Clinical trial NCT03292952
Conditions: ADHD
Sponsor: Zevra Therapeutics
Start date: 2017-12-20; Completion date: 2018-05-16
Enrollment: 155 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is a multicenter, dose-optimized, double-blind, randomized, placebo-controlled, parallel efficacy laboratory classroom study with KP415 in children with Attention-Deficit/Hyperactivity Disorder (ADHD).

Detailed description:
The study will consist of a Screening Period, an Open-Label Dose Optimization Phase, a Double-Blind Treatment Phase and a Follow-Up Visit, as follows:

* Screening Period: Subjects will undergo a screening period up to 49 days prior to entering into the Open-Label Dose Optimization Phase.
* Open-Label Dose Optimization Phase: During the Dose Optimization Phase, subjects will be titrated to doses of 20, 30 or 40 mg KP415 based on tolerability and best individual dose-response in the opinion of the Investigator.
* Double-Blind Treatment Phase: Eligible subjects will be randomized to receive single daily doses of KP415 or Placebo for 7 days according to a randomization schedule. The dose of KP415 given in the Treatment Phase will be the same as the optimized dose of KP415 at the end of the Dose Optimization Phase. All subjects will receive their assigned treatment daily for 7 days. The dose will be the same at each day of the Treatment Period. Efficacy and safety assessments will be performed after the last dose of the Treatment Period.
* Follow-Up Visit: 3 ±2 days after administration of the last dose of the Treatment Phase, subjects will enter a Follow-Up Visit to evaluate safety parameters.

Arms: arm 1: KP415 (serdexmethylphenidate \[SDX\] Cl/ d-methylphenidate \[d-MPH\] HCl) oral capsule:

28/6 mg SDX/d-MPH (molar equivalent to 20 mg d-MPH HCl), 42/9 mg SDX/d-MPH (molar equivalent to 30 mg d-MPH HCl), 56/12 mg SDX/d-MPH (molar equivalent to 40 mg d-MPH HCl) arm 2: Placebo oral capsule arm 3: KP415 (serdexmethylphenidate \[SDX\] Cl/ d-methylphenidate \[d-MPH\] HCl) oral capsule:

28/6 mg SDX/d-MPH (molar equivalent to 20 mg d-MPH HCl), 42/9 mg SDX/d-MPH (molar equivalent to 30 mg d-MPH HCl), 56/12 mg SDX/d-MPH (molar equivalent to 40 mg d-MPH HCl)
Interventions: intervention 1: KP415 oral capsule intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: Daily dose intervention 2: Daily dose

Protocol documents:
SAP_002.pdf: 
 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
1 
CONFIDENTIAL 
 
A Multicenter, Dose-Optimized, Double-Blind, Randomized, Placebo-Controlled, Parallel 
Efficacy Laboratory Classroom Study with KP415 in Children with Attention-
Deficit/Hyperactivity Disorder 
 
Protocol: KP415.E01 
 
Version Number:2.0 
 
18 JUN 2018 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
KemPharm, Inc. 
1180 Celebration Blvd, Suite 103 
Celebration, FL 34747 
Phone: 321-939-3416 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


18 June, 2018
June 18, 2018


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
3 
CONFIDENTIAL 
TABLE OF CONTENTS 
1.1 
List of Abbreviations ..................................................................................................... 4 
1.2 
Protocol Summary ........................................................................................................ 6 
1.3 
Study Design Schematic ............................................................................................... 8 
1.4 
Study Objectives ........................................................................................................... 8 
1.5 
Statistical Hypotheses and Endpoints .......................................................................... 9 
1.6 
Sample Size Determination ........................................................................................ 12 
1.7 
Data Sources .............................................................................................................. 12 
1.8 
Documentation Convention ....................................................................................... 13 
1.9 
Verification of Results ................................................................................................ 13 
1.10 
Subject Disposition ..................................................................................................... 13 
1.11 
Populations for Analyses ............................................................................................ 13 
1.12 
Statistical Analyses ..................................................................................................... 14 
1.12.1 
General Approach ...................................................................................................... 14 
1.12.2 
Analysis of the Primary Efficacy Endpoint(s) .............................................................. 15 
1.12.3 
Analysis of the Secondary efficacy Endpoint(s) .......................................................... 16 
1.12.4 
Safety Analyses........................................................................................................... 17 
1.12.5 
Laboratory Data ......................................................................................................... 19 
1.12.6 
Vital Signs ................................................................................................................... 19 
1.12.7 
Physical Exam ............................................................................................................. 19 
1.12.8 
12-lead ECG ................................................................................................................ 19 
1.12.9 
Prior and Comcomitant Medications ......................................................................... 19 
1.12.10 
Pregnancy Tests ......................................................................................................... 19 
1.12.11 
URINE Alcohol/Drugs of Abuse .................................................................................. 19 
1.12.12 
Urine MPH Screen ...................................................................................................... 20 
1.12.13 
Drug Accountability and Compliance ......................................................................... 20 
1.12.14 
C-SSRS ......................................................................................................................... 20 
1.12.15 
Abuse Potential Safety Analyses ................................................................................ 20 
1.12.16 
Exploratory Analyses .................................................................................................. 20 
1.12.17 
Baseline Descriptive Statistics .................................................................................... 21 
1.12.18 
Planned Interim Analyses ........................................................................................... 21 
1.12.19 
Sub-Group Analyses ................................................................................................... 21 
1.13 
References .................................................................................................................. 22 
1.14 
Appendices ................................................................................................................. 23 
1.14.1 
Appendix 1. Table of Contents for Statistical Tables, Figures, and Listings ............... 23 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
4 
CONFIDENTIAL 
1.1 
LIST OF ABBREVIATIONS 
 
AE
Adverse Event
ADHD
Attention-deficit hyperactivity disorder
ADHD-RS-5
Attention-deficit hyperactivity disorder rating scale 5
AIC
Akaike’s Information Criteria
ALT
Alanine transaminase
AST
Aspartate transaminase
BIC
Schwarz’s Bayesian Criteria
BMI
Body Mass Index
CGI-S
Clinical Global Impressions–Severity
CGI-I
Clinical Global Impressions–Improvement
CI
Confidence Interval
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of Variation
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOS
End of Study 
ET
Early Termination
FU
Follow-up
ITT
Intent-to-Treat
LLN
Lower Limit of Normal
LS
Least-square
MAR
Missing at Random
MCAR
Missing Completely at Random
MedDRA
Medical Dictionary of Regulatory Activities
MMRM
Mixed-Effect Model Repeated Measure model
MPH
Methylphenidate
PERMP
Permanent Product Measure of Performance
PERMP-A
Permanent Product Measure of Performance-Attempted
PERMP-C
Permanent Product Measure of Performance-Correct
PP
Per-Protocol
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
Q1
25th Percentile (1st Quartile)
Q3
75th Percentile (3rd Quartile)
QTcF 
Time between the start of the Q wave and the end of the T wave (QT interval) in the 
heart's electrical cycle, corrected for heart rate with Fridericias’s formula 
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SE
Standard Error
SKAMP
Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
5 
CONFIDENTIAL 
SKAMP-A
SKAMP-Attention
SKAMP-C
SKAMP-Combined
SKAMP-D
SKAMP-Deportment
TEAE
Treatment-Emergent Adverse Event
ULN
Upper Limit of Normal
WREMB-R
Weekly Rating of Evening and Morning Behavior - Revised
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
6 
CONFIDENTIAL 
1.2 
PROTOCOL SUMMARY 
Name of Company
KemPharm, Inc.
Study Product
KP415 (a prodrug of d-methylphenidate, d-MPH)
Protocol Number
KP415.E01
Protocol Title
A Multicenter, Dose-Optimized, Double-Blind, Randomized, 
Placebo-Controlled, Parallel Efficacy Laboratory Classroom Study 
with KP415 in Children with Attention-Deficit/Hyperactivity 
Disorder 
Study Objectives
Primary: To determine the efficacy of KP415 compared to placebo 
in treating children 6-12 years old with ADHD in a laboratory 
classroom setting. 
Secondary: 1. To determine the onset and duration of the clinical 
effect of KP415 in treating ADHD in children 6-12 years old in a 
laboratory classroom setting. 2. To determine the safety and 
tolerability of KP415 compared to placebo in treating children 6-
12 years old with ADHD in a laboratory classroom setting. 
Study Design
The study is a multicenter, dose-optimized, double-blind, 
randomized, placebo-controlled, parallel efficacy laboratory 
classroom study with KP415 in children with Attention-
Deficit/Hyperactivity Disorder (ADHD). The study will consist of a 
Screening Period, an Open-Label Dose Optimization Phase, a 
Double-Blind Treatment Phase and a Follow-Up Visit, as follows: 
• 
Screening Period: Subjects will undergo a screening 
period up to 49 days prior to entering into the Open-Label Dose 
Optimization Phase. 
• 
Open-Label Dose Optimization Phase: During the Dose 
Optimization Phase, subjects will be titrated to doses of 20, 30 or 
40 mg open-label KP415 based on tolerability and best individual 
dose-response in the opinion of the Investigator. 
• 
Double-Blind Treatment Phase: Eligible subjects will be 
randomized at Visit 5 (Baseline) to receive single daily doses of 
KP415 or Placebo for 7 days according to a randomization 
schedule. The dose of KP415 given in the Treatment Phase will be 
the same as the optimized dose of KP415 at the end of the Dose 
Optimization Phase. All subjects will receive their assigned 
treatment daily for 7 days. The dose will be the same at each day 
of the Treatment Period. Efficacy and safety assessments will be 
performed after the last dose of the Treatment Period (Visit 6). 
• 
Follow-Up Visit: 3 ±2 days after administration of the last 
dose of the Treatment Phase, subjects will enter a Follow-Up Visit 
to evaluate safety parameters. 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
7 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Duration of Study Participation
Subjects will participate in the study as outpatients for up to 85 
days. 
Number of Subjects
An appropriate number of subjects will enter the Screening 
Period to enroll approximately 176 subjects in the Open-Label 
Dose Optimization Phase, and to randomize approximately 140 
subjects in the Double-Blind Treatment Phase, with the intention 
to complete with approximately 126 subjects. 
Number of Sites
5 sites in the United States of America
Study Population
Children 6-12 years old with Attention-Deficit/Hyperactivity 
Disorder who meet the inclusion/exclusion criteria. 
Efficacy Endpoints
The primary efficacy evaluation is based on SKAMP and PERMP 
scores at pre-dose, and at 0.5. 1, 2, 4, 8, 10, 12, and 13 hours 
post-dose during the full laboratory classroom day at Visit 6. The 
baseline SKAMP score is measured at pre-dose at Visit 5. 
 
Primary Efficacy Variable: 
o 
Average of the change from baseline (measured at Visit 5) of 
the SKAMP-C scores collected post-dose across the laboratory 
classroom day at Visit 6. 
 
Secondary Efficacy Variables: 
o 
Change from baseline (measured at Visit 5) of the SKAMP-C 
scores measured at each time point on the laboratory 
classroom day at Visit 6.  
o 
The serial measures at different times post-dosing will be 
used to determine onset and duration of the clinical effect of 
KP415. 
o 
Change from baseline of the scores measured at each time 
point and the average of the scores collected across the 
laboratory classroom day at Visit 6, for the following 
endpoints: 
 
SKAMP-D and SKAMP-A scores 
 
PERMP scores 
  PERMP-A and PERMP-C scores 
  WREMB-R scores (total score, and morning and evening 
subscore) at Baseline (Visit 2), Visit 5 and Visit 6. 
 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
8 
CONFIDENTIAL 
1.3 
STUDY DESIGN SCHEMATIC 
 
 
 
1.4 
STUDY OBJECTIVES 
 
Primary: 
 
To determine the efficacy of KP415 compared to placebo in treating children 6-12 years old with ADHD in a 
laboratory classroom setting. 
Secondary: 
 
To determine the onset and duration of the clinical effect of KP415 in treating ADHD in children 6-12 years old 
in a laboratory classroom setting. 
 
To determine the safety and tolerability of KP415 compared to placebo in treating children 6-12 years old with 
ADHD in a laboratory classroom setting. 
 
The primary interest of Study KP415.E01 is to assess efficacy of KP415 compared to placebo in treatment of children 6-
12 years with ADHD in a laboratory classroom setting, which is an analog setting of regular school classrooms. 
 
The study intends to employ the 13-Item SKAMP rating scale as the primary efficacy measurement for the assessment of 
behavioral impairment for ADHD children in the laboratory classroom setting.  The SKAMP was initially developed in 1992 
by Swanson, Kotkin, Agler, M-Flynn, and Pelham (Swanson, 1992), and has been used mainly in a laboratory classroom 
setting in which the application of a labor intensive coding system associated with the scale is possible (Greenhill et al., 
1996; McBurnett et al., 1997; Swanson et al., 1998; Wigal et al., 1998; Swanson & Greenhill, 1999).  The SKAMP has 
demonstrated sound psychometric properties, including moderate to high test-retest reliabilities, concurrent validity, 
and discriminant validity, especially in those situations where a non-treatment or placebo condition is involved.  To date, 
the SKAMP has been widely and successfully utilized in several clinical trials of moderate sample sizes to assess treatment 
efficacy in ADHD children with respect to their behavioral impairments in the laboratory classroom setting with reference 
to placebo (McCracken et al., 2003; Wigal et al., 2005, Biederman et al., 2007). 
 
In this study, nine assessment sessions (one pre-dose and eight post-dose) will occur over the laboratory classroom 
assessment day (i.e., Visit 6), and the SKAMP rating scale will be evaluated at different times, or in other words, 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
9 
CONFIDENTIAL 
measured repeatedly. Therefore, the study intends to analyze the SKAMP rating scale using a Mixed-effects Model for 
Repeated Measures (MMRM) so that the issue of within-subject measurement correlation can be handled 
appropriately. The MMRM model is commonly used in clinical trials in which the design with repeated measures is 
employed. To address the primary objective of this study, the MMRM model will define the average of the change from 
baseline (measured before the first dose in the Treatment Phase [at pre-dose of Visit 5]) over the eight post-dose 
session scores (post-dose at Visit 6), as the primary efficacy comparison of KP415 vs. placebo treatments, whereas the 
comparison of KP415 vs. placebo at each session will be used to address the secondary efficacy objective of the study. 
 
1.5 
STATISTICAL HYPOTHESES AND ENDPOINTS 
 
 
Primary: 
o The primary hypothesis is that the test drug is superior (mean change in post-dose SKAMP-C 
scores from baseline are lower) when compared to placebo. The baseline measurement is 
collected pre-dose at Visit 5, after 2 days of no drug administration. SKAMP-C scores are then 
collected across the laboratory classroom day at Visit 6. We will evaluate efficacy by looking at 
the direction of effect. The null and alternative hypotheses are:  
 
o 
𝐻଴: ∆𝑆𝐾𝐴𝑀𝑃−𝐶
തതതതതതതതതതതതതതതതത௖௢௡௧௥௢௟−∆𝑆𝐾𝐴𝑀𝑃−𝐶
തതതതതതതതതതതതതതതതത௧௘௦௧= 0 
𝐻஺: ∆𝑆𝐾𝐴𝑀𝑃−𝐶
തതതതതതതതതതതതതതതതത௖௢௡௧௥௢௟−∆𝑆𝐾𝐴𝑀𝑃−𝐶
തതതതതതതതതതതതതതതതത௧௘௦௧≠0 
The hypothesis test is the main effect of the primary efficacy analysis model and will be based 
on the residual error of the model. The treatment-by-time interaction will be pre-specified in 
the primary efficacy model regardless of the statistical significance of the interaction term.  
 
Primary Efficacy Endpoint(s):  
o The primary efficacy endpoint will be the mean change from the pre-dose baseline measurement at 
Visit 5 and SKAMP-C (∆𝑆𝐾𝐴𝑀𝑃−𝐶 
തതതതതതതതതതതതതതതതതത) scores collected post-dose across the laboratory classroom day at 
Visit 6. 
 
The Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale (SKAMP) scale is a validated 
rating of subjective impairment of classroom behaviors. It is comprised of 13 items (grouped 
under the subcategories of attention, deportment, quality of work, and compliance) on which 
subjects are rated according to a 7-point scale (0 = normal to 6 = maximal impairment) by 
trained study personnel (Swanson 1999). The SKAMP-Combined (SKAMP-C) score is obtained 
by summing the rating values for the 13 items of the SKAMP scale. 
 
