Missing year, month, and day: no imputation 
 
If imputation of a start date (and end date if both were imputed) results in a start date occurring 
after the end date, the imputed start date will be reset to equal the end date. If an imputed start or 
end date occurs after the database lock date, the imputed date will be reset to the database lock 
date. Imputed partial dates will only be used for identifying whether an AE was treatment-
emergent or a medication was concomitant. Listings will display the partial dates as recorded on 
the electronic CRF. 
3.1.4.2 Assigning Missing Scores in ADHD-RS 
Electronic Patient Reported Outcome (ePRO) data are entered in the Patient Cloud using the 
device (iPad) provided by Medidata Rave EDC. Paper PRO eCRFs are available only in the rare 
event the device is not working. 
 
Scores for the following items will be set to missing for subjects who indicated their absence 
from school at the time of the assessment. 
 
• Completing or returning homework 
• Performing academically in school 
• Controlling behavior in school 
3.1.4.2.1 Missing Items in ADHD-RS  
Missing items for the ADHD-RS scales will be handled as follows: 
 
1. If more than 3 items have missing data, the total score will be set to missing. If the total score 
is missing then both subscales (Inattention and Hyperactivity/Impulsivity) will be set to missing. 
 
2. If 3 items or fewer have missing or invalid data, the values for the missing items will be 
imputed using the mean of the non-missing items rounded to the nearest integer for the purpose 
of calculating the total score and subscale scores. 
 
For the primary efficacy analysis, the change from baseline in ADHD Rating Score (ADHD-RS) 
total score will be analyzed using a Mixed Model Repeated Measures (MMRM) analysis of 
covariance (ANCOVA) model in which the missing data are handled implicitly under the 
assumption of Missing-At-Random (MAR). 




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• Time since ADHD Diagnosis (months) = (date of informed consent – date of ADHD 
diagnosis + 1)/30.4375 
• Time since ADHD Symptoms Onset (months) = (date of informed consent – date of 
ADHD symptoms + 1)/30.4375 
 
Treatment compliance during the treatment period will utilize the following calculation: 
 
Treatment Compliance (%) = 100*(number of capsules dispensed – number of capsules returned) 
/ number of capsules expected to be taken.  
 
Weight and Height Z-scores will be calculated as follows:  
z-score = (observed value - mean of the reference population) / standard deviation of the 
reference population. 
The calculation of the weight and height z-scores (and percentiles) is based on a SAS® program 
from the CDC1 which utilizes the United States 2000 CDC Growth Charts (ages 2 to <20 years; 
updated in the year 2000) as the reference population, developed with data from five national 
health examination surveys (Kuczmarski2). 
3.2. Analysis Populations and Subgroups 
3.2.1. Definition of Analysis Populations 
3.2.1.1 Intent to Treat (ITT) Population 
The ITT Population will consist of all randomized subjects who received at least one dose of 
study medication and have a baseline and at least one post-randomization ADHD-RS Total 
Score. All efficacy analyses will be conducted in the ITT Population. 
3.2.1.2 Safety Population  
The Safety Population will consist of all randomized subjects who received at least one dose of 
study medication and who have at least one post-dose safety assessment. Safety endpoints will 
be analyzed using the Safety Population. 
3.2.1.3 Per-Protocol (PP) Population 
The PP Population will consist of all randomized subjects who received at least one dose of 
study medication and have the baseline and at least one post-randomization ADHD-RS Total 
Score, and did not use prohibited medications deemed to impact efficacy. The PP Population will 
be used for sensitivity analyses of the primary efficacy endpoint. 
3.2.2. Definition of Subgroups 
No subgroup analyses are planned for this study. 