The SKAMP scale is collected at Baseline (pre-dose at Visit 5 after 2 days of no drug 
administration) and at 9 time points during Visit 6: pre-dose, 0.5, 1, 2, 4, 8, 10, 12, and 13 hours 
post-dose. 
 
 
Secondary Efficacy Endpoint(s): 
o  ∆𝑆𝐾𝐴𝑀𝑃−𝐶 
തതതതതതതതതതതതതതതതതതscores from baseline at each time point on the laboratory classroom day at Visit 6.  
o The serial measures of SKAMP-C scores at different times post-dosing will be used to determine onset 
and duration of the clinical effect of KP415. 
o The mean change from baseline at each time point collected across the laboratory classroom day at 
Visit 6 for the following endpoints: 
 
SKAMP-D and SKAMP-A scores 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
10 
CONFIDENTIAL 
 
SKAMP-Deportment (SKAMP-D) score is a measure of behavior and is comprised of 4 
items. 
 
SKAMP-Attention (SKAMP-A) score is a measure of attention and is comprised of 4 
items. 
 
PERMP scores 
 
The Permanent Product Measure of Performance (PERMP) is an individually calibrated 
five-page mathematics worksheet consisting of 400 problems. The PERMP score is 
calculated by dividing the number of correct problems (PERMP-C) by the number of 
problems attempted (PERMP-A). 
 
The PERMP score is collected at Baseline (pre-dose at Visit 5 after 2 days of no drug 
administration) and at 9 time points during Visit 6: pre-dose, 0.5, 1, 2, 4, 8, 10, 12, and 
13 hours post-dose. 
 
PERMP-A (Number of problems attempted) and PERMP-C scores (Number of problems correct) 
o WREMB-R (Overall), Morning, Evening  
 
The 11-item Weekly Rating of Evening and Morning Behavior - Revised (WREMB-R) 
questionnaire is a parent-rated questionnaire that was developed to assess behaviors for their 
severity during the morning hours (3 items) and evening hours (8 items) (Carlson 2007). The 
possible score for each item ranges from 0 (no difficulty) to 3 (a lot of difficulty). 
 
The WREMB-R is collected at Visit 2, Visit 5, and Visit 6. The assessment at Visit 2 is the baseline 
assessment (after washout of ADHD medications, if applicable); the assessments at Visits 5 and 
6 are evaluations at the end of the Dose Optimization and Treatment Phase, respectively. 
WREMB-R scores will be compared separately for the Dose Optimization (Visit 5 versus baseline 
at Visit 2) and Treatment Phase (Visit 6 versus baseline at Visit 2). 
*We expect that secondary endpoint results will follow the primary endpoint in direction. 
 
Efficacy Baseline: For the primary and secondary SKAMP and PERMP efficacy endpoints, Baseline is considered 
Visit 5. For all other endpoints, Baseline is considered Visit 2 (or closest time-point prior to first dose of open-
label study medication). 
 
 
Safety Endpoint(s): 
o Treatment-Emergent Adverse Events (TEAEs) 
 
Adverse Events with new onset during the study between the initiation of study drug and 5 
days after the last dose of study drug will be considered TEAEs. 
o Laboratory tests  
 
Total Hematology as well as differential and Coagulation: red blood cell count, white blood cell 
count with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), 
hemoglobin, hematocrit and platelets, Prothrombin Time (PT) and Partial Thromboplastin Time 
(PTT) 
 
Serum Chemistry: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
albumin, alkaline phosphatase, bicarbonate, total bilirubin, blood urea nitrogen, 
phosphorus (inorganic) calcium, chloride creatinine phosphokinase, creatinine, gamma 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
11 
CONFIDENTIAL 
glutamyl transferase, glucose, lactate dehydrogenase, potassium, sodium, total protein, 
Screening only thyroid stimulating hormone (TSH), and uric acid. 
 
Urinalysis results: specific gravity, presence of hemoglobin, albumin, glucose, pH, and leukocyte 
esterase  
o Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, and oral temperature) 
o Height, weight, and BMI (will be derived using height and weight) 
o Frequency of body system results. Results include: Normal; Abnormal, Not Clinically Significant; or 
Abnormal, Clinically Significant 
o ECG parameters  
 
Electrocardiograms (ECGs) will be interpreted overall as: Normal or Abnormal 
 
The following ECG parameters are collected: 
 
Heart rate (bpm) 
 
PR interval (ms) 
 
RR interval (ms)  
 
QRS complex (ms) 
 
QT interval (ms)  
 
QTc interval (ms) [Fridericia’s formula - QTcF] 
 
ECGs are obtained at the Screening visit and at Early Termination (ET) or Follow-Up (FU) visit. 
o C-SSRS 
 
Suicidal ideation will be assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS, 
Pediatric Version) (Posner et al. 2010). There are 5 items asked during the subject’s lifetime and 
during the past 6 months. 
 
The C-SSRS is collected at all study visits. 
 
 
Exploratory Endpoints: 
o ADHD-RS-5 (Overall), Hyperactivity/Impulsivity subscale, Inattentiveness subscale 
 
The Attention-deficit hyperactivity disorder rating scale 5 (ADHD-RS-5) is an 18-item scale 
based on Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) (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-5 scores range from 0 to 54. The 18 items 
are then divided into two 9-item subscales: One for hyperactivity/impulsivity and the other for 
inattentiveness. 
 
The ADHD-RS-5 is collected at Visits 2 (Baseline), 3, 4, and 5. 
o CGI-S 
 
The Clinical Global Impressions–Severity (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 is collected at Visits 2 (Baseline), 3, 4, and 5. 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
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o CGI-I 
 
The Clinical Global Impressions–Improvement (CGI-I) is scored from 1 (very much improved) to 
7 (very much worse). 
 
The CGI-I is collected at Visits 2 (Baseline), 3, 4, and 5. 
o 
Conners 3-P 
 
The Conners 3-P (short form) is a 43-item parent/guardian/caregiver report that provides 
evaluation of 6 assessment subscales: Inattention (IN), Hyperactivity/Impulsivity (HY), Learning 
Problems (LP), Executive Functioning (EF), Aggression (AG) and Peer Relations (PR). In addition, 
there are 2 validity/response style subscales: Positive Impression (PI) and Negative Impression 
(NI). Each item is scored on a 4-point scale ranging from Not true at all (Never, Seldom) to Very 
much true (Very often, Very frequently). The additional questions and scores beyond item 43 
on the forms will not be used. 
 
For each item, sites will use a software package (www.mhs.com/MHS-
Assessment?prodname=conners3) to calculate raw total scores. The score for each of the items 
contributes uniquely to one of the eight sub-scores, 6 assessment subscales and 2 
validity/response style subscales. 
 
Using the software, the raw total scores of the 6 assessment subscales will then be converted 
to T-scores specific for the age and gender of the child being evaluated. The DSM-5 scoring 
option will be used. T-scores for each of the 6 assessment subscales will be assessed. The 2 
validity/response style subscales (raw total scores) will also be captured in the database. 
 
The Conners 3-P is collected at Visits 2 (Baseline), 3, 4, 5, and 6. 
1.6 
SAMPLE SIZE DETERMINATION 
 
Drug efficacy studies are sized to be able to detect at least the Minimum Clinically Important Difference (MCID). MCID 
has not been established for the SKAMP-C scores. However, Rai et al. (Rai et al. 2015) noted “0.5 standard deviations 
has been suggested to correspond to the MCID in a number of studies“. Biederman et al. (Biederman et al. 2007) also 
noted, in a similar study on lisdexamfetamine dimesylate, “Previous studies of amphetamine products using the 
SKAMP-D to assess efficacy in children with ADHD have disclosed an effect size of greater than .50.” 
 
Assuming a mean difference between test and control for ΔSKAMP-C of 0.5 units and a standard deviation (SD) of 1.0, 
126 subjects would need to complete the study, assuming 80% power when testing a significance level of α= 0.05 (2-
sided two-sample z-test).  
 
Assuming an approximate 20% dropout during the Open-Label Dose Optimization Phase, 176 subjects are planned to 
be enrolled in the Open-Label Dose Optimization Phase. We assume that there will be an approximate 10% dropout 
rate during the Double-Blind Treatment Phase. Therefore, approximately 140 subjects will be randomized into the 
Double-Blind Treatment Phase with the intention to complete with approximately 126 subjects.  
 
Subjects will be randomized (1:1) into two groups: KP415 (N~63) or Placebo (N~63). Randomization will be stratified by 
site. 
 
1.7 
DATA SOURCES 
 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
13 
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At each study site, data will be entered on the electronic Case Report Forms (eCRFs) stored on IBM Clinical 
Development (run by Merge Healthcare, an IBM company). Laboratory evaluations will be received from a central 
laboratory and will be integrated with the clinical database. A 12-lead ECG will be read by a centralized ECG laboratory 
(ERT) and results will be transferred to the DCRI and integrated with the clinical database. One master list of 
randomized trial assignments will be uploaded to IBM Clinical Development from DCRI Statistics. Prior to database lock, 
programmed computer edit checks will be run against the database to identify discrepancies and verify reasonableness 
of the data. Queries to resolve discrepancies will be generated and resolved by the sites. Periodically, DCRI Statistics 
will receive or download from DCRI Data Export Services the eCRF database as Clinical Data Interchange Standards 
Consortium Study Data Tabulation Model (CDISC SDTM version 3.1.3) datasets. CDISC Analysis Data Model (ADaM 
version 2.1) datasets will be created by DCRI Statistics for production of tables, figures, and listings. All planned 
reporting will be based off of CDISC datasets, but in the case of emergent safety data, some reporting may occur from 
the raw eCRF data. All programs written to create analysis datasets and perform analyses will be validated according to 
SOPs established by the DCRI Statistical Programming group.  
 
1.8 
DOCUMENTATION CONVENTION 
 
The statistical analyses described in this SAP, as well as production of tables, listings, and figures will be performed 
using SAS®, version 9.4 or higher (SAS Institute, Cary, NC). Additional statistical software may be used as needed. 
 
1.9 
VERIFICATION OF RESULTS 
 
All tables, listings, and graphs will be verified and reviewed before considered final. The verification process will ensure 
that the numbers are produced by a statistically valid method and that the execution of the computations is correct. 
Qualified statisticians or statistical programmers employed by the DCRI who have not been previously involved in the 
production of the original programming will perform the verification procedures. Methods of verification include 
independent programming, prior to issuance of the draft statistical report, of all analysis datasets/ADaM and 
comparison to data listings. Tables, listings, and graphs will be reviewed for accuracy, consistency with this analysis 
plan, consistency within tables/listings/graphs, and consistency with corresponding output. Once verification is 
complete, all documentation of the verification process will be filed in a statistical programming documentation 
notebook as required by the Statistical Standard Operations Procedures of the DCRI. 
 
1.10 SUBJECT DISPOSITION 
 
The disposition of subjects (number randomized, number who received any amount of the randomly assigned 
treatment, number completing study drug administration, number who withdrew consent or discontinued from study 
drug early, and number lost to follow-up, and number who completed the trial) will be summarized overall and by 
treatment arm. The number of subjects screened for inclusion and a breakdown of reasons for exclusion will be 
summarized. The timing and reasons for early discontinuation of study drug and/or withdrawal from the study will be 
summarized by treatment group. A listing of all patients discontinued from the study after enrollment, broken down by 
site and treatment group will be provided. The listing will include: reason for discontinuation, treatment group, 
duration of treatment, and whether or not the blind was broken. Also, for patients who discontinued from the study 
after enrollment, a listing of adverse events will be provided. Lastly, the number of subjects with major protocol 
violations will be summarized and listed. 
 
1.11 POPULATIONS FOR ANALYSES 
 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
14 
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 
Intent-to-Treat (ITT) Population: All randomized subjects who receive at least one dose of double-blind study 
medication and have at least one of the SKAMP-C assessments at Visit 6. Subjects will be grouped according to 
their randomized allocation (KP415 or placebo), regardless of whether the allocated therapy was administered 
or switched. 
 
Per-Protocol (PP) Population: ITT subjects who received the morning dose of double-blind study medication at 
the laboratory test session, who have all SKAMP-C assessments at Visit 6, who did not miss more than 2 days of 
therapy during the double-blind Treatment Phase, and did not use prohibited medications during the double-
blind treatment period. Subjects included in the PP population will have received the study drug assigned to 
them by their randomization in a manner consistent with the intention of the protocol; subjects who 
prematurely discontinue study drug because of non-compliance or unwillingness to comply with the 
procedures required by the protocol will be excluded. 
 
Overall Safety Population: All subjects that entered the Open-Label Dose Optimization phase and received at 
least one dose of open-label study medication and had at least one post-dose safety assessment. This will 
include subjects who were randomized as well as those subjects who were never randomized. This population 
will be used for safety analyses.  
 
Baseline analyses, including demographics and other subject characteristics, will be performed using all 
populations. Further details are provided in section 1.12.17. All efficacy analyses will be performed using both 
the ITT and PP populations. All safety analyses will be performed using the Overall Safety population.  
 
In each analysis population, the distribution of dose levels will be reported as follows: 
 
For the Dose Optimization Phase, the number of subjects in each week by dose level and the average* 
dose level between study visit intervals. 
 
For the Treatment Phase, the number of subjects in each treatment group by dose level. 
 
*Calculation of the average dose level: For the intervals between Visit 2 and Visit 3 and between Visit 3 and Visit 
4, we will first get the number of days in the interval (the denominator). The formula will be as follows: date dose 
ended – date dose started +1. To calculate the sum of the doses during that interval (the numerator), we will first 
derive the number of days in the interval that study drug was taken. Using the number of days in the interval, we 
will subtract the number of days that the subject reported as having a missed dose. We will then take the 
number of days remaining and multiply that by the dose administered to get the sum. If there are any overdoses 
reported, we will add the additional dose to the numerator. We will then use the formula: sum of all doses in the 
interval/number of days in the interval = average dose. For the interval between Visit 4 and Visit 5, we will 
subtract the number of washout days from both the numerator and denominator to derive the average using the 
same formula. 
 
1.12 STATISTICAL ANALYSES 
 
1.12.1 
GENERAL APPROACH 
 
o Statistical significance: Statistical comparisons will be performed using two-sided significance tests. An alpha 
level of 0.05 will determine significance (unless otherwise noted).  
 
o Descriptive statistics:  
o Continuous variables will be presented as n, mean, standard deviation, coefficient of variation (CV%), 
standard error (SE), median, Q1, Q3, and minimum and maximum. For comparisons of treatment 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
15 
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groups, if data is normally distributed we will use the t-test with unequal variances. If data is not 
normally distributed, we will use the non-parametric Wilcoxon/Mann-Whitney rank-sum test. 
o Categorical variables will be presented as percentage (number). Group comparisons will use the 
conventional chi-square test or Fisher’s Exact Test. 
o Binary variables will be presented as percentage (number). Group comparisons will use the 
conventional chi-square test or Fisher’s Exact Test. 
 
o Handling of Missing Data: 
 
Missing data will be assessed in the primary and secondary efficacy analyses. Every effort will be made to 
minimize the occurrence of missing data. However, if data which are not efficacy related are missing, the 
general approach will be to use only data which are complete with regard to the variable(s) and time point(s) 
being analyzed for descriptive summaries, or the evaluation of safety endpoints.  
 
The Mixed-Effect Model Repeated Measure (MMRM) approach will be used in the primary and secondary 
efficacy analyses. Despite careful planning and study conduct, the occurrence of incomplete data cannot be 
completely eliminated. MMRM is based on the assumption of data that is missing at random (MAR). The 
MMRM uses all available data. If a score is missing, it has no effect on other scores from that same subject. Any 
missing data will be assumed to be MAR. As such, the MMRM approach provides valid inference and no 
additional steps need to be taken to handle the missing data. 
 
 
o Handling of Missing Items or Scales: 
 
In the context of health outcomes in the format of rating scales, either the entire scale can be missing (unit 
non-response) or several items from the scale can be missing (item non-response). If <20% of items are missing 
from a scale, the items will be imputed using the mean of the remainder of the items. If >= 20% of items are 
missing from a scale, the entire scale will be considered missing and will be excluded from the analysis.  
 
 
1.12.2 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The primary efficacy endpoint treatment effect is the change from baseline in all post-dose SKAMP-C scores over the 
day during Visit 6. Though the SKAMP questionnaire uses the Likert scale, the SKAMP-C, which aggregates the scores 
from all the domains, it will be treated as a continuous measure. 
 
To estimate the difference between test (KP415) and control (placebo), a repeated measures analysis using MMRM will 
be performed. The MMRM model will include post-dose time (session), treatment, the interaction of time and 
treatment, and site as fixed effects, and subject as random effect; and, the baseline SKAMP-C scores will be pre-
specified in the model as a covariate. We will present the model-adjusted average change from baseline of all post-
dose SKAMP-C scores for each treatment group and treatment group differences (KP415-placebo) with standard errors 
(SEs) and 95% confidence intervals (CIs). SAS procedure PROC MIXED will be utilized to conduct the primary efficacy 
analysis. If the model specified is not estimable, the compound symmetry type of the covariance matrix will be used.  
The SAS code for the MMRM model is as follows: 
 
proc mixed data=adef method=reml; 
Class trt02p usubjid atptn siteid; 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
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Model chg= trt02p atptn trt02p*atptn base siteid/ ddfm=residual solution chisq; 
repeated atptn /type= toep  group=trt02p local subject=usubjid rcorr; 
parms / ols;   
Lsmeans trt02p/diff cl pdiff alpha=0.05; 
run; 
 
trt02p=treatment group; usubjid=subject ID number; atptn= assessment time point; siteid=site; chg=change in SKAMP-
C score from Baseline, base = SKAMP-C Baseline (pre-dose at Visit 5) score 
 
 
Below is a sample table of results: 
 
KP415 (N=  )
Placebo (N= )
Treatment Difference: 
KP415-Placebo 
Pre-Dose (Baseline Visit 5)
      Mean (SD) 
xx.x (xx.x)
xx.x(xx.x)
Pre-Dose (Visit 6)
     Mean (SD) 
xx.x (xx.x)
xx.x(xx.x)
Average Post-Dose Change 
from Baseline 
    LS Mean (SE)
xx.x (xx.x)
xx.x (xx.x)
xx.x (xx.x)
    95% Confidence Interval
xx.x – xx.x
xx.x – xx.x
xx.x – xx.x
    p-value
x.xxx
 
To check if the assumptions of the MMRM model are met, residuals will be examined through histograms, normal 
plots, Shapiro-Wilk’s test, and plots of the residuals versus fitted values. If there is strong evidence that the 
assumptions are not satisfied (defined as both the p-value<0.05 and W statistics <0.85), the non-parametric Wilcoxon 
Rank-Sum test will be utilized to perform between-treatment comparisons for the average score and at each post-dose 
time point.  
 
1.12.3 
ANALYSIS OF THE SECONDARY EFFICACY ENDPOINT(S) 
 
The secondary endpoint analyses described in this section will be performed if the primary endpoint hypothesis test is 
significant. If the primary endpoint hypothesis test is not significant, only descriptive statistics will be generated at each 
time point during Visit 6 and for the average of the scores collected during Visit 6. The following will be reported: n, 
mean, standard deviation, coefficient of variation (CV%), standard error (SE), median, Q1, Q3, and minimum and 
maximum. 
 
If the primary endpoint hypothesis test is significant, the following additional analyses will be performed: 
 
o The mean difference in SKAMP-C scores from baseline measured at each time point at Visit 6. Similar to the 
primary endpoint analysis, MMRM will be used to estimate the least square means, SEs and their 
corresponding 95% confidence intervals (CIs) between treatment groups for each time point at Visit 6.  
 
Below is a sample table of results: 
 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
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Time point 
Change from Baseline (Visit 5 pre-dose) in SKAMP-C Score 
 
Visit 6 
LS Mean (SE) 
Difference in LS Mean (SE) 
95 % Confidence Interval 
Unadjusted 
p-value 
 
KP415 (N= ) 
Placebo (N= ) 
KP415-Placebo 
KP415-Placebo 
 
Pre-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x – xx.x 
x.xxx 
0.5 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x – xx.x 
x.xxx 
1 hour post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x – xx.x 
x.xxx 
2 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x – xx.x 
x.xxx 
4 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x – xx.x 
x.xxx 
8 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x – xx.x 
x.xxx 
10 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x – xx.x 
x.xxx 
12 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x – xx.x 
x.xxx 
13 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x – xx.x 
x.xxx 
Mean difference in 
change from baseline 
across all post-dose 
time-points 
 
 
xx.x(xx.x) 
xx.x – xx.x 
x.xxx 
o Onset and duration of the clinical effect of KP415. The onset of effect is defined as the first post-dose 
assessment time showing statistical significance (p<0.05) between KP415 and placebo as measured by the 
SKAMP-C Score. The duration of treatment effect is defined as the length of the time interval, such that 
statistical significance was reached at each time point of this interval. Onset and duration results will be 
presented in a table as well as graphically displayed. 
 
o All other secondary efficacy endpoints. Scores and subscores of SKAMP and PERMP will be treated as 
continuous data. Individual time point estimates will be determined using the same model analysis methods 
and output described for the SKAMP-C endpoint. 
 
o Raw means ± SE of changes from Baseline of secondary efficacy endpoints (scores and subscores of SKAMP and 
PERMP) will be plotted versus time by treatment. Baseline (Visit 5) and Visit 6 LS Means ± SE of change from 
Baseline of secondary efficacy endpoints (scores and subscores of SKAMP and PERMP) will be plotted versus 
time by treatment. The statistical significance of treatment differences at each time point will be indicated. 
o 
WREMB-R scores will be analyzed as continuous measures. Scores will be examined separately for the Open-
Label Dose Optimization Phase and the Double-Blind Treatment Phase. For the Open-Label Dose Optimization 
Phase, change in mean scores between Baseline (Visit 2) and Visit 5 will be analyzed using a paired t-test. Mean 
scores and 95% confidence intervals will be plotted by visit. For the Double-Blind Treatment Phase, changes in 
mean scores from baseline between treatment groups will be analyzed using a two-sample t-test. Mean scores 
and 95% confidence intervals will be plotted by visit and treatment. The statistical significance of treatment 
differences at Visit 6 between treatment groups will be indicated. 
 
1.12.4 
SAFETY ANALYSES 
 
All analyses of safety will be conducted using the Overall Safety Population. The frequencies of adverse events (AEs), 
the results of laboratory assessments, physical examinations, vital signs, ECG results, and the frequency of suicidal 
ideation or behavior (assessed using the C-SSRS) will be summarized descriptively by treatment arm and overall. All AE-


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
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related data will be summarized separately for the Dose Optimization Phase and Treatment Phase Frequencies of AEs 
in each phase will be expressed in percentage relative to the respective number of subjects in each phase (a 
denominator for the Dose Optimization Phase and another denominator for the Treatment Phase). Safety analyses 
performed during the Treatment Phase will be presented by treatment group (KP415 vs. Placebo) as well as overall. 
AEs will be coded in accordance with the Medical Dictionary for Regulatory Activities (MedDRA). AEs will be graded 
with regard to severity according to criteria defined in the Common Terminology Criteria for Adverse Events v4.0 
(CTCAE). Each AE will be counted once only for a given subject. A listing of AEs will be provided including: treatment 
arm, sex, age, preferred term (PT), study phase, onset date/time, time to onset, stop date/time, duration, action taken 
with study treatment, severity, outcome, relationship to study treatment, and whether it was a serious adverse event 
(SAE).  
 
AEs with new onset during the study between the initiation of study drug and 5 days after the last dose of study drug 
will be considered treatment-emergent (TEAEs). This will include any AE with onset prior to initiation of study drug and 
increased severity after the treatment initiation. TEAEs will be summarized by system organ class and preferred term, 
and by treatment arm. The most common (occurring in >2% of subjects) TEAEs will be summarized by preferred term 
and by Dose Optimization and Treatment phases. In the Treatment phase, the most common TEAEs occurring more 
frequently in subjects in the KP415 treatment group than in subjects on placebo will be presented. Overall incidence 
rates (regardless of severity and relationship to study drug) and incidence rates for moderate or severe AEs will be 
summarized by treatment arm. A summary of SAEs and AEs leading to early discontinuation from the study will be 
presented by treatment arm. SAE rate will be calculated overall and by treatment arm. To compare the SAE rate by 
treatment arm, we will perform a Fisher’s Exact test.  
 
AEs will also be flagged for potential for abuse based on the following MedDRA PTs: Euphoria-related terms (Euphoric 
mood; Elevated mood; Feeling abnormal; Feeling drunk; Feeling of relaxation; Dizziness; Thinking abnormal; 
Hallucination; Inappropriate affect), Terms indicative of impaired attention, cognition, and mood (Somnolence; Mood 
disorders and disturbances), Dissociative/psychotic terms (Psychosis; Aggression; Confusion and disorientation), and 
Related terms not captured elsewhere (Drug tolerance; Habituation; Drug withdrawal syndrome; Substance-related 
disorders). Abuse-related AEs will be categorized by PT and tabulated by treatment group and dose. A listing of abuse-
related AEs will be provided including: treatment group, time of onset, duration of event, dose of drug taken, severity, 
action taken, and outcome. 
 
Post-treatment changes from baseline for all safety laboratory tests, vital signs, and ECGs will be summarized using 
descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum and maximum). The eight statistics will be 
given at each time point for current reading and for change from baseline. For physical exam, vital signs (weight, height, 
BMI), ECG, and lab/urinalysis results, the last observation (ET/FU) will be compared to the baseline result. If any 
laboratory tests, vital signs, or ECGs are collected at an unscheduled visit post-baseline, results will be included in 
listings. Those subjects with significant laboratory abnormalities will be identified in data listings.  
 
For the purposes of safety analyses, Baseline is considered the closest time point prior to first dose of open-label study 
medication. For the safety measurements of height, weight, BMI, chemistry and hematology panels, urinalysis, and 
ECGs, baseline is measured at the Screening visit. For all other tests, baseline is measured at Visit 2. If tests are 
scheduled to be measured at both Screening and Visit 2 and Visit 2 tests are missing, screening measurements will be 
used as the baseline. 
 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
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Additional safety analyses include descriptive statistical summaries of abnormal laboratory values, frequency 
distributions and shift tables summarizing abnormal laboratory values, vital signs, concomitant medications, prior 
medications, medical history, and pregnancy test results. 
 
1.12.5 
LABORATORY DATA 
 
Descriptive statistics for baseline and end of study (EOS) will be generated for abnormal laboratory data (hematology 
and chemistry values). Additionally, shift tables will be presented. The shift tables tabulate the number of lab values 
determined to be “Normal” and “Abnormal” at baseline and post-baseline time points. The classifications on shift 
tables will categorize lab values as “Normal” when they are in acceptable range, using a combination of clinician 
judgment specific to each lab test, and the reference ranges. Laboratory values outside the normal range will be graded 
on the Labs Listing as 1x, 2x, 3x, 5x, or 10x the upper limit (or .5x, 1x the lower limit) of normal value based on 
appropriate increases or decreases. Laboratory data will also be summarized graphically to show the magnitude and 
changes in individual subject values over time relative to normal ranges. Details of any abnormalities will be listed. 
 
1.12.6 
VITAL SIGNS 
 
Descriptive statistics for observed values and changes from baseline will be tabulated by treatment group at each visit. 
Vital sign data plots will be produced to graphically display data summaries.  
 
1.12.7 
PHYSICAL EXAM 
 
Results (Normal; Abnormal, Not Clinically Significant; or Abnormal, Clinically Significant) for each body system (general 
appearance, skin, lymph nodes, head and neck, lungs, cardiovascular system, abdomen, musculoskeletal/extremities, 
mental status, neurological system, and thyroid) will be presented by baseline and EOS. Results will be tabulated by 
treatment group and overall. 
 
1.12.8 
12-LEAD ECG 
 
Overall interpretation (Normal, Abnormal NCS, and Abnormal CS) will be summarized by treatment group and overall 
(where applicable) at the Screening and EOS Visit (ET or FU) along with corresponding shifts between Screening and 
EOS assessments. In addition, descriptive statistics for observed values and changes from Baseline in ECG 
measurements will be tabulated by treatment group at the EOS Visit. If an ECG measurement was repeated, only the 
repeated measurement will be presented. Details of any abnormalities will be listed. 
 
1.12.9 
PRIOR AND COMCOMITANT MEDICATIONS 
 
Prior and concomitant medication use will be tabulated by generic drug name.  
 
1.12.10 
PREGNANCY TESTS 
 
Pregnancy test results at baseline, Visit 5, and EOS will be listed for female subjects of child-bearing potential. 
 
1.12.11 
URINE ALCOHOL/DRUGS OF ABUSE 
 
Urine alcohol/drugs of abuse screen results at Screening will be listed. 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
20 
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1.12.12 
URINE MPH SCREEN 
 
Urine MPH screen results (positive or negative) at Screening, Visit 2 and Visit 5 will be listed. 
 
1.12.13 
DRUG ACCOUNTABILITY AND COMPLIANCE 
 
Compliance will be tabulated by visit (weekly from Visit 3 through Visit 6), study phase (Dose Optimization and 
Treatment Phase), and overall. Percent compliance by visit will be calculated by dividing the number of missed doses 
reported at that visit by the number of days between that visit and the previous visit. For the interval between Visit 4 
and Visit 5, 2 days will be subtracted for the wash-out period.  
 
Number of missed doses and reason for missed dose will be listed by subject at Visits 3, 4, 5, and 6. Drug accountability 
for abuse potential will be tabulated by subject and will include any instances of overdose (more capsules taken than 
indicated), lost/stolen medication, and unused drug not returned by the end of the trial. 
1.12.14 
C-SSRS 
 
The number of instances where the response is “yes” to items 1 and 2 will be tabulated as well as the number of 
subjects excluded due to suicidality. 
 
1.12.15 
ABUSE POTENTIAL SAFETY ANALYSES 
In accordance with the 2017 FDA Guidance for Industry, Assessment of Abuse Potential of Drugs, the following analyses 
will be performed in the Overall Safety Population: 
 
o Systematic categorization and tabulation of AEs that are abuse potential-related, using the MedDRA Preferred 
Terms, including euphoria-related terms, terms of altered attention, cognition and mood, and 
dissociative/psychotic terms (FDA Guidance 2017, Sellers and Romach 2017). An analysis by dose, age, and 
gender; and by case, in order to understand the incident that led to the AEs, establish the time at which AEs 
appear following drug administration, the duration of the AEs, and which AEs overlap temporally. 
o Analysis of subject’s study drug accountability assessments that may provide information about the incidence of 
signals suggestive of abuse, such as substance use disorders, overdose, drug diversion or drug loss. 
1.12.16 
EXPLORATORY ANALYSES 
o Changes in ADHD severity will be compared from week to week in the ITT and PP population based on ADHD-
RS-5, CGI-S, CGI-I, and Conners 3-P. 
o For the ADHD-RS-5, CGI-S, and CGI-I endpoints, we will present the projection trajectories as a function 
of time (i.e. by study visit), without treatment group comparison. Change in mean scores between 
Baseline (Visit 2) and subsequent study visits will be analyzed using a paired t-test. Means and 95% 
confidence intervals of endpoints will be plotted by visit. 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
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o To assess changes in ADHD severity between treatment arms, the Conners 3-P T-scores will be analyzed 
as continuous measures. The treatment effects will be examined at all assessment time points. Scores 
will be examined separately for the Open-Label Dose Optimization Phase and the Double-Blind 
Treatment Phase. For the Open-Label Dose Optimization Phase, change in mean scores between 
Baseline (Visit 2) and subsequent study visits will be analyzed using a paired t-test. Mean scores and 
95% confidence intervals will be plotted by visit. For the Double-Blind Treatment Phase, changes in 
mean scores from baseline between treatment groups will be analyzed using the previously described 
repeated measures model. LS Means ± SE will be plotted versus visit by treatment. The statistical 
significance of treatment differences at Visit 6 will be indicated. 
o Note: For the Conners 3-P, the statistical analysis will be performed with the 6 assessment subscale T 
scores. For the 2 total raw validity/response style subscale scores, descriptive statistics only will be 
calculated, by treatment group. 
o 
No imputation or adjustments for missing data will be performed for the exploratory endpoints. 
1.12.17 
BASELINE DESCRIPTIVE STATISTICS 
 
Key baseline clinical characteristics will be summarized by treatment group within all study populations (ITT, PP, and 
Overall Safety). Characteristics include: age, gender, ADHD subtype, ethnicity, race, weight, height, ADHD rating scale, 
and CGIS. Baseline is considered the closest time-point prior to first dose of open-label study medication. 
 