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3.3. Analysis Variables 
3.3.1. Efficacy Variables 
Efficacy variables will include: 
• Change from baseline in ADHD-RS total score 
• Change from baseline in ADHD-RS for hyperactivity/impulsivity score 
• Change from baseline in ADHD-RS for inattention score 
• Change from baseline in CGI-S score 
• CGI-I score 
3.3.2. Safety Variables 
Safety variables will include:  
• Incidence of treatment emergent adverse events (TEAEs) 
• Incidence of TEAEs leading to treatment discontinuation 
• Incidence of serious adverse events (SAEs) 
• Change from baseline in clinical laboratory values (hematology, chemistry) 
• Incidence of shift from baseline (hematology, chemistry, urinalysis)  
• Change from baseline in vital signs (systolic and diastolic blood pressure, pulse, 
respiratory rate and temperature)  
• Change and percent change from baseline in body weight, height, weight and height z-
scores, and weight and height percentiles 
• Change and percent change from baseline in CSHQ scores 
• Incidence of Columbia-Suicide Severity Rating Scale (C-SSRS) measured suicidal 
ideation and/or behavior  
• Change from baseline in ECGs 
3.4. Subjects Disposition and Evaluability 
3.4.1.  Subject Disposition 
Subject disposition will be summarized for all subjects randomized by treatment group and 
overall. Disposition will also be summarized separately for each age cohort. The number and 
percentage of subjects randomized, dosed, included in each analysis population, completing 
treatment and completing the study will be presented. The number and percentage of those who 
discontinue treatment and discontinue from the study, along with the reasons for discontinuation 
will be presented. The number of subjects screened and reasons for screen failure will also be 
summarized.  
 
A listing of subject disposition will also be presented.  
3.4.2.  Protocol Deviations 
Important protocol deviations will be summarized for all subjects in the ITT population by 
treatment group and overall, within and across age cohorts.  
 
All protocol deviations will be presented in a subject listing.  


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3.5. Demographics and Baseline Characteristics 
3.5.1.  Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be summarized for each of the analysis 
populations by treatment group, overall and separately for each age cohort. Frequencies and 
percentages will be presented for sex, race and ethnicity. Subjects of multiple races will be 
counted under each race once. Descriptive statistics will be presented for age, height, weight, and 
body mass index at baseline.   
 
All demographics and baseline characteristics will be presented in a subject listing.  
3.5.2.  ADHD Diagnosis 
ADHD diagnosis will be summarized for the ITT and PP Populations by treatment group and 
overall separately for each age cohort. Descriptive statistics will be provided for time since 
ADHD diagnosis (in months) and time since onset of ADHD symptoms (in months), if recorded. 
Frequencies and percentages will be presented for attention-deficit/hyperactivity disorder, 
conduct disorder, and oppositional defiant disorder from the MINI Kid diagnostic modules. 
Refer to Section 3.1.6 for the calculation of the time since ADHD diagnosis/symptoms onset. 
 
All ADHD baseline characteristics will be presented in a subject listing.  
3.5.3. Medical History 
All relevant medical history will be coded using Medical Dictionary of Regulatory Activities 
(MedDRA) Version 25.1 and will be classified by system organ class (SOC) and preferred term.  
Medical History will be summarized for the ITT population by treatment group and overall 
separately for each age cohort. The number and percentage of subjects having a medical 
condition by SOC and preferred term will be presented. Each subject will be counted once under 
each SOC and preferred term within SOC. The summary will be sorted alphabetically by SOC, 
and within SOC, by decreasing frequency of preferred term for all subjects. 
 
Medical history will be presented in a subject listing. 
3.6. Concomitant Medications 
3.6.1.  Prior and Concomitant Medications 
All reported prior and concomitant medications will be coded using the World Health 
Organization (WHO) Version B3 September 2022.   
 
Concomitant medications are defined as medications that are being taken while on study drug.  
Concomitant medications will be summarized for the ITT population by treatment group and 
overall separately for each age cohort. The number and percentage of subjects who took at least 
one concomitant medication as well as the number and percentage of subjects who took each 
type of medication will be presented by Anatomic Therapeutic Class (ATC) level 4 term and 
preferred term. Each subject will be counted once under each ATC level 4 term and preferred 
term within ATC level 4 term. The summary will be sorted alphabetically by ATC level 4 term, 


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and within ATC level 4 term, by decreasing frequency of preferred term for all subjects.  
 