Counts and percentages will be presented for categorical variables. Continuous variables will be presented as medians 
(Q1, Q3). For continuous variables, data will be assessed as to whether they are normally distributed using the SW test. 
If there is no evidence of lack of normality (SW p>0.05), then the two treatment arms will be compared statistically 
using the t-test with unequal variances. If the SW indicates that there is evidence that the variable is not normally 
distributed (SW p<0.05), then the non-parametric Wilcoxon rank sum test will be used to compare treatment groups. 
To compare categorical variables between treatment groups, chi-square or Fisher’s exact tests will be used as 
appropriate. 
 
1.12.18 
PLANNED INTERIM ANALYSES  
 
There are no planned interim analyses.  
 
1.12.19 
SUB-GROUP ANALYSES 
 
The following subgroups have been pre-specified: 
 
Gender 
 
Site  
 
Dose 
 
Age (ages 6-9 and ages 10-12) 
 
The estimated treatment effect of KP415 within each of the subgroup sets listed above will be examined. The subgroup 
analyses will be conducted using the same analysis model outlined for the primary efficacy endpoint. The subgroup 
analyses will performed for the ITT population 
 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
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1.13 REFERENCES 
 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). 
Arlington, VA, American Psychiatric Association, 2013. 
Biederman J, Boellner SW, Childress A, Lopez FA, Krishnan S, Zhang Y. Lisdexamfetamine dimesylate and mixed 
amphetamine salts extended-release in children with ADHD: a double-blind, placebo-controlled, crossover analog 
classroom study. Biol Psychiatry. 2007; 62(9): 970-6. 
Busner J, Targum SD. The Clinical Global Impressions Scale: Applying a research tool in clinical practice. Psychiatry 4:28–
37, 2007. 
Carlson GA, Dunn D, Kelsey D, Ruff D, Ball S, Ahrbecker L, Allen AJ. A pilot study for augmenting atomoxetine with 
methylphenidate: safety of concomitant therapy in children with attention-deficit/hyperactivity disorder (2007). Child 
Adolesc Psychiatry Ment Health. 1(1):10. 
Food and Drug Administration, Assessment of Abuse Potential of Drugs. (2017, January). Guidance for Industry, U.S. 
Department of Health and Human Services, Center for Drug Evaluation and Research, Washington, DC. 
Rai SK, Yazdany J, Fortin PR and Aviña-Zubieta JA. Approaches for estimating minimal clinically important differences in 
systemic lupus erythematosus. Arthritis Research & Therapy. 2015; 17(1): 143. 
Posner K, Brent D, Lucas C, Gould M, Stanley B, Brown G, Fisher P, Zelazny J, Burke A, Oquendo M, Mann J. Columbia-
Suicide Severity Rating Scale (C-SSRS) Pediatric Baseline Version. New York, NY: The Research Foundation for Mental 
Hygiene, Inc., 2010. 
Sellers EM, Romach MK. Categorization of Abuse Potential-Related Adverse Events. Clin Pharmacol Drug Dev. 2017 Oct 
11. doi: 10.1002/cpdd.394. [Epub ahead of print]. 
Swanson JM, Agler D, Fineberg E, Wigal S, Flynn S, Fineberg K, Quintana Y and Talebi H, The University of California, 
Irvine, Laboratory School Protocol for Pharmacokinetic and Pharmacodynamic Studies. in: L Greenhill, B Osman (Eds.) 
Ritalin. 2nd ed. Mary Ann Liebert, Larchmont, NY; 1999:405–430. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
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1.14 APPENDICES 
 
1.14.1 
APPENDIX 1. TABLE OF CONTENTS FOR STATISTICAL TABLES, FIGURES, AND LISTINGS 
 
Tables 
 
Subject Screening and Summary of Reasons for Exclusion 
Summary of Reasons for Early Termination 
Subject Disposition Summary, All Enrolled Subjects 
Visit Completion Status by Treatment Group 
Shift in Dose Levels Between Visits During the Open-Label Dose Optimization Phase 
Average Dose Levels Between Visits During the Open-Label Dose Optimization Phase 
Overview of Dose Levels During the Treatment Phase 
Protocol Violations by Treatment Group 
Demographics and Baseline Characteristics by Treatment Group 
Medical History by Treatment Group 
Overview of Adverse Events  
Overview of Serious Adverse Events  
All Treatment Emergent Adverse Events by System Organ Class and Preferred Term  
Most Common Treatment Emergent Adverse Events in the Open-Label Dose Optimization Phase 
Most Common Treatment Emergent Adverse Events by Treatment Group in the Treatment Phase 
Abuse-Related Adverse Events by Dose  
Shift from Baseline to Worst Post-Baseline Value: Hematology Tests by Treatment Group 
Shift from Baseline to Worst Post-Baseline Value: Chemistry Tests by Treatment Group 
Shift from Baseline to Worst Post-Baseline Value: Urinalysis by Treatment Group 
Shift from Baseline to Worst Post-Baseline ECG Results by Treatment Group 
Summary of Hematology Tests by Treatment Group 
Summary of Chemistry Tests by Treatment Group 
Summary of Urinalysis by Treatment Group 
Overall Interpretation of ECG and Shift from Baseline by Treatment Group 
Summary of ECG Results by Treatment Group 
Summary of Vital Signs by Treatment Group 
Summary of Vital Signs (Weight, Height, BMI) by Treatment Group 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
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Physical Exam Body System Results by Treatment Group 
Prior Medications by Generic Name by Treatment Group 
Concomitant Medications by Generic Name by Treatment Group 
Summary of C-SSRS by Treatment Group 
Descriptive Summary of SKAMP-C Endpoint 
Descriptive Summary of SKAMP-D and SKAMP-A Endpoints 
Descriptive Summary of PERMP Endpoint 
Descriptive Summary of PERMP-A and PERMP-C Endpoints 
Descriptive Summary of WREMB-R Endpoints 
Descriptive Summary of ADHD-RS-5 Endpoints 
Descriptive Summary of CGI-I and CGI-S Endpoints 
Descriptive Summary of Conners 3-P Endpoints 
MMRM Analysis of SKAMP-C Endpoint – Primary Analysis 
Mean SKAMP-C Scores by Time Point 
Analysis of the Onset and Duration of the Clinical Effect of KP415 
Mean SKAMP-D and SKAMP-A Endpoints by Time Point 
Mean PERMP Endpoint by Time Point 
Mean PERMP-A and PERMP-C Endpoints by Time Point 
Mean WREMB-R Scores – Open-Label Dose Optimization Phase 
Mean WREMB-R Scores – Treatment Phase 
Mean ADHD-RS-5 Scores – Open-Label Dose Optimization Phase 
Mean ADHD-RS-5 Scores – Treatment Phase 
Mean CGI Scores – Open-Label Dose Optimization Phase 
Mean CGI Scores – Treatment Phase 
Mean Conners 3-P T Scores – Open-Label Dose Optimization Phase 
Mean Conners 3-P T Scores – Treatment Phase 
 
Listings 
Subject Disposition, Discontinued Subjects – Overall Safety Population 
All Adverse Events – Enrolled Subjects Population 
Adverse Events – Overall Safety Population 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
25 
CONFIDENTIAL 
Adverse Events, Discontinued Subjects – Enrolled Subjects Population 
Treatment Emergent Adverse Events – Overall Safety Population 
Abuse-Related Adverse Events – Overall Safety Population 
Study Drug Compliance for Abuse Potential –Overall Safety Population 
Subjects Excluded from the Efficacy Analysis –Overall Safety Population  
Protocol Violations – Overall Safety Population 
Pregnancy Test – Enrolled Subjects Population 
Urine Alcohol/Drugs of Abuse Screen – Screened Subjects Population 
Urine MPH Screen – Enrolled Subjects Population 
Significant Laboratory Abnormalities –Overall Safety Population 
Significant ECG Abnormalities – Overall Safety Population 
 
Figures 
Bar Plot of Dose Level Changes during Dose Optimization Phase  
Worst Post-Baseline vs. Baseline Laboratory (Scaled by Normal Values): Hematology Tests  
Worst Post-Baseline vs. Baseline Laboratory (Scaled by Normal Values): Hematology Tests by Treatment Group 
Worst Post-Baseline vs. Baseline Laboratory (Scaled by Normal Values): Chemistry Tests  
Worst Post-Baseline vs. Baseline Laboratory (Scaled by Normal Values): Chemistry Tests by Treatment Group 
Worst Post-Baseline vs. Baseline Laboratory (Scaled by Normal Values): Urinalysis Tests  
Worst Post-Baseline vs. Baseline Laboratory (Scaled by Normal Values): Urinalysis Tests by Treatment Group 
Worst Post-Baseline vs. Baseline ECG Results  
Worst Post-Baseline vs. Baseline ECG Results by Treatment Group 
Summary Plot of Vital Signs 
Summary Plot of Vital Signs by Treatment Group 
WREMB-R Scores Over Time 
ADHD-RS-5 Scores Over Time 
CGI Scores Over Time 
Conners 3-P Scores- Open-Label Dose Optimization Phase Over Time 
Treatment Difference Over Time in SKAMP-C 
Treatment Difference Over Time in SKAMP-D 
Treatment Difference Over Time in PERMP 


 
 
 
 
 
 
 
 
Statistical Analysis Plan for study KP415.E01 
 
 
26 
CONFIDENTIAL 
Treatment Difference Over Time in PERMP-A 
Treatment Difference Over Time in PERMP-C 
Treatment Difference Over Time in WREMB-R Scores 
Treatment Difference Over Time in Conners 3-P Scores Treatment Phase  

SAP_003.pdf: 
 
Duke Clinical Research Institute 
Clinical Trials Statistics 
Form Number:   ST-F2-005 
Page 1 of 2 
Version:  4.0 
Effective Date:   31 Jan 2017 
Form Title: Agreement to Planned Analyses  
 
ST-F2-005, V 4.0, Effective 31 Jan 2017 
Agreement to Planned Analyses 
 
Trial:  KP415.E01 
 
Analysis Plan Date:  8/8/2018 
 
Purpose of analysis plan(s):  ☐  DMC/Interim analysis or safety report 
 
 
 
 
☐  Substudy analysis 
☐  Final (main trial) analysis 
☐  Confirmatory analysis 
☐  Operational reporting 
☐  Central Statistical Surveillance  
☐  Outcomes registry analysis  
☒  Addendum to analysis plan version 2.0 
☐  Other:  Click here to enter text. 
 
In signing this document, I am confirming that I have reviewed and approve the analysis plan(s) 
referenced above. 
 
Faculty/Reviewing Biostatistician (signature): 
 
 
Faculty/Reviewing Biostatistician’s Title: 
Associate Professor of Biostatistics 
Printed name: 
Sheng Luo 
Date: 8/9/2018 
 
 
 
Principal Investigator (signature): 
 
 
Principal Investigator’s Title and Affiliation: 
Professor of Psychiatry & Behavioral Sciences 
 
Printed name: 
Scott H. Kollins 
Date: 09AUG2018 
 
 
 
Sponsor Representative (signature): 
 
 
Sponsor Representative’s Title and Institution: 
 
 
Printed name: 
Rene A Braeckman 
Date: 
 
Sponsor approval required whenever sponsor requests to review the analysis plan. 
9 August 2018
Vice President, Clinical Development
Kempharm, Inc


 
Duke Clinical Research Institute 
Clinical Trials Statistics 
Form Number:   ST-F2-005 
Page 2 of 2 
Version:  4.0 
Effective Date:   31 Jan 2017 
Form Title: Agreement to Planned Analyses  
 
ST-F2-005, V 4.0, Effective 31 Jan 2017 
 


 
CONFIDENTIAL 
1 
 
A Multicenter, Dose-Optimized, Double-Blind, Randomized, Placebo-Controlled, 
Parallel Efficacy Laboratory Classroom Study with KP415 in Children with 
Attention-Deficit/Hyperactivity Disorder 
 
Protocol: KP415.E01 
 
08 AUG 2018 
 
 
Addendum to the Statistical Analysis Plan 
 
 
KemPharm, Inc. 
1180 Celebration Blvd, Suite 103 
Celebration, FL 34747 
Phone: 321-939-3416 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
2 
 
In addition to the analyses described in Version 2.0 of the Statistical Analysis Plan (SAP), the following 
post-hoc analyses will be performed as outlined below. The rationale for the post-hoc analyses is to 
assess the primary and secondary endpoints (SKAMP and PERMP) using an alternate baseline definition 
(at Visit 6) to correct for differences in SKAMP-C scores between KP415 and placebo observed at pre-
dose Visit 6. 
 
Two new sets of analyses will be performed: 
 
1. Change from baseline SKAMP and PERMP scores (SKAMP-C, SKAMP-A, SKAMP-D, PERMP-A, and 
PERMP-C) using the Visit 6 pre-dose assessment as baseline. 
 
To estimate the difference between test (KP415) and control (placebo), a repeated measures analysis 
using MMRM will be performed similar to the primary efficacy analysis. The exact same model and 
covariates will be used as described in Version 2.0 of the SAP; the only difference will be the definition 
of baseline. Baseline will be defined as the pre-dose measurement at Visit 6 rather than the pre-dose 
measurement at Visit 5.  
 
Below is a sample table of how the results for the primary efficacy endpoint using SKAMP-C score 
changes from pre-dose Visit 6 will be presented: 
 
 
KP415 (N=  ) 
Placebo (N=  ) 
Treatment Difference: 
KP415-Placebo 
Pre-Dose (Baseline Visit 6) 
     Mean (SD) 
xx.x (xx.x) 
xx.x(xx.x) 
 
Average Post-Dose Change 
from Baseline 
 
 
 
     LS Mean (SE) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
     95% Confidence Interval 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
     p-value 
 
 
x.xxx 
 
 
Similar to the analysis described above, MMRM will be used to estimate the least square means, SEs and 
their corresponding 95% confidence intervals (CIs) between treatment groups for each post-dose time 
point at Visit 6 for the SKAMP and PERMP endpoints (SKAMP-C, SKAMP-A, SKAMP-D, PERMP-A, and 
PERMP-C).  
 
Below is a sample table of how those results will be presented: 
 


 
CONFIDENTIAL 
3 
 
Visit 6 
Change from Baseline (Visit 6 pre-dose) in SKAMP-C Score 
Time point 
LS Mean (SE) 
Difference in LS Mean (SE) 
95 % Confidence Interval 
p-value 
 
KP415 (N= ) 
Placebo (N= ) 
KP415-Placebo 
KP415-Placebo 
 
0.5 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
1 hour post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
2 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
4 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
8 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
10 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
12 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
13 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
Mean difference in 
change from baseline 
across all post-dose 
time-points 
 
 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
 
Onset and duration of the clinical effect of KP415. Using the change from baseline (pre-dose Visit 6 – 
alternate definition) SKAMP-C score at each post-dose Visit 6 time point and the alternate definition of 
baseline (pre-dose Visit 6) as covariate, the onset and duration of clinical effect will be analyzed. The 
onset of effect is defined as the first post-dose assessment time showing statistical significance (p<0.05) 
between KP415 and placebo as measured by the SKAMP-C Score. The duration of treatment effect is 
defined as the length of the time interval, such that statistical significance was reached at each time 
point of this interval. Onset and duration results will be presented in a table. 
 