All prior and concomitant medications will be presented in a subject listing. 
3.7. Study Drug Exposure and Compliance 
Study drug exposure and treatment compliance will be summarized for the ITT population by 
treatment group and overall separately for each age cohort. 
3.7.1. Study Drug Exposure 
Descriptive statistics will be provided for the total number of doses (capsules) received, total 
number of missed doses and duration of treatment (days). Number and percentage of subjects at 
each optimized dose level administered (i.e., 13.1 mg/2.6 mg, 26.1 mg/5.2 mg, 39.2 mg/7.8 mg, 
and 52.3 mg/10.4 mg) will be presented. Reasons for missed doses will also be summarized. 
3.7.2. Treatment Compliance 
Treatment compliance (%) will be classified into the following categories: < 80%, 80-100%, 
>100 to 120%, and > 120%. The number and percentage of subjects within each of these 
compliance categories will be presented. Refer to Section 3.1.6 for the calculation of the 
treatment compliance. 
3.8. Efficacy Analyses 
All efficacy analyses will be performed for the ITT Population by treatment group and overall 
and separately for each age cohort.   
3.8.1. Primary Efficacy Endpoint 
3.8.1.1 Change from Baseline in ADHD Rating Scale (ADHD-RS) Total Score 
Change from baseline in ADHD-RS total score will be analyzed using a mixed model repeated 
measures (MMRM) analysis of covariance (ANCOVA) model fitted using all observed data. In 
cases when ADHD-RS scores were not collected using an ePRO device, but were instead 
collected on a paper CRF, data from both modalities will be used in the primary analysis. A 
sensitivity analysis using only ePRO data will also be performed. Refer to Section 6 for the 
sample SAS code for the model. 
The dependent variable will be change from baseline in ADHD-RS (ADHD-RS IV for Cohort 1 
and ADHD-RS-V] for Cohort 2) total score for all post-baseline assessments for each subject. 
The model will include fixed effects for treatment, age cohort, gender (stratification factor for 
randomization), baseline ADHD-RS total score, analysis visit and analysis visit-by-treatment 
interaction as well as a random effect for the subject. The mixed model will utilize restricted 
maximum likelihood estimation with the Kenward-Roger method used to compute the 
denominator degrees of freedom for tests of fixed effects. The model will assume an 
unstructured covariance matrix. If the model does not converge under the unstructured 
covariance matrix when using the SAS PROC MIXED default Newton-Raphson algorithm, other 
numerical methods such as the Fisher scoring algorithm will be tried. 
 


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If the model using the unstructured covariance matrix still fails to converge, the following 
structures will be executed sequentially until convergence is attained: heterogeneous Toeplitz, 
heterogeneous Compound Symmetry, heterogeneous first-order autoregressive, Toeplitz, 
Compound Symmetry, and first-order autoregressive. If a structured covariance is used, then a 
robust sandwich estimator will be utilized for estimating the variance of the treatment effect 
estimate. 
 
The least-squares (LS) mean and 95% CI for the change from baseline in ADHD-RS total score 
will be extracted from the model for each post-baseline visit and presented by treatment group. 
The Visit 6 difference between least square (LS) means of Azstarys® and placebo will also be 
presented along with the corresponding 95% CI and two-sided p-value. Treatment difference 
statistics will also be presented for the earlier post-baseline visits, but considered descriptive 
only.  
  
The presentation will also include descriptive statistics of ADHD-RS total score for baseline and 
post-baseline visits, as well as the corresponding changes from baseline based on observed data. 
 
The primary estimand for this study is the difference in LS means of Azstarys® and placebo with 
respect to change from baseline in ADHD-RS total score at Visit 6, based on the primary 
endpoint MMRM model fitted to the ITT population. There will be no adjustments made for the 
use of prohibited therapies or other intercurrent events. The p-value associated with the primary 
estimand will be used to test the primary hypothesis of this study, that mean change from 
baseline to Visit 6 ADHD-RS total score for Azstarys® is different from that of placebo. If 
Azstarys® is shown to be statistically superior to placebo, then the superiority of Azstarys® to 
placebo will be tested for each cohort separately at a two-sided 0.05 level of significance.     
 
LS mean changes from baseline over time with 95% CI from the analysis model will be plotted 
by treatment group and presented side by side for each age cohort. 
3.8.1.2 Sensitivity Analyses of Primary Efficacy Results 
Robustness of the primary efficacy endpoint in the presence of missing data or early treatment 
discontinuations will be explored by the following sensitivity analyses. 
• MMRM on observed values (ePRO and paper) using multiple imputation method as 
described in Section 3.1.4.2.2 
• MMRM on ePRO data only using multiple imputation method as described in Section 
3.1.4.2.2 
• MMRM on observed values for subjects with non-missing ADHD-RS Total Score at 
Visit 6 (i.e., completers only case) 
• MMRM on observed values for subjects in PP Population 
 
If the primary analysis renders a significant treatment difference, a tipping point analysis will be 
performed in order to examine the sensitivity of inferences to departures from the missing at 
random (MAR) assumption. As missing values following early discontinuations may not be 
consistent with a MAR assumption, a sensitivity analysis using multiple imputation under a 
missing not at random (MNAR) assumption will be performed searching for a tipping point that 
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The imputed values for Azstarys® subjects’ visits post discontinuation will be made worse by 
adding a delta defined as k times the treatment difference between Azstarys® and placebo 
obtained from the MI steps described in Section 3.1.4.2.2, where k is a shift parameter that is 
incremented in order to identify the point at which the primary analysis result becomes non-
significant (the tipping point). Consideration will then be given to how plausible the imputed 
values are at the tipping point. If not plausible, then the conclusion for the primary analysis under 
the MAR assumption is supported.  
 
The tipping point analysis will be conducted as follows: 
 
Generate scenarios with varying values of k (e.g., 20%, 40%, etc.) until the significance of the 
prespecified analysis assuming MAR is overturned (e.g., from p-value <0.05 to p-value ≥0.05). 
The worsening by adding k times the treatment differences is applied to all the post-
discontinuation imputed values for each set of “complete” data from MI step 3 described in 
Section 3.1.4.2.2. As an example, if a subject from the Azstarys treatment group had 2 post-
discontinuation visits imputed, the values of both of these 2 imputed visits would be made worse 
by adding k times the Azstarys versus Placebo treatment difference at each of these 2 visits.  
 
Note that when k = 0%, this approach produces an analysis that is consistent with MAR and is 
equivalent to the primary analysis with MI. When k = 100%, this approach produces an analysis 
that is equivalent to “jump to reference,” since the treatment differences are removed. When k 
>100%, the analysis reflects a “worse‐than‐control” scenario.  
3.8.2. Secondary Efficacy Endpoints  
3.8.2.1 Change from Baseline in ADHD-RS for Hyperactivity/Impulsivity and 
Inattention 
If the primary endpoint comparison for change from baseline in ADHD-RS total score is 
significant overall and for Cohort 1, the superiority of Azstarys® to placebo with respect to the 
secondary efficacy endpoints will be tested for Cohort 1 only using a fixed sequence testing 
procedure (first for ADHD-RS for hyperactivity/impulsivity and then for ADHD-RS for 
inattention) to maintain Type 1 error control.     
Change from baseline in ADHD-RS for hyperactivity/impulsivity and ADHD-RS for inattention 
will be summarized in a MMRM ANCOVA analogous to the primary efficacy analysis described 
in Section 3.9.1.1, except that the dependent variables will be change from baseline in ADHD-
RS score for hyperactivity/impulsivity score and change from baseline in ADHD-RS score for 
inattention. 
3.8.2.2 Change from Baseline in CGI-S and CGI-I 
Descriptive statistics will be presented for baseline (Visit 2), all post baseline measurements 
(Visits 3 to 6), and changes from baseline to all post-baseline measurements of CGI-S by 
treatment group, overall and separately for each age cohort. A MMRM ANCOVA model will be 
fitted using all data as observed. The dependent variable will be change from baseline in CGI-S 
post-baseline assessments for each subject. The model will include fixed effects for treatment,  


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age cohort, gender (stratification factor for randomization), baseline CGI-S, analysis visit (Visit 
3, 4, 5, and 6), and analysis visit-by-treatment interaction as well as a random effect for the 
subject. The mixed model will be fitted in the same manner as described above for the primary 
endpoint analysis. From the MMRM model, the Visit 6 difference between LS means of 
Azstarys® and placebo will be presented along with the corresponding 95% CI and two-sided p-
value.  
Descriptive statistics will be presented for all post baseline measurements of CGI-I by treatment 
group, overall and for each age cohort separately. A MMRM ANOVA model will be fitted using 
all data as observed. The dependent variable will be CGI-I post-baseline assessments for each 
subject. The model will include fixed effects for treatment, age cohort, gender (stratification 
factor for randomization), baseline CGI-S, analysis visit (Visit 3, 4, 5, and 6), and analysis visit-
by-treatment interaction as well as a random effect for the subject. The mixed model will be 
fitted in the same manner as described above for the primary endpoint analysis. From the 
MMRM model, the Visit 6 difference between LS means of Azstarys® and placebo will be 
presented along with the corresponding 95% CI and two-sided p-value.  
Visit 6 CGI-I score will also be compared between treatment groups using a Cochran-Mantel-
Haenszel (CMH) chi square test within each age cohort stratified by gender. An overall CMH 
test will also be conducted stratified by gender and age (4 strata). 
3.9. Safety Analysis 
All safety analyses will be performed for the Safety Population by treatment group and overall 
and separately for each age cohort.   
3.9.1. Adverse Events 
All AEs will be coded using the MedDRA Version 25.1 and will be classified by SOC and 
preferred term. Severity will be graded as mild, moderate or severe.  
 