 
2. Absolute SKAMP and PERMP values with Visit 6 baseline as a covariate. 
 
Similar to the primary efficacy analysis, a repeated measures analysis using MMRM will be performed to 
estimate the difference in absolute SKAMP-C scores between treatment groups. The MMRM model will 
include post-dose time (session), treatment, the interaction of time and treatment, and site as fixed 
effects, and subject as random effect; and, the pre-dose SKAMP-C scores (at Visit 6) will be pre-specified 
in the model as a covariate. The model-adjusted means of all post-dose SKAMP-C scores for each 
treatment group and treatment group differences (KP415-placebo) with standard errors (SEs) and 95% 
confidence intervals (CIs) will be presented. SAS procedure PROC MIXED will be utilized to conduct the 
analysis. If the model specified is not estimable, the compound symmetry type of the covariance matrix 
will be used.  The SAS code for the MMRM model for the SKAMP-C primary efficacy endpoint is as 
follows: 
 
proc mixed data=adef method=reml; 
Class trt02p usubjid atptn siteid; 
Model aval= trt02p atptn trt02p*atptn base siteid/ ddfm=residual solution chisq; 
repeated atptn /type= toep group=trt02p local subject=usubjid rcorr; 
parms / ols;   
Lsmeans trt02p/diff cl pdiff alpha=0.05; 
run; 
 


 
CONFIDENTIAL 
4 
 
trt02p=treatment group; usubjid=subject ID number; atptn= assessment time point; siteid=site; aval= 
absolute SKAMP-C score, base = SKAMP-C baseline (pre-dose at Visit 6) score 
 
Below is a sample table of how the results for the primary efficacy endpoint using absolute SKAMP-C 
scores and pre-dose Visit 6 as covariate will be presented: 
 
 
KP415 (N=  ) 
Placebo (N=  ) 
Treatment Difference: 
KP415-Placebo 
Pre-Dose (Baseline Visit 6) 
     Mean (SD) 
xx.x (xx.x) 
xx.x(xx.x) 
 
Absolute Scores 
 
 
 
     LS Mean (SE) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
     95% Confidence Interval 
(xx.x , xx.x) 
(xx.x , xx.x) 
(xx.x , xx.x) 
     p-value 
 
 
x.xxx 
 
 
MMRM will be used to estimate the least square means, SEs and their corresponding 95% confidence 
intervals (CIs) between treatment groups for each post-dose time point at Visit 6 for the SKAMP and 
PERMP endpoints (SKAMP-C, SKAMP-A, SKAMP-D, PERMP-A, and PERMP-C).  
 
Below is a sample table of how those results will be presented: 
 
Visit 6 
Absolute SKAMP-C Score 
Time point 
LS Mean (SE) 
Difference in LS Mean (SE) 
95 % Confidence Interval 
p-value 
 
KP415 (N= ) 
Placebo (N= ) 
KP415-Placebo 
KP415-Placebo 
 
0.5 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
1 hour post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
2 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
4 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
8 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
10 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
12 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
13 hours post-dose 
xx.x(xx.x) 
xx.x(xx.x) 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
Mean score across all 
post-dose time-points 
 
 
xx.x(xx.x) 
(xx.x , xx.x) 
x.xxx 
 
Onset and duration of the clinical effect of KP415. Using the absolute SKAMP-C score at each post-dose 
Visit 6 time point and the alternate definition of baseline (pre-dose Visit 6) as covariate, the onset and 
duration of clinical effect will be analyzed. The onset of effect is defined as the first post-dose 
assessment time showing statistical significance (p<0.05) between KP415 and placebo as measured by 
the absolute SKAMP-C Score. The duration of treatment effect is defined as the length of the time 
interval, such that statistical significance was reached at each time point of this interval. Onset and 
duration results will be presented in a table. 
 
 
 


 
CONFIDENTIAL 
5 
 
Listing of new tables and figures 
Table 
Post-hoc Analysis of Mean SKAMP-C Endpoint Primary Analysis  
Intent-to-Treat Population 
Table 
Post-hoc Analysis of Mean SKAMP-C Endpoint Primary Analysis 
Per-Protocol Population 
Table 
Post-hoc Analysis of Mean Change in SKAMP-C Endpoint Primary Analysis 
Intent-to-Treat Population 
Table 
Post-hoc Analysis of Mean Change in SKAMP-C Endpoint Primary Analysis 
Per-Protocol Population 
Table 
Post-hoc Analysis of Mean SKAMP-C Scores by Time Point 
Intent-to-Treat Population 
Table 
Post-hoc Analysis of Mean SKAMP-C Scores by Time Point 
Per-Protocol Population 
Table 
Post-hoc Analysis of Onset and Duration of Clinical Effect of KP415 as Measured by Mean 
SKAMP-C Scores 
Intent-to-Treat Population 
Table 
Post-hoc Analysis of Onset and Duration of Clinical Effect of KP415 as Measured by Mean 
SKAMP-C Scores 
Per-Protocol Population 
Table 
Post-hoc Analysis of Mean Change in SKAMP-C Scores by Time Point 
Intent-to-Treat Population 
Table 
Post-hoc Analysis of Mean Change in SKAMP-C Scores by Time Point 
Per-Protocol Population 
Table 
Post-hoc Analysis of Onset and Duration of Clinical Effect of KP415 as Measured by Mean Change 
in SKAMP-C Scores 
Intent-to-Treat Population 
Table 
Post-hoc Analysis of Onset and Duration of Clinical Effect of KP415 as Measured by Mean Change 
in SKAMP-C Scores 
Per-Protocol Population 
Table 
Post-hoc Analysis of Mean SKAMP-D Scores by Time Point 
Intent-to-Treat Population 
Table 
Post-hoc Analysis of Mean SKAMP-D Scores by Time Point  
Per-Protocol Population 
Table 
Post-hoc Analysis of Mean Change in SKAMP-D Scores by Time Point 
Intent-to-Treat Population 
Table 
Post-hoc Analysis of Mean Change in SKAMP-D Scores by Time Point 
Per-Protocol Population 
Table 
Post-hoc Analysis of Mean SKAMP-A Scores by Time Point 
Intent-to-Treat Population 
Table 
Post-hoc Analysis of Mean SKAMP-A Scores by Time Point  
Per-Protocol Population 
Table 
Post-hoc Analysis of Mean Change in SKAMP-A Scores by Time Point 
Intent-to-Treat Population 
Table 
Post-hoc Analysis of Mean Change in SKAMP-A Scores by Time Point 
Per-Protocol Population 
Table 
Post-hoc Analysis of Mean PERMP-A Scores by Time Point 
Intent-to-Treat Population 
Table 
Post-hoc Analysis of Mean PERMP-A Scores by Time Point 
Per-Protocol Population 
Table 
Post-hoc Analysis of Mean Change in PERMP-A Scores by Time Point 
Intent-to-Treat Population 
Table 
Post-hoc Analysis of Mean Change in PERMP-A Scores by Time Point 
Per-Protocol Population 
Table 
Post-hoc Analysis of Mean PERMP-C Scores by Time Point 
Intent-to-Treat Population 
Table 
Post-hoc Analysis of Mean PERMP-C Scores by Time Point 
Per-Protocol Population 
Table 
Post-hoc Analysis of Mean Change in PERMP-C Scores by Time Point 
Intent-to-Treat Population 
Table 
Post-hoc Analysis of Mean Change in PERMP-C Scores by Time Point 
Per-Protocol Population 
Figure 
Post-hoc Analysis of Treatment Difference in Change in Means Over Time in SKAMP-C Scores 
Intent-to-Treat Population 
Figure 
Post-hoc Analysis of Treatment Difference in Means Over Time in SKAMP-C Scores 
Intent-to-Treat Population 
Figure 
Post-hoc Analysis of Treatment Difference in Change in Means Over Time in SKAMP-A Scores 
Intent-to-Treat Population 
Figure 
Post-hoc Analysis of Treatment Difference in Means Over Time in SKAMP-A Scores 
Intent-to-Treat Population 
Figure 
Post-hoc Analysis of Treatment Difference in Change in Means Over Time in SKAMP-D Scores 
Intent-to-Treat Population 
Figure 
Post-hoc Analysis of Treatment Difference in Means Over Time in SKAMP-D Scores 
Intent-to-Treat Population 
Figure 
Post-hoc Analysis of Treatment Difference in Change in Means Over Time in PERMP-A Scores 
Intent-to-Treat Population 
Figure 
Post-hoc Analysis of Treatment Difference in Means Over Time in PERMP-A Scores 
Intent-to-Treat Population 
Figure 
Post-hoc Analysis of Treatment Difference in Change in Means Over Time in PERMP-C Scores 
Intent-to-Treat Population 


 
CONFIDENTIAL 
6 
 
 
 
 
 
Figure 
Post-hoc Analysis of Treatment Difference in Means Over Time in PERMP-C Scores 
Intent-to-Treat Population 

Prot_001.pdf: 
 
Protocol KP415.E01 Amendment #2 
CONFIDENTIAL 
KemPharm, 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. 
 
 
 
 
April 6, 2018 
 
 
A Multicenter, Dose-Optimized, Double-Blind, 
Randomized, Placebo-Controlled, Parallel Efficacy 
Laboratory Classroom Study with KP415 in Children 
with Attention-Deficit/Hyperactivity Disorder 
 
 
 
 
Protocol No: KP415.E01 
Original Protocol Date: August 04, 2017 
Amendment #1: November 13, 2017 
Amendment #2: April 06, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




Protocol KP415.E01 Amendment #2 
CONFIDENTIAL 
KemPharm, Inc. 
 
 
Page 3 of 81 
 
April 6, 2018 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................6 
PROTOCOL SYNOPSIS ..........................................................................................................8 
1. 
SCHEDULE OF EVENTS .............................................................................................. 23 
2. 
STUDY DESIGN SCHEMATIC .................................................................................... 27 
3. 
BACKGROUND.............................................................................................................. 28 
3.1. 
Attention-Deficit Hyperactivity Disorder (ADHD) .................................................... 28 
3.2. 
Laboratory Classroom Studies ................................................................................... 28 
4. 
KP415: A PRODRUG CONJUGATE ............................................................................ 28 
5. 
OVERVIEW OF CLINICAL STUDIES WITH KP415 ................................................ 29 
5.1. 
Study KP415.101 ....................................................................................................... 29 
5.2. 
Study KP415.109 ....................................................................................................... 30 
6. 
STUDY RATIONALE .................................................................................................... 31 
7. 
STUDY OBJECTIVES ................................................................................................... 31 
7.1. 
Primary Objective ...................................................................................................... 31 
7.2. 
Secondary Objectives ................................................................................................ 31 
8. 
INVESTIGATIONAL PLAN .......................................................................................... 32 
8.1. 
Study Design ............................................................................................................. 32 
8.2. 
Study Duration .......................................................................................................... 32 
9. 
SUBJECT SELECTION ................................................................................................. 32 
9.1. 
Number of Subjects ................................................................................................... 32 
9.2. 
Study Population ....................................................................................................... 33 
9.2.1. Inclusion Criteria (at Screening, except when noted otherwise) ......................................... 33 
9.2.2. Exclusion Criteria (at Screening, except when noted otherwise) ........................................ 34 
9.2.3. Eligibility Criteria (End of Dose Optimization Phase) ....................................................... 38 
9.2.4. Rescreening ...................................................................................................................... 38 
10. 
STUDY TREATMENTS ............................................................................................. 38 
10.1. KP415 Dose Optimization ......................................................................................... 38 
10.2. Study Drug Administration in the Double-Blind Treatment Phase .............................. 39 
10.3. Treatment Assignment/Randomization ...................................................................... 39 
10.4. Blinding ..................................................................................................................... 40 
10.5. Compliance ............................................................................................................... 40 
11. 
STUDY PROCEDURES ............................................................................................. 40 
11.1. Screening Procedures ................................................................................................. 41 
11.2. Open-Label Dose Optimization Phase (Visit 2-5)....................................................... 43 
11.2.1. 
Visit 2 (Day 0).............................................................................................................. 43 
11.2.2. 
Visit 3 (Day 7 ±3 days) ................................................................................................. 44 
11.2.3. 
Visit 4 (Day 14 ±3 days) ............................................................................................... 45 
11.2.4. 
Visit 5 (Day 21 ±3 days) ............................................................................................... 47 
11.2.5. 
Unscheduled Visits ....................................................................................................... 49 
11.3. Treatment Phase: Days 22-27 & Visit 6 (Day 28) ...................................................... 50 


Protocol KP415.E01 Amendment #2 
CONFIDENTIAL 
KemPharm, Inc. 
 
 
Page 4 of 81 
 
April 6, 2018 
 
11.4. Early Termination Visit ............................................................................................. 51 
11.5. Follow-Up Visit ......................................................................................................... 52 
11.6. End of Study (EOS) ................................................................................................... 53 
12. 
CONCOMITANT MEDICATIONS AND RESTRICTIONS ................................... 53 
12.1. Medication Restrictions ............................................................................................. 53 
12.2. General Restrictions................................................................................................... 54 
13. 
INVESTIGATIONAL PRODUCT ............................................................................. 55 
13.1. Active Pharmaceutical Ingredients ............................................................................. 55 
13.2. Clinical Trial Material ............................................................................................... 55 
13.3. Pharmaceutical Formulation ...................................................................................... 56 
13.4. Packaging and Labeling ............................................................................................. 56 
13.4.1. 
Open-Label Dose Optimization Phase........................................................................... 56 
13.4.2. 
Double-Blind Treatment Phase ..................................................................................... 56 
13.5. Dispensing Procedures ............................................................................................... 57 
13.5.1. 
Open-Label Dose Optimization Phase........................................................................... 57 
13.5.2. 
Double-Blind Treatment Phase ..................................................................................... 57 
13.6. Storage of Study Drug ............................................................................................... 58 
13.7. Study Drug Accountability ........................................................................................ 59 
14. 
SAFETY AND EFFICACY ASSESSMENTS ............................................................ 59 
14.1. Medical History ......................................................................................................... 59 
14.2. Physical Examination ................................................................................................ 59 
14.3. ADHD Diagnosis and Severity Assessments .............................................................. 59 
14.4. Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................... 61 
14.5. Vital Signs ................................................................................................................. 61 
14.6. 12-Lead Electrocardiogram ........................................................................................ 62 
14.7. Clinical Laboratory Measurements ............................................................................ 62 
14.8. Pregnancy Test .......................................................................................................... 63 
14.9. Adverse Event Assessments ....................................................................................... 63 
15. 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS .............................. 64 
15.1. Withdrawal of Subjects from the Study ...................................................................... 64 
15.2. Replacement of Subjects ............................................................................................ 64 
16. 
EFFICACY ENDPOINTS ........................................................................................... 64 
16.1. Primary Efficacy Variable: ........................................................................................ 65 
16.2. Secondary Efficacy Variables: ................................................................................... 65 
16.3. Safety Endpoints: ....................................................................................................... 65 
17. 
STATISTICAL CONSIDERATIONS ........................................................................ 65 
17.1. Statistical Hypotheses ................................................................................................ 65 
17.1.1. 
Primary Efficacy Endpoint(s): ...................................................................................... 65 
17.1.2. 
Secondary Efficacy Endpoints ...................................................................................... 66 
17.2. Sample Size Calculation ............................................................................................ 66 
17.3. Populations for Analysis ............................................................................................ 69 
17.4. Statistical Analyses .................................................................................................... 69 
17.4.1. 
General Approach ........................................................................................................ 69 
17.4.2. 
Analysis of the Primary Efficacy Endpoint ................................................................... 70 
17.4.3. 
Analysis of the Secondary Endpoints ............................................................................ 70 


Protocol KP415.E01 Amendment #2 
CONFIDENTIAL 
KemPharm, Inc. 
 
 
Page 5 of 81 
 
April 6, 2018 
 
17.4.4. 
Sensitivity Analyses ..................................................................................................... 71 
17.4.5. 
Safety Analysis ............................................................................................................ 71 
17.4.6. 
Baseline Descriptive Statistics ...................................................................................... 72 
17.4.7. 
Planned Interim Analyses ............................................................................................. 72 
17.4.8. 
Sub-Group Analyses ..................................................................................................... 72 
17.4.9. 
Tabulation of Individual Participant Data...................................................................... 72 
 
Exploratory Analyses ................................................................................................................ 72 
17.4.10. ......................................................................................................................................... 72 
18. 
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ................... 73 
18.1. Adverse Events .......................................................................................................... 73 
18.1.1. 
Recording and Monitoring of Adverse Events ............................................................... 73 
18.1.2. 
Definition ..................................................................................................................... 73 
18.1.3. 
AE Grading .................................................................................................................. 73 
18.1.4. 
AE Relationship to Study Drug ..................................................................................... 74 
18.2. Serious Adverse Events ............................................................................................. 74 
18.2.1. 
Serious Adverse Event Reporting ................................................................................. 74 
18.3. Adverse Event Treatment and Follow-Up .................................................................. 76 
18.4. Overdosage ................................................................................................................ 76 
19. 
PREGNANCY ............................................................................................................. 76 
20. 
PROTOCOL VIOLATIONS ...................................................................................... 77 
21. 
DATA MANAGEMENT AND RECORD KEEPING ............................................... 77 
21.1. Data Management ...................................................................................................... 77 
21.2. Record Keeping ......................................................................................................... 78 
21.3. Access to Source Data/Documents ............................................................................. 78 
22. 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................... 78 
23. 
ETHICS AND GOOD CLINICAL PRACTICE COMPLIANCE ............................ 79 
24. 
INSURANCE ............................................................................................................... 79 
24.1. Insurance Compensation ............................................................................................ 79 
25. 
COMPLETION OF STUDY ....................................................................................... 79 
26. 
STUDY ADMINISTRATIVE INFORMATION ........................................................ 79 
26.1. Protocol Amendments ................................................................................................ 79 
27. 
REFERENCES ............................................................................................................ 80 
 
 
 


Protocol KP415.E01 Amendment #2 
CONFIDENTIAL 
KemPharm, Inc. 
 