TEAEs are defined as AEs that begin in the time period following the first administration of 
study medication through 5 days after the last dose of study medication or existing AEs that 
worsen in the time period following the first dose of study medication through 5 days after the 
last dose of study medication. Investigator assessed causality to study drug will be categorized as 
“probably related”, “possibly related” or “unrelated”. For summary purposes, “probably related” 
and “possibly related” will be considered “related.” Any missing relationships will be considered 
as “related” as well.  
 
An overall summary of AEs will include the total number and percentage of subjects who 
experienced any TEAEs, SAEs, study drug-related TEAEs or SAEs, TEAEs leading to study 
drug discontinuation or study withdrawal, and TEAEs leading to death. In addition, the greatest 
severity of a TEAE experienced by each subject will be summarized.  
 
A summary of TEAEs will include the number and percent of subjects who experience at least 
one TEAE, as well as the number and percent of subjects who experience at least one TEAE 
within each specific SOC and PT. A summary by PT only will also be presented. SAEs, drug-
related TEAEs, TEAEs leading to study drug discontinuation or study withdrawal and TEAEs 
leading to death will be summarized similarly. TEAE incidences will also be summarized by 


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maximum severity grade. 
 
For the presentation of AE incidences, the SOCs will be sorted by decreasing frequency, and 
within SOC, the PTs will be presented by decreasing frequency.  
 
All AEs and SAEs, whether treatment emergent or not, will be listed for all subjects. A listing of 
AEs leading to treatment discontinuation will be provided as well.  
3.9.2. Clinical Laboratory Evaluation 
All laboratory results will be summarized using standard units. 
 
For all quantitative hematology and chemistry parameters listed in Section 2.2.4.2, descriptive 
statistics will be presented for observed and change from baseline values at End of 
Treatment/Early Termination.  
 
All clinical laboratory values will be presented in subject listings. Out of normal range values 
and clinically significant laboratory results will also be listed. 
 
All pregnancy, MPH and drug abuse test results will be presented in a subject listing.   
3.9.3. Vital Signs 
Descriptive statistics for systolic and diastolic blood pressures, pulse rate, respiratory rate and 
temperature will be presented for the observed and change from baseline values at each analysis 
visit, using the visit windows defined in Section 3.1.5.  
 
The incidence of clinically notable vital signs will also be summarized by analysis visit. These 
will be defined as systolic blood pressure ≥ 130 mmHg, diastolic blood pressure ≥ 90 mmHg, 
pulse rate ≥ 130 beats/min, and respiratory rate ≥ 30 breaths/min. 
 
All vital sign results will be presented in a subject listing. 
3.9.4. Body Weight and Height 
Descriptive statistics for body weight (in kg) and height (in cm) will be presented for the 
observed, change and percent change from baseline values at each analysis visit.  
 
Additionally, weight and height z-scores and percentiles will be summarized.  The z-score 
system expresses the anthropometric value as a number of standard deviations (SDs) below or 
above the mean of a reference population. A positive z-score indicates that a child’s 
weight/height is above average while a negative z-score indicates that it is below average. Since 
z-scores are standardized values of a normal distribution with mean 0 and SD of 1, there is a 
direct correlation to percentiles. A percentile indicates the percentage of observations that fall 
below a certain value of the reference population. A z-score of 0 corresponds to the 50th 
percentile in the reference population; a z-score of ±1 corresponds to approximately the 16th and 
84th percentiles, respectively; and a z-score of ±2 corresponds to approximately the 2nd and 98th 
percentiles, respectively. Refer to Section 3.1.6 for the calculation of  z-scores and percentiles.  


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The descriptive statistics will include n, mean, standard deviation (SD), median, 1st and 3rd 
quartile (Q1, Q3), and range (minimum and maximum). In addition, descriptive statistics will be 
tabulated by sex and optimized dose. 
 