 
Page 6 of 81 
 
April 6, 2018 
 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ADHD 
Attention-deficit hyperactivity disorder 
ADHD-RS-5 
Attention-deficit hyperactivity disorder rating scale 5 
ADL 
Activity of Daily Living 
ALT 
Alanine transaminase 
ARO 
Academic Research Institution 
AST 
Aspartate transaminase 
AUC 
Area under the plasma concentration-time curve 
β-hCG 
Beta human chorionic gonadotropin 
BLQ 
Below the limit of quantification 
BMI 
Body Mass Index 
CBT 
Cognitive Behavioral Therapy 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impressions–Severity 
CGI-I 
Clinical Global Impressions–Improvement 
CI 
Confidence Interval 
Cmax 
Maximum observed plasma concentration 
CNS 
Central nervous system 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DMDD 
Disruptive Mood Dysregulation Disorder 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOS 
End of Study  
ER 
Extended Release 
ET 
Early Termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HPMC 
Hydroxypropyl methylcellulose 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IP 
Investigational Product 
IR 
Immediate Release 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 


Protocol KP415.E01 Amendment #2 
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LLN 
Lower Limit of Normal 
LS 
Least-square 
MedDRA 
Medical Dictionary of Regulatory Activities 
MAO 
Monoamine Oxidase 
MAR 
Missing at Random 
MCID 
Minimum Clinically Important Difference 
MINI-KID 
Mini International Neuropsychiatric Interview for Children and Adolescents 
MMRM 
Mixed-Effect Model Repeated Measure model 
MPH 
Methylphenidate 
NCE 
New Chemical Entity 
NMAR 
Not Missing at Random 
ODD 
Oppositional Defiant Disorder 
OTC 
Over the Counter 
PD 
Pharmacodynamic 
PERMP 
Permanent Product Measure of Performance 
PERMP-A 
Permanent Product Measure of Performance-Attempted 
PERMP-C 
Permanent Product Measure of Performance-Correct 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
Q1 
25th Percentile (1st Quartile) 
Q3 
75th Percentile (3rd Quartile) 
QTcF 
Time between the start of the Q wave and the end of the T wave (QT interval) in 
the heart's electrical cycle, corrected for heart rate with Fridericias’s formula 
RS 
Randomized Safety 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SKAMP 
Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale 
SKAMP-A 
SKAMP-Attention 
SKAMP-C 
SKAMP-Combined 
SKAMP-D 
SKAMP-Deportment 
SOE 
Schedule of Events 
SNRI 
Serotonin Norepinephrine Reuptake Inhibitor 
SSRI 
Selective Serotonin Reuptake Inhibitor 
SW 
Shapiro-Wilk 
T1/2 
Apparent plasma terminal elimination half-life 
TEAE 
Treatment-Emergent Adverse Event 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
WREMB-R 
Weekly Rating of Evening and Morning Behavior - Revised 
Tmax 
Time to achieve the maximum observed plasma concentration 
 
 


Protocol KP415.E01 Amendment #2 
CONFIDENTIAL 
KemPharm, Inc. 
 
 
Page 8 of 81 
 
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PROTOCOL SYNOPSIS 
TITLE 
A Multicenter, Dose-Optimized, Double-Blind, Randomized, 
Placebo-Controlled, Parallel Efficacy Laboratory Classroom 
Study with KP415 in Children with Attention-
Deficit/Hyperactivity Disorder 
SPONSOR 
KemPharm, Inc. 
PROTOCOL NUMBER 
KP415.E01 
INVESTIGATIONAL 
PRODUCT 
KP415 (a prodrug of d-methylphenidate, d-MPH) 
NAME OF ACTIVE 
INGREDIENT 
The chemical name of the KP415 prodrug 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 (single d-
methylphenidate 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). 
ROUTE 
Oral 
NUMBER OF SITES 
5 sites in the United States of America 
STUDY DESIGN 
The study is a multicenter, dose-optimized, double-blind, 
randomized, placebo-controlled, parallel efficacy laboratory 
classroom study with KP415 in children with Attention-
Deficit/Hyperactivity Disorder (ADHD). The study will 
consist of a Screening Period, an Open-Label Dose 
Optimization Phase, a Double-Blind Treatment Phase and a 
Follow-Up Visit, as follows: 
• Screening Period: Subjects will undergo a screening 
period up to 49 days prior to entering into the Open-
Label Dose Optimization Phase. 
• Open-Label Dose Optimization Phase: During the 
Dose Optimization Phase, subjects will be titrated to 
doses of 20, 30 or 40 mg KP415 based on tolerability 
and best individual dose-response in the opinion of the 
Investigator. 
• Double-Blind Treatment Phase: Eligible subjects 
will be randomized to receive single daily doses of 
KP415 or Placebo for 7 days according to a 
randomization schedule. The dose of KP415 given in 
the Treatment Phase will be the same as the optimized 
dose of KP415 at the end of the Dose Optimization 
Phase. All subjects will receive their assigned 
treatment daily for 7 days. The dose will be the same 
at each day of the Treatment Period. Efficacy and 
safety assessments will be performed after the last 


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dose of the Treatment Period. 
• Follow-Up Visit: 3 ±2 days after administration of the 
last dose of the Treatment Phase, subjects will enter a 
Follow-Up Visit to evaluate safety parameters. 
PRIMARY OBJECTIVE 
To determine the efficacy of KP415 compared to placebo in 
treating children 6-12 years old with ADHD in a laboratory 
classroom setting. 
SECONDARY 
OBJECTIVES 
• To determine the onset and duration of the clinical 
effect of KP415 in treating ADHD in children 6-12 
years old in a laboratory classroom setting. 
• To determine the safety and tolerability of KP415 
compared to placebo in treating children 6-12 years 
old with ADHD in a laboratory classroom setting. 
NUMBER OF SUBJECTS 
An appropriate number of subjects will enter the Screening 
Period to enroll approximately 176 subjects in the Open-
Label Dose Optimization Phase, and to randomize 
approximately 140 subjects in the Double-Blind Treatment 
Phase, with the intention to complete with approximately 126 
subjects. Subjects who terminate early in the Treatment Phase 
will not be replaced. 
SUBJECT SELECTION 
CRITERIA 
Inclusion Criteria (at Screening, except when noted 
otherwise) 
1. 
Subject must be at least 6 years old and less than 13 
years old at the start of the Dose Optimization Phase 
(Day 0). 
2. 
Subject must have a body weight of at least 21 kg at 
Screening. 
3. 
Female subjects must agree when 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. 
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 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 of 12 
years and older (including girls who will become 12 


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years or older 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”. 
4. 
Subject must be in general good health defined as the 
absence of any clinically relevant abnormalities as 
determined by the Investigator based on physical and 
neurological examinations, vital signs, ECGs, 
medical history, and clinical laboratory values 
(hematology, chemistry and urinalysis) at Screening. 
If any of the hematology, chemistry, or urinalysis 
results are not within the laboratory's reference range, 
then the subject can be included only if the 
Investigator determines the deviations to be not 
clinically relevant. 
5. 
At least one parent/legal guardian of the subject must 
voluntary give written permission for him/her to 
participate in the study. 
6. 
Subject 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 the Mini 
International Neuropsychiatric Interview for Children 
and Adolescents (MINI-KID). 
8. 
Subject must have a score of at least 3 (mildly 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. 
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 Dose 
Optimization Phase (Day 0), and abstain from taking 
these to the end of the Follow-Up Visit or Early 
Termination; and wash out non-stimulant ADHD 
medications from 21 days prior to the start of the 
Dose Optimization Phase (Day 0), and abstain from 


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taking these to the end of the Follow-Up Visit or 
Early Termination. 
10. 
An ADHD-Rating Scale-5 (ADHD-RS-5) total score 
(DuPaul et al. 2016) of at least 28 at Visit 2 (Day 0). 
For subjects requiring washout of ADHD 
medications, this criterion refers to a score following 
washout. 
11. 
Subjects need to be able to perform at least the basic 
level of problems on the PERMP, based on a 
calibration assessment (Placement PERMP) 
performed at Visit 2 (Day 0). 
12. 
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. If the subject is cared for by a caregiver for 
relevant parts of a school day, and if in this case, in 
the opinion of the Investigator, the caregiver of the 
subject is more suitable for certain assessments (for 
example, Conners 3-P and WREMB-R), the caregiver 
will need to agree to the applicable procedures and 
visits. 
13. 
Subject, parent/legal guardian and caregiver (if 
applicable) must be able to speak and understand 
English, and be able to communicate satisfactorily 
with the Investigator and study coordinator. 
14. 
Subject must be able to swallow size 3 capsules as 
demonstrated by easily swallowing a size 3 capsule at 
Screening. 
Exclusion Criteria (at Screening, except when noted 
otherwise) 
1. 
If female, must not be pregnant or breastfeeding, and 
if of childbearing potential, must have a negative 
serum pregnancy test at Screening. In addition, a 
positive pregnancy test before the last dose of study 
drug will exclude a subject from further participation 
in the study. “Of childbearing potential” is defined in 
Section 14.8. 
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 


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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. 
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, 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. A past history of febrile seizure, drug-induced 
seizure, or alcohol withdrawal seizure is allowed. 
Subject taking anticonvulsants for seizure control 
currently or within the past 2 years before Screening 
are not eligible for study participation. 
6. 
Subject has a current (last month) psychiatric 
diagnosis other than specific phobia, motor skills 
disorders, oppositional defiant disorder, sleep 
disorders, elimination disorders, adjustment 
disorders, learning disorders, or communication 
disorders. Participants with school phobia or 
separation anxiety will not be eligible. 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. 
7. 
Subject has any history of attempted suicide or 
clinically significant suicidal ideation based on the C-
SSRS assessment, in the opinion of the Investigator, at 
Screening or at any time before the last dose of study 
drug. 


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8. 
Subject has any clinically significant unstable 
medical abnormality, chronic disease, 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 drug absorption, 
distribution, metabolism, or excretion of study drug. 
Active medical conditions that are minor or well-
controlled are not exclusionary if they do not affect 
risk to the subject or the study results. In cases in 
which the impact of the condition upon risk to the 
subject or study results is unclear, the medical 
monitor should be consulted. Any subject with a 
known cardiovascular disease or condition (even if 
controlled) must be discussed with the medical 
monitor during Screening. 
9. 
Subject has a history or presence of abnormal ECGs, 
which in the Investigator's opinion is clinically 
significant. Screening site ECGs will be centrally 
over-read, and eligibility will be determined by the 
Investigator based on the results of the over-read 
report. 
10. 
Subject has a history of, or currently has a 
malignancy, except for non-melanomatous skin 
cancer. 
11. 
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. 
12. 
Subjects with a history of substance abuse or 
treatment (including alcohol) within 1 year prior to 
Screening. 
13. 
Subject shows evidence of substance or alcohol use 
or is currently using tobacco or other nicotine-
containing products, or has a positive urine alcohol or 
urine drug screen at Screening. Subjects with a 
positive 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. 


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14. 
Subject has a positive urine methylphenidate screen 
at the start of the Dose Optimization Phase (Day 0, 
Visit 2). 
15. 
Subject who has initiated Cognitive Behavioral 
Therapy (CBT) for the treatment of ADHD less than 
1 month prior to Screening (subjects on stable CBT 
will be allowed), has initiated behavioral therapy 
(including school based interventions) less than 1 
month prior to Screening, or is receiving behavioral 
therapy and in the opinion of the Investigator will not 
be able to follow a stable routine for the duration of 
the study. Unavoidable changes in school-based 
interventions that occur during study participation 
will not be exclusionary, but should be documented 
by the Investigator, to the extent possible. 
16. 
Subject has participated in a classroom study within 6 
months prior to the start of Screening, or has 
participated in any other clinical study with an 
investigational drug/product within 90 days prior to 
Screening, or is currently participating in another 
clinical trial. 
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 
intolerance to adequate dose and duration of treatment 
with methylphenidate products. Judgment of adequate 
dose and duration is at the discretion of the 
Investigator.  
19. 
Subjects are using or planning to use prohibited drugs 
during the trial as specified in the protocol. 
20. 
Subject has a history of severe allergies or adverse 
drug reactions to more than one class of medications. 
21. 
Subject has a history of allergic reaction or a known 
or suspected sensitivity to methylphenidate or any 
substance that is contained in the study drug. 
22. 
Subject has any food allergies or dietary restrictions 
that are determined by the Investigator as too severe 
to be easily accommodated for during the study. 
23. 
Subject was home-schooled within 12 months prior 
to Screening. 
24. 
Subject, parent/legal guardian and caregiver (if 
applicable at the Investigator’s discretion) has 


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commitments during the study that would interfere 
with attending study visits. 
25. 
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. 
26. 
Subject's parent/legal guardian is an investigational 
site staff member or a relative of an investigational 
site staff member. 
27. 
Subjects with a family member living in the same 
household participating in another ADHD clinical 
trial during the period of Screening through the 
Follow-Up Visit will be excluded. Subjects with a 
family member living in the same household 
participating in the current clinical trial during the 
administration of study drug (Visits 2 to 6) will be 
excluded. Different subjects from the same family are 
allowed in this trial if they are in different cohorts, 
and there is no overlap in time from Visit 2 to Visit 6. 
28. 
Subject is, in the opinion of the Investigator, 
unsuitable in any other way to participate in this 
study. 
Eligibility Criteria (End of Dose Optimization Phase) 
Subjects will need to meet the following additional eligibility 
criteria at the end of the Dose Optimization Phase in order to 
enter into the Double-Blind Treatment Phase: 
1. 
A reduction of ≥30% reduction of ADHD-RS-5 from 
baseline (Day 0) during the Open-Label Dose 
Optimization Phase. 
2. 
A CGI-I score of 1 or 2 points (“Very Much 
Improved” or “Much Improved”) at the end of the 
Open-Label Dose Optimization Phase. 
3. 
Acceptable tolerability of the optimized KP415 dose 
experienced during the Dose Optimization Phase. 
These assessments will be made based on the days before 
Visit 5 while still taking study drug (and NOT based on the 
2 days of no study drug before Visit 5). 
Rescreening 
Subjects who are screened outside the screening window may 
be rescreened for participation in a later cohort. Subjects who 
received any dose of study drug and are terminated early or 
are not eligible to continue in the Treatment Phase, are not 
eligible to participate in another cohort of the study (and will 


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not be rescreened). 
TEST PRODUCT, DOSE, 
AND ROUTE OF 
ADMINISTRATION 
The KP415 capsules contain two active pharmaceutical 
ingredients: d-methylphenidate (d-MPH) hydrochloride as the 
immediate release (IR) d-MPH component, and KP415 
prodrug as the extended release (ER) d-MPH component. In 
terms of d-MPH equivalent amounts, all capsule strengths 
contain 30% of d-MPH (IR component) and 70% of d-MPH 
from the KP415 prodrug (ER component). 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. 
Total 
d-MPH 
dose 1 
(mg) 
d-MPH 2 
 
 
(mg) 
KP415 
Prodrug 3 
 
(mg) 
20 
6 
28 (14) 
30 
9 
42 (21) 
40 
12 
56 (28) 
1. Based on the d-MPH amount plus the equivalent amount of d-MPH as 
KP415 prodrug. 
2. The dose of d-MPH is expressed in terms of d-methylphenidate 
hydrochloride. 
3. The dose of KP415 prodrug is expressed in terms of KP415 chloride. 
The amount of d-MPH hydrochloride equimolar to each KP415 
prodrug dose is listed between parentheses. 
 