All body weight and height results will be presented in a subject listing. 
3.9.5. Physical Examinations 
All physical examination results will be presented in a subject listing. 
3.9.6. ECGs 
Descriptive statistics will be presented for the observed and change from baseline values of heart 
rate, and RR and QT intervals at End of Treatment/Early Termination. Frequencies and 
percentages will also be provided for overall ECG interpretation (normal; abnormal, not 
clinically significant; abnormal, clinically significant). 
 
All ECG results will be presented in a subject listing. 
3.9.7. CSHQ 
The CSHQ total Sleep Disturbance Score and the change and percent change from baseline 
CSHQ score will be analyzed descriptively by treatment overall and by age cohort. A MMRM 
ANCOVA model will be fitted using all data as observed. The dependent variable will be change 
from baseline to all post-baseline assessments of the CSHQ score for each subject. The model 
will include fixed effects for treatment, age cohort, gender (stratification factor for 
randomization), baseline CSHQ, analysis visit (3, 4, 5, and 6), and analysis visit-by-treatment 
interaction as well as a random effect for the subject. From the MMRM model, the Visit 6 
difference between LS means of Azstarys® and placebo will be presented along with the 
corresponding 95% CI. The MMRM analysis of the change from baseline CSHQ scores will also 
be conducted separately for each age cohort. 
Descriptive statistics will also be presented by analysis visit for the change and percent change 
from baseline in scores for Bedtime Resistance, Sleep Onset Delay, Sleep Duration, Sleep 
Anxiety, Night Wakings, Parasomnias, Sleep Disordered Breathing, and Daytime Sleepiness by 
treatment overall and by age cohort. 
All CSHQ results will be presented in a subject listing. 
3.9.8. C-SSRS 
C-SSRS outcomes at each visit will be summarized by the number and percentage of subjects in 
each treatment group with the following: suicidal ideation, suicidal behavior, and suicidal 
ideation or behavior (ideation and behavior combined). 
All C-SSRS results will be presented in a subject listing. 


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3.10. Interim Analysis: Blinded Sample Size Re-Estimation 
3.10.1. Analysis Objective 
A blinded sample size re-estimation will be conducted for Cohort 1 (4 - <5 years and 10 months) 
when approximately 50% of Cohort 1 subjects complete their Visit 6 assessment or discontinue 
prior. The common within-group SD for the change from baseline to 28 days post-baseline in 
ADHD-RS total score, which was assumed to be 10 in the initial sample size calculation, will be 
re-estimated. The sample size of 130 for Cohort 1 may be increased, if the SD estimate is larger 
than initially assumed.   
3.10.2. Analysis Method 
Change from baseline in ADHD-RS total score through end of treatment will be calculated for 
each ITT subject who completed their Visit 6 assessment or discontinued prior. The common 
within-group standard deviation (σ) will be estimated for the change from baseline in ADHD-RS 
total score to Visit 6 using the methodology of Gould and Shih3 :  
 
𝜎𝜎2  ≈ 
𝑛𝑛−1
𝑛𝑛−2 (𝑠𝑠2 −
∆2
4 )   
 
where n=number of subjects included in interim analysis, s=standard deviation of pooled sample, 
and ∆=6, the treatment difference under the alternative hypothesis. 
 
Two separate estimates of σ will be derived. One including only those subjects who had an 
ADHD-RS total score at Visit 6, and the other including those who had an ADHD-RS total score 
at Visit 6 and those who discontinued prior to Visit 6.  For those who discontinued and did not 
have an ADHD-RS total score at Visit 6, their last ADHD-RS total score prior to discontinuation 
will be used. From the two estimates of σ, the one that is largest will be used for the sample size 
re-estimation.   
 
This adjusted variance estimate was recommended by Friede and Kieser4 and is similar to the 
estimate proposed by Zucker5. Friede and Kieser6 and Waksman7  showed this estimate to be 
superior to the one obtained from the EM algorithm which was also proposed by Gould and 
Shih3. All statistical analyses will be performed using SAS® Version 9.4. Subjects will not be 
identified by treatment group and only an overall standard deviation will be calculated. If the 
estimate of σ for the change from baseline to Visit 6 in ADHD-RS total score is greater than 10 
but less than or equal to 12, the independent statistician will recommend an increase in the 
sample size to 142 for Cohort 1. If the SD is less than or equal to 10 or greater than 12, Cohort 1 
will  retain its original planned size of 130. The sponsor will only receive the recommendation to 
either keep or increase the sample size of Cohort 1 (see Section 3.10.4). The sponsor will not be 
provided with the estimated value of σ. Since the study will remain masked for the sample size 
assessment, no alpha penalty for the final analysis will be incurred.  
3.10.3. Maintaining the Treatment Masking 
Only the study data required for the blinded sample size re-estimation (BSSR) will be sent to 
Suzanne Granger, the independent statistician at PROMETRIKA. This will include a transfer of 
the ADHD-RS data as well as datasets which contain the randomization date for each subject and 


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dosing information to confirm subject inclusion in the ITT analysis set. No information regarding 
the randomized treatments or treatments received will be sent to PROMETRIKA. Those 
performing the BSSR will remain blinded. 
 