In the Open-Label Dose Optimization Phase, daily treatments 
of 20, 30 and 40 mg open-label KP415 capsules will be 
administered (one capsule/day), for the titration to an optimal 
daily KP415 dose. At Visits 4 and 5, study drug will be 
administered at the school site by study staff on the morning 
of the abbreviated laboratory classroom days. Two days 
before Visit 5, subjects must not take study drug (this is 
important for obtaining a baseline of the SKAMP/PERMP 
scores). On the other days of the Dose Optimization Phase, 
the medication will be taken in the morning at home. The 
dose taken at the school site at Visit 5 will be the last dose of 
unblinded study drug. 
 
In the Double-Blind Treatment Phase, the following 
treatments will be administered: 
• Treatment A: one KP415 capsule (test product) once daily 
for 7 days. 
• Treatment B: one matching placebo capsule once daily for 
7 days. 
The daily dose of KP415 in the Treatment Phase will be same 


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as the optimal dose of KP415 at the end of the Dose 
Optimization Phase, either 20, 30 or 40 mg KP415, or 
matching placebo. Blinded study medications of each 
treatment will be administered from Sunday (the day after 
Visit 5) to Saturday (Visit 6). On Saturday (Visit 6), the 
blinded doses of study drug will be administered at the school 
site by study staff on the morning of the laboratory classroom 
day. On the other days of the Treatment Phase, the medication 
will be taken in the morning at home. 
All study drugs will be given orally with 240 mL water. 
Additional water may be given if needed for both treatments. 
LABORATORY 
CLASSROOM  
SESSIONS 
At Visit 4 and Visit 5, each subject will complete 
abbreviated practice laboratory classroom sessions with 4 
SKAMP/PERMP assessments designed to mirror the pre-
dose to 2-hour post-dose period of the full-length laboratory 
classroom session of Visit 6. The pre-dose assessment (after 
2 days of no drug) at Visit 5 will be recorded as the baseline 
for the SKAMP and PERMP. 
At Visit 6, subjects will complete a full-length laboratory 
classroom session that is designed to model a typical school 
day plus after-school activity totaling up to 13 hours after the 
7th and last dose of KP415 or Placebo in the Double-Blind 
Treatment Phase. 
ADHD 
SEVERITY/EFFICACY 
EVALUATION CRITERIA 
The following scales will be used during the Open-Label 
Dose Optimization Phase to globally assess the changes in 
ADHD severity from week to week: 
• ADHD-Rating Scale-5 (ADHD-RS-5) The ADHD-
RS-5 is an 18-item scale based on Diagnostic and 
Statistical Manual of Mental Disorders, 5th edition 
(DSM-5) (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-
5 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 
inattentiveness. Scores will be obtained during a 
clinician-directed interview with the 
parent/guardian/caregiver at each visit. 
• 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 


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(among the most severely ill) (Busner and Targum 
2007). 
• Clinical Global Impressions–Improvement (CGI-I). 
The CGI-I is scored from 1 (very much improved) to 
7 (very much worse). 
The following scale will be used to assess the effect ofKP415 
during the Open-Label Dose Optimization Phase and the 
efficacy of KP415 versus placebo during the Double-Blind 
Treatment Phase: 
• Conners 3rd Edition-Parent (Conners 3-P). The 
Conners 3-P (short form) is a 43-item 
parent/guardian/caregiver report that provides 
evaluation of inattention, hyperactivity/impulsivity, 
learning problems, executive functioning, aggression, 
and peer relationships. The parent/guardian/caregiver 
will assess changes in ADHD symptoms via the 
Conners 3-P questionnaire at baseline (Visit 2, Day 0) 
and at each visit during the Dose-Optimization and the 
Treatment Phase. 
•  Weekly Rating of Evening and Morning Behavior - 
Revised (WREMB-R) Scale: The 11-item WREMB-R 
questionnaire is a parent-rated questionnaire that was 
developed to assess behaviors for their severity during 
the morning hours (3 items) and evening hours (8 
items) (Carlson 2007). The possible score for each 
item ranges from 0 (no difficulty) to 3 (a lot of 
difficulty). The Investigator or designee will obtain 
the scores for the WREMB-R questionnaire by 
interviewing the parent/guardian/caregiver at Visits 2, 
5 and 6. The assessment at Visit 2 is the baseline 
assessment (after washout of ADHD medications, if 
applicable); the assessments at Visits 5 and 6 are 
evaluations at the end of the Dose Optimization and 
Treatment Phase, respectively. 
The following scales will be used to assess the efficacy of 
KP415 versus placebo during the Double-Blind Treatment 
Phase: 
• Swanson, Kotkin, Agler, M-Flynn, and Pelham 
(SKAMP) Rating Scale will be performed at Visit 4, 
Visit 5, and Visit 6. 
The SKAMP scale is a validated rating of classroom 
behaviors. It is comprised of 13 items (grouped under 
the subcategories of attention, deportment, quality of 
work, and compliance), on which subjects are rated 
according to a 7-point scale (0 = normal to 6 = 
maximal impairment) by trained study personnel 


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(Swanson 1999). The SKAMP-Combined (SKAMP-
C) score is obtained by summing the rating values for 
each of the 13 items. The SKAMP-Deportment 
(SKAMP-D) score is a measure of behavior and 
comprises of 4 items. The SKAMP-Attention 
(SKAMP-A) score is a measure of attention and 
comprises 4 items. Higher SKAMP scores signify 
greater impairment. The SKAMP-C score will be 
used in the primary efficacy endpoint. 
• Permanent Product Measure of Performance 
(PERMP) Rating Scale will be performed at Visit 4, 
Visit 5 and Visit 6. A Placement PERMP will be 
performed at Visit 2 (Day 0) to assure that subjects 
can complete at least the basic level of math 
problems and to determine the appropriate level of 
math to be assigned during the practice laboratory 
classroom day at Visit 4. Based on the practice 
laboratory classroom day at Visit 4, the final level of 
math for each subject will be determined for use in 
the remainder of the study (Visits 5 and 6). 
The PERMP is an individually calibrated five-page 
mathematics worksheet consisting of 400 problems. 
Subjects will be instructed by site staff to work at 
their seats and complete as many problems as 
possible in 10 minutes. Performance will be 
evaluated using two scores: The number of problems 
attempted (PERMP-A) and the number of problems 
correct (PERMP-C). 
SAFETY EVALUATION 
CRITERIA 
Adverse events, vital signs, physical examination, ECGs, 
clinical laboratory measurements, and C-SSRS scores will be 
evaluated for safety. 
DURATION OF SUBJECT 
PARTICIPATION AND 
DURATION OF STUDY 
Subjects will participate in the study as outpatients for up to 
85 days, including up to 49 days of Screening; a 21-day (±3 
days) Dose Optimization Phase, a 7-day Treatment Phase, 
and a Follow-Up Visit (3 ±2 days after the administration 
of the last dose of the Treatment Phase). 
MEDICATION 
RESTRICTIONS 
Subject’s meeting all eligibility requirements will be 
prohibited/limited to receive certain medications in the trial: 
• Stimulant ADHD medications (with the exception of 
study drug), including herbal medications, are prohibited 
from 5 days prior to the start of the Dose Optimization 
Phase (Day 0) to the end of the Follow-Up Visit or Early 
Termination Visit. These include: methylphenidate, 
amphetamine, Ritalin®, Ritalin® SR, Metadate® ER, 
Concerta®, dextromethylphenidate, Focalin®, 
dextroamphetamine, Dexedrine®, Adderall®. 


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• Non-Stimulant ADHD medications are prohibited from 
21 days prior to the start of the Dose Optimization Phase 
(Day 0) to the end of the Follow-Up Visit or Early 
Termination Visit. These include: Atomoxetine, 
guanfacine, clonidine; and SSRIs such as fluoxetine and 
paroxetine. 
• 
The following medications are prohibited from 21 days 
prior to the start of the Dose Optimization Phase (Day 0) 
to the end of the Follow-Up Visit or Early Termination 
Visit: 
o Tricyclic antidepressants. 
o Monoamine oxidase inhibitors (MAOIs). 
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 Coumarin anticoagulants 
 
• 
Sedative hypnotics/sleep enhancers (with the exception of 
melatonin) are prohibited from 14 days prior to the start of 
the Dose Optimization Phase (Day 0) to the end of the 
Follow-Up Visit or Early Termination Visit. 
• 
Melatonin is allowed if subjects have taken it for more 
than 30 days before the start of the Dose Optimization 
Phase (Day 0) and are on a stable dose. Otherwise, 
melatonin is prohibited from 5 days prior to the start of the 
Day 0 to the end of the Follow-Up Visit or Early 
Termination Visit. 
Medications allowed during the course of the study include 
nasal steroids, bronchodilators, acetaminophen and 
nonsteroidal anti-inflammatory medications; non-sedating 
antihistamines such as cetirizine, loratadine, and 
fexofenadine; mometasone; and approved courses of 
prescription and nonprescription medications for the 
treatment of acute illnesses.  
EFFICACY ENDPOINTS 
The primary efficacy evaluation is based on SKAMP and 
PERMP scores at pre-dose, and at 0.5. 1, 2, 4, 8, 10, 12, 
and 13 hours post-dose during the full laboratory classroom 
day at Visit 6. The baseline SKAMP score is measured at 
pre-dose at Visit 5. 
Primary Efficacy Variable: 
• 
Average of the change from baseline (measured at 
Visit 5) of the SKAMP-C scores collected across the 


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laboratory classroom day at Visit 6. 
Secondary Efficacy Variables: 
• 
Change from baseline (measured at Visit 5) of the 
SKAMP-C scores measured at each time point on the 
laboratory classroom day at Visit 6. The serial 
measures at different times post-dosing will be used to 
determine onset and duration of the clinical effect of 
KP415. 
• 
Change from baseline of the scores measured at each 
time point and the average of the scores collected 
across the laboratory classroom day at Visit 6, for the 
following endpoints: 
o SKAMP-D and SKAMP-A scores 
o PERMP scores 
o PERMP-A and PERMP-C scores 
• 
WREMB-R scores (total score, and morning and 
evening subscore) at Baseline (Visit 2), Visit 5 and 
Visit 6. 
SAFETY ENDPOINTS 
The occurrence of Treatment-Emergent Adverse Events 
(TEAEs) will be assessed starting following the first dose of 
open-label drug (KP415), and ending with the Follow-Up 
Visit or Early Termination Visit. Additional safety 
evaluations will include physical examinations, vital signs, as 
well as height and weight, ECG parameters, clinical 
laboratory tests, and a follow-up C-SSRS administered at 
each study visit. AEs during the Open-Label Dose 
Optimization Phase and the Double-Blind Treatment Phase 
will be will be reported and analyzed separately. 
ANALYSIS 
POPULATIONS 
Intent-to-Treat (ITT) Population: All randomized subjects 
who receive at least one dose of double-blind study 
medication and have at least one SKAMP-C assessments at 
Visit 6. 
Per-Protocol (PP) Population: ITT subjects who received 
the morning dose of double-blind study medication at the 
laboratory test session, who have all 8 post-dose SKAMP-C 
assessments at Visit 6, who did not miss more than 2 days of 
therapy during the Double-Blind Treatment Phase, and did 
not use prohibited medications during the Double-Blind 
Treatment Phase. 
Overall Safety Population: All subjects who entered the 
Open-Label Dose Optimization phase and received at least 
one dose of open-label study medication and had at least 
one post-dose safety assessment. 
STATISTICAL 
ANALYSES – 
TREATMENT PHASE 
Efficacy: Primary and secondary efficacy analyses will be 
performed on the ITT and PP populations. Descriptive 
statistics for the all SKAMP and PERMP scores and subscale 


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scores will be calculated for each time point on the laboratory 
classroom days, and for the average of the scores collected 
across the laboratory classroom day. The difference between 
treatments (KP415 vs. placebo) will be evaluated for each 
variable using repeated measures analyses. The treatment 
comparison will be conducted as a two-sided test at the 5% 
level of significance. Standard errors and 95% confidence 
intervals (CIs) will be calculated. 
Onset of clinical effect is defined as the earliest post-dose 
time point at which the difference between KP415 and 
Placebo is statistically significant (p<0.05). The duration of 
the treatment effect is defined as the length of the time 
interval, such that statistical significance was reached at each 
time point of this interval. 
 
Subgroup analyses will include efficacy and safety endpoints 
by study site, dose, age, and gender. 
Safety: The frequencies of adverse events (AEs), the results 
of laboratory assessments, physical examinations, vital signs, 
ECGs, and suicidal ideation (assessed using the C-SSRS) will 
be summarized descriptively (by treatment, if applicable) in 
the Overall Safety Population. 
STUDY PROCEDURES 
The study procedures are outlined in the Schedule of 
Events (Section 1).  


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1. SCHEDULE OF EVENTS 
ASSESSMENTS 
SCREEING 
PHASE 
OPEN-LABEL 
DOSE OPTIMIZATION PHASE 27 
TREATMEN
T PHASE 
ET 29 
(EOS) 
FOLLOW-UP 
(EOS) 
Study Day  
-49 to 
-1 
0 
1-6 
(±3 
Days) 
7 
(±3 
Days) 
8-13 
(±3 
Days) 
14 
(±3 
Days) 
15-20 
(±3 
Days) 
21 
(±3 
Days) 
22-27 
(±3 
Days) 
28 28 
(±3 
Days) 
- 
29-33 
(±2 
Days) 
Visit Number 
1 
2 
 
3 
 
4 
 
5 
 
6 
- 
7 
Parental Permission/Written 
or Verbal Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
ADHD Diagnosis and 
Confirmation 1 
X 
 
 
 
 
 
 
 
 
 
 
 
Placement PERMP 2 
 
X 
 
 
 
 
 
 
 
 
 
 
Capsule Swallowing Test 3 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 4 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Physical Examination 5 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Body Weight, Height, BMI 6
X 
 
 
 
 
 
 
 
 
 
X 
X 
Vital Signs 7 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
12-Lead ECG 8 
X 
 
 
 
 
 
 
 
 
 
X 
X  
Chemistry/ 
Hematology/Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Urine Alcohol/Drugs of 
Abuse Screen 9 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine MPH Screen 10 
X 
X 
 
 
 
 
 
X 
 
 
 
 
Pregnancy Test 11 
X 
X 
 
 
 
 
 
X 
 
 
X 
X 
C-SSRS 12 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Washout ADHD Meds 13 
X 
 
 
 
 
 
 
 
 
 
 
 
Open-Label KP415 Dosing 
14 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Randomization 15 
 
 
 
 
 
 
 
X 
 
 
 
 
Double-Blind Study Drug 
Administration 16 
 
 
 
 
 
 
 
 
X 
X 
 
 
Drug Accountability & 
Compliance Assessment 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
Laboratory Classroom 
Sessions 17 
 
 
 
 
 
X 
 
X 
 
X 
 
 
ADHD-RS-5 18 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
CGI-S 19 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
CGI-I 20 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Conners 3-P 21 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 


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ASSESSMENTS 
SCREEING 
PHASE 
OPEN-LABEL 
DOSE OPTIMIZATION PHASE 27 
TREATMEN
T PHASE 
ET 29 
(EOS) 
FOLLOW-UP 
(EOS) 
Study Day  
-49 to 
-1 
0 
1-6 
(±3 
Days) 
7 
(±3 
Days) 
8-13 
(±3 
Days) 
14 
(±3 
Days) 
15-20 
(±3 
Days) 
21 
(±3 
Days) 
22-27 
(±3 
Days) 
28 28 
(±3 
Days) 
- 
29-33 
(±2 
Days) 
Visit Number 
1 
2 
 
3 
 
4 
 
5 
 
6 
- 
7 
WREMB-R Questionnaire 22
 
X 
 
 
 
 
 
X 
 
X 
 
 
2-day washout of open-label 
KP415 23 
 
 
 
 
 
 
X 
 
 
 
 
 
SKAMP and PERMP 24 
 
 
 
 
 