The data used in the BSSR will be as up-to-date as possible and as clean as possible since this 
will not be a locked database at the time of the data snapshot. During the BSSR, all ongoing 
subjects will complete their scheduled study assessments and subject enrollment will continue. 
 
At PROMETRIKA, all data, programs, and output related to the BSSR will be kept in a secure 
electronic study folder with access restricted to only those personnel who will perform and 
validate the BSSR analyses. Restricted access on this study folder will be maintained until after 
the study database is locked. Only once the final data analysis has been completed will this 
information be transferred to the Sponsor. 
3.10.4. Distribution of Results 
Suzanne Granger will inform Lucia Ayra, Clinical Supplies Manager and Ron Tashjian, Sr. 
Director Clinical Operations, and copy (cc: via email) Charles Oh, Chief Medical Officer and 
Santhi Adusumilli, Clinical Trial Manager of the recommendation resulting from the BSSR in a 
memorandum which will be sent via email as a password protected file. The only information 
that will be communicated is: 
 
• increase the sample size to 142 for Cohort 1, or 
• retain the original planned sample size of 130 in Cohort 1. 
 
Lucia Ayra and Ron Tashjian will be responsible for informing Corium personnel, as needed. 
4. MODIFICATIONS FROM STATISTICAL METHODS IN THE 
PROTOCOL  
The following are modifications in this SAP to the statistical methods described in the study 
protocol.  
• The definition of ITT Population was modified to require a baseline ADHD-RS Total 
Score, since primary efficacy endpoint is change from baseline in ADHD-RS total score. 
• Shifts from normal range (low, normal, high) in laboratory values from baseline to post-
baseline assessments will not be analyzed. 
• C-SSRS data at each visit will be summarized by the number and percentage of subjects 
in each treatment group with suicidal ideation or suicidal behavior. Changes from 
baseline will not be analyzed. 
• Baseline CGI-S will be included as a covariate in the MMRM analyzing CGI-I post-
baseline assessments. 
• In addition to analyses of the CSHQ Total Sleep Disturbance Score, descriptive statistics 
will also be presented by analysis visit for the change and percent change from baseline 
in scores for Bedtime Resistance, Sleep Onset Delay, Sleep Duration, Sleep Anxiety, 


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Night Wakings, Parasomnias, Sleep Disordered Breathing, and Daytime Sleepiness by 
treatment overall and by age cohort. 
 
 


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5. REFERENCES  
1. CDC SAS Program. Centers for Disease Control and Prevention (CDC), Division of Nutrition, 
Physical Activity, and Obesity, Growth Chart Training: 
https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm. 
2. Kuczmarski RJ, Ogden CL, Guo SS, et al. 2000 CDC growth charts for the United States: 
Methods and development. National Center for Health Statistics. Vital Health Stat 11(246). 
2002. 
3. Gould AL, Shih WJ. Sample size re-estimation without unblinding for normally distributed 
outcomes with unknown variance. Communications in Statistics – Theory and Methods 1992; 
21:10, 2833-2853. 
4. Zucker DM, Wittes JT, Schabenberger O, Brittain E. Internal pilot studies II: Comparison of 
various procedures. Statistics in Medicine 1999; 18:3493-3509. 
5. Friede T, Kieser M. On the inappropriateness of an EM algorithm based procedure for blinded 
sample size re-estimation. Statistics in Medicine 2002; 21:165-176. 
6. Kieser M, Friede T. Simple procedures for blinded sample size adjustment that do not affect 
the type I error rate. Statistics in Medicine 2003; 22:3571-3581. 
7. Waksman J. Assessment of the Gould-Shih procedure for sample size re-estimation. 
Pharmaceutical Statistics 2007; 6:53-65. 
 
 
 
 


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6. SAMPLE SAS CODES