X 
 
X 
 
X 
 
 
Adverse Events 25 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 26 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
EOS = End of Study; ET = Early Termination; BMI = Body Mass Index; 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 confirmed by the Mini International Neuropsychiatric Interview for Children and 
Adolescents (MINI-KID). 
2. A Placement Permanent Product Measure of Performance (PERMP) will be performed at Visit 2 
(Day 0) to assure that subjects can complete at least the basic level of math problems and to 
determine the appropriate level of math to be assigned during the practice laboratory classroom day at 
Visit 4. Subjects must be able to perform at least the basic level of problems to enroll in the trial. 
3. Capsule Swallowing Test: Subjects will take a size 3 capsule with 240 mL of water at Screening. The 
capsule may not contain any active drug substance. Subjects must be able to easily swallow the size 3 
capsule to be eligible for further study participation. 
4. Medical History: A complete medical history including chronic conditions, relevant surgical 
procedures (with start date), history of alcohol and recreational drug use. 
5. Complete physical examination at Screening, and at ET (if possible) or Follow-Up. 
6. All physical examinations will include the measurement of body weight. Height and BMI at 
Screening only. 
7. 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. Vital signs will be collected once 
at each visit. On the full laboratory classroom day (Day 28 ±3 days, Visit 6), vital signs will be 
collected at any time before dosing. 
8. Electrocardiogram (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. The QT interval corrected for heart rate will be calculated with 
Fridericia’s formula (QTcF). ECGs will be obtained at Screening, and at Early Termination or 
Follow-Up. 
9. Urine Screen for Alcohol and Drugs of Abuse: Urine samples will be tested for alcohol, and drugs of 
abuse (amphetamines, methamphetamines, benzodiazepines, barbiturates, cannabinoids, cocaine, 
opioids including oxycodone) at Screening (Visit 1). If the urine test is positive for any of the analytes 
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 at 


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Screening may test positive for ADHD medications such as amphetamines and methamphetamines. 
These medications must be washed out by Day 0. 
10. Urine Screen for Methylphenidate (MPH): Urine samples will be tested for MPH at Screening (Visit 
1), at Visit 2, and before administration of study drug at Visit 5. A urine dipstick (e.g., NarcoCheck®) 
will be used to screen for the presence of MPH in the urine. If a subject's current ADHD medication 
at Screening contains MPH, the urine screen at Screening may test positive for MPH. Since all 
ADHD medications must be washed out by Day 0, they must test negative on Day 0 (Visit 2) for 
subjects to be eligible to continue in the study. 
11. Pregnancy Test: performed for female subjects of childbearing potential. A serum β-hCG pregnancy 
test will be performed at Screening. A urine pregnancy test will be performed at Visit 2, Visit 5 and at 
Follow-Up or Early Termination. A positive pregnancy test at Screening, or before the last dose of 
study drug will exclude a subject from further participation in the study. 
12. 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 visits of 
the Dose Optimization Phase (Visits 2, 3, 4 and 5), at Visit 6, and at Follow-Up or Early Termination. 
Subjects who have any history of attempted suicide or clinically significant suicidal ideation based on 
the C-SSRS assessment, in the opinion of the Investigator, at any time before the last dose of study 
drug, will be excluded from further participation in the study. 
13. Subjects must wash out ADHD medications prior to Day 0 (Visit 2). Stimulant ADHD medications 
(with the exception of study drug), including herbal medications, are prohibited from 5 days prior to 
the start of the Dose Optimization Phase (Day 0) to the end of the Follow-Up Visit or Early 
Termination Visit. Before or on the day during the screening period that subjects 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”). Non-Stimulant ADHD medications are prohibited from 21 days prior to the start of the 
Dose Optimization Phase (Day 0) to the end of the Follow-Up Visit or Early Termination Visit. Other 
prohibited medications with their associated time windows when they are prohibited are listed in 
Section 12.1 of the protocol. 
14. KP415 Dose Optimization: Subjects will begin taking open-label KP415 at home the morning 
following Visit 2. The starting dose of KP415 (Days 1-7 ±3 days) will be 30 mg/day. KP415 dose 
adjustments, if needed, will be performed at approximately weekly intervals between visits (at Visits 
3 and 4). Actual visit dates may deviate from exactly being spaced 7 days apart such that the total 
duration of the Dose Optimization Phase is 3 weeks (21 ±3 days). The daily doses of KP415 used in 
the Dose Optimization Phase will be 20, 30 and 40 mg (dose optimization range of ≥20 and ≤40 mg). 
At Visits 3 and 4, 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 KP415 dose should be increased, decreased, or remain the same for 
the next week of dosing. If subjects experience symptoms of intolerance during the at-home 
treatment, they must contact the clinical site, and, at the discretion of the Investigator, their KP415 
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. 
At Visit 5, the Investigator will evaluate the eligibility criteria for continuation into the subsequent 
Double-Blind Treatment Phase. For subjects eligible for the Treatment Phase, the optimal daily 
KP415 dose will be used as the daily KP415 dose (or matching placebo) in the Treatment Phase. 
15. Randomization: Subjects able to tolerate at least 20 mg/day of KP415 during the Dose Optimization 
Phase and with an adequate dose-response will be randomized on a 1:1 basis to a treatment of KP415 
(Treatment A) or placebo (Treatment B). The appropriate blinded study drug to be taken at home 
once-a-day in the morning on each of the following 6 days (Days 22-27 ±3 days) will be dispensed to 
the subjects. 
16. Study Drug Administration (Double-Blind Treatment Phase): Subjects on an optimized KP415 dose 
of 20, 30, and 40 mg at the end of the Dose Optimization Phase will receive 20, 30, and 40 mg, 


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respectively, of KP415 capsules or matching placebo capsules once-per-day for 7 days in the 
morning. No adjustment of the dose of study drug will be permitted. All study drugs will be given 
orally. On Days 22-27 ±3 days, subjects will take study drug at home under supervision of their 
parent or legal guardian. The final dose of study drug will be administered on the 7th day of the 
Double-Blind Treatment Phase (Day 28 ±3 days; Visit 6) at the laboratory school by study staff. The 
capsule with study drug will be swallowed with approximately 240 mL of water. Additional water 
may be given if needed, and the volume of additional water will be recorded. 
17. Laboratory Classroom Days: At Visit 4 and Visit 5, each subject will complete abbreviated practice 
laboratory classroom sessions with 4 SKAMP/PERMP assessments designed to mirror the pre-dose to 
2-hour post-dose period of the full-length laboratory classroom session of Visit 6. At Visit 6, subjects 
will complete a full-length laboratory classroom session that is designed to model a typical school day 
plus after-school activity totaling up to 13 hours after the 7th and last dose of KP415 or Placebo in the 
Double-Blind Treatment Phase. 
18. ADHD-Rating Scale-5 (ADHD-RS-5) assessment: 1 assessment at the indicated visits.  
19. Clinical Global Impressions–Severity (CGI-S) scale assessment: 1 assessment at the indicated visits. 
20. Clinical Global Impressions–Improvement (CGI-I) scale assessment: 1 assessment at the indicated 
visits. CGI-I score of 1 or 2 points (“Very Much Improved” or “Much Improved”) at the end of the 
Open-Label Dose Optimization Phase. 
21. Conners 3rd Edition-Parent (Conners 3-P): The parent/guardian/caregiver will assess changes in 
ADHD symptoms via the Conners 3-P questionnaire at baseline (Visit 2) and at each visit during the 
Dose-Optimization Phase and the Treatment Phase. 
22. Weekly Rating of Evening and Morning Behavior - Revised (WREMB-R) Scale: The Investigator or 
designee will obtain the scores for the WREMB-R questionnaire by interviewing the 
parent/guardian/caregiver at Visits 2, 5 and 6.  
23. Washout of open-label KP415 for 2 days before Visit 5: No study drug will be administered during 
the 2 days before the baseline SKAMP and PERMP assessment at pre-dose of Visit 5. The 2 days of 
NO drug (2 skipped doses) entail the doses on the day before Visit 5 and the day before that. 
24. Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) and Permanent Product Measure of 
Performance (PERMP) score assessments:  
• 
Visit 4 (Day 14 ±3 days): Abbreviated practice laboratory classroom session with 
SKAMP/PERMP assessments at pre-dose and at 0.5, 1, and 2 hours post-dose. At this visit, the 
final level of math for each subject will be determined for use in the remainder of the study 
(Visits 5 and 6). 
• 
Visit 5 (Day 21 ±3 days): Abbreviated practice laboratory classroom session with 
SKAMP/PERMP assessments at pre-dose and at 0.5, 1, and 2 hours post-dose. The pre-dose 
assessment (after 2 days of no drug) will be recorded as the baseline for the SKAMP and 
PERMP. 
• 
Visit 6 (Day 28 ±3 days): Full laboratory classroom day with SKAMP/PERMP assessments at 
pre-dose and at 0.5, 1, 2, 4, 8, 10, 12 and 13 hours post-dose. 
At Visits 4, 5, and 6, subjects will be administered unblinded study drug at the study site. 
25. Adverse Events: To be assessed and recorded in the eCRF following the first dose of open-label drug 
(KP415), on Day 1, through either Follow-Up or Early Termination. Subject’s parent/guardian will be 
instructed to contact the study site for the reporting of AEs during the dosing periods at home. 
26. Concomitant Medications: new and/or changed medications and dose, medical treatments and/or 
therapies will be recorded at Screening through either Follow-Up or Early Termination. 
27. Actual visit dates in the Dose Optimization Phase may deviate from exactly being spaced 7 days apart 
such that the total duration of the Dose Optimization Phase ranges between 18 and 24 days (21 ±3 
days). 
28. The end of the Treatment Phase is on Day 28 ±3 days (Visit 6), after all post-dosing procedures 
including all laboratory classroom assessments are completed. 
29. At the discretion of the Investigator, ensuring the safety of the subjects, any ET procedures that were 


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already performed on the same day as part of the procedures of the Dose Optimization or Treatment 
Phase, do not need to be repeated. 
2. STUDY DESIGN SCHEMATIC 
 
Note: The study days listed for Visits 3, 4, and 5 may deviate with ±3 days for individual subjects such that 
the total duration of the Dose Optimization Phase is 21 days ±3 days (duration ranging from 18 to 24 days). 
Any deviation of the targeted 21-day Dose Optimization Phase will be carried over into the actual days for 
the subsequent visits: Visit 6 at Day 28 ±3 days, and Visit 7 at days ranging from Day 29 ±3 days to Day 33 
±3 days. 
 
 


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3. BACKGROUND 
3.1. Attention-Deficit Hyperactivity Disorder (ADHD) 
ADHD is a common neurobehavioral disorder that occurs in 6-8% of children and 4-5% of adults 
worldwide (Wilens et al. 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 
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®, Concerta®, Daytrana®, Ritalin®, 
Methylin®, Quilivant®, 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. 
3.2. Laboratory Classroom Studies 
Methylphenidate has been an important treatment option for ADHD for many years, including for 
the treatment of children with ADHD. Patients with ADHD are titrated to their optimal dose of 
methylphenidate based on assessments of efficacy and tolerability. Clinical studies with school-age 
children with ADHD in a laboratory classroom setting (Lawrence et al. 2004; Swanson et al. 2004) 
are ideally suited for the assessment of stimulant medications and has been previously employed in 
studies of methylphenidate (Swanson et al. 2003, 2004) and amphetamine medications (McCracken 
et al. 2003; Swanson et al. 1998). Analog classroom studies facilitate repeated observational 
measures of attention, deportment, and cognitive performance, and assessment of time course 
effects in a controlled setting (Swanson et al. 2003; Lawrence et al. 2004). The model enables 
investigators to collect with carefully controlled methods, documented assessments of drug effect 
by direct observation over multiple time points throughout the day. 
4. KP415: A PRODRUG CONJUGATE 
KemPharm is developing KP415 as an extended release (ER) prodrug of d-threo-MPH HCl. 
Chemically, KP415 consists of a single d-threo-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 covalent linkage makes KP415 a new chemical entity (NCE). 
Results from preliminary in vivo studies in rats have shown that the prodrug has unique 
pharmacokinetic (PK) properties that suggest it will have reduced intranasal and intravenous abuse 
potential. 


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As a prodrug, KP415 represents a potential abuse-deterrent form of MPH with abuse-deterrent 
properties that are imparted at the molecular level. Some of the KP415 attributes that make it worthy 
of further development are highlighted below: 
• KP415 has negligible pharmacological activity at key receptors that are responsible for the 
efficacy of d-MPH for the treatment of ADHD. 
• When administered intranasally or intravenously in rats, KP415 resulted in d-MPH plasma 
concentrations that are significantly reduced when compared to d-MPH HCl. 
• KP415 exhibits chemical stability when subjected to certain hydrolytic conditions with the 
intention to extract methylphenidate. 
5. OVERVIEW OF CLINICAL STUDIES WITH KP415 
The pharmacology, metabolism and toxicology of methylphenidate are well established (Challman 
2000, Leonard 2004). Methylphenidate is a CNS stimulant approved for the treatment of ADHD 
and narcolepsy. Methylphenidate inhibits the reuptake of dopamine and norepinephrine, increased 
dopaminergic and noradrenergic activity in the prefrontal cortex may explain its efficacy in ADHD. 
Common side effects of methylphenidate include nervousness, agitation, anxiety, sleep problems 
(insomnia), stomach pain, decreased appetite, weight loss, nausea, vomiting, dizziness, palpitations, 
headache, vision problems, increased heart rate, increased blood pressure, sweating, skin rash, 
psychosis, and numbness, tingling, or cold feeling in hands or feet. When abused, methylphenidate 
produces toxicity similar to other CNS stimulant overdoses (Morton 2000). Supra-therapeutic doses 
have shown to cause delirium, hallucinations, bruxism (jaw-grinding), and trismus (jaw clenching) 
(Morton 2000). 
5.1. Study KP415.101 
This Phase 1 proof-of-concept trial (Study KP415.101) was designed to assess the PK of 32 mg of 
KP415 API (liquid, dissolved in water) compared with 36 mg of Concerta® (tablet) after oral 
administration under fasted conditions. Twenty-four (24) healthy adult volunteers were enrolled in 
this open-label, single-dose, two-treatment, two-period PK trial. Dosing levels in each treatment 
were not molar equivalent amounts of d-MPH: 36 mg Concerta® contained approximately 12% 
more d-MPH than 32 mg of the KP415 prodrug API (standalone KP415). 
KP415 API prodrug effectively released the active d-MPH into the bloodstream which is consistent 
with previously collected preclinical data. After KP415 API prodrug dosing, the mean peak 
concentration (Cmax) of d-MPH was 2.9 ng/mL at a median Tmax of 8 hr compared to 8.0 ng/mL at 
6 hr after Concerta®. 
The mean systemic exposure (AUC0-last) for d-MPH was 44 ng•hr/mL after KP415 API prodrug 


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versus 97 ng•hr/mL after Concerta® dosing. The mean total systemic exposure (AUC0-inf) for d-
MPH was 100 ng•hr/mL after KP415 API prodrug versus 102 ng•hr/mL after Concerta® dosing. 
The mean terminal elimination plasma half-life (T1/2) of d-MPH was 25 hr after KP415 API prodrug 
versus 4 hr after Concerta®. 
After oral dosing of standalone KP415, it appears that that there is rapid absorption of prodrug 
followed by slow release of d-MPH resulting in a gradual onset followed by a slow extended release 
of d-MPH. The later Tmax and longer T1/2 for d-MPH after KP415 dosing indicate that KP415 as a 
prodrug of d-MPH has extended-release (ER) properties that support a once-per-day dosing 
schedule for an ADHD indication. The ER properties inherent in the KP415 prodrug molecule can 
subsequently provide sustained d-MPH exposure, as desired for a once-per-day treatment of ADHD 
in adults. Since plasma concentrations of the inactive intact KP415 molecule were measured after 
oral KP415 dosing, circulating levels of prodrug may contribute to the ER profile of KP415-derived 
d-MPH. No l-MPH levels were detected after KP415 dosing and very low l-MPH levels were 
measured after Concerta® dosing. 
Both treatments were generally well-tolerated. There were no apparent changes in vital signs and 
ECG parameters between treatments. Safety laboratory values were approximately the same after 
the treatment phase versus those measured at Screening. 
5.2. Study KP415.109 
This Phase 1 open-label PK study included a treatment group wherein healthy adult volunteers were 
dosed with oral daily doses of 12 mg d-MPH API (immediate release component) and 56 mg KP415 
prodrug API, each administered as an oral liquid in water immediately after each other. The total 
daily equivalent d-MPH dose was 40 mg. This dose was the same as the highest dose that will be 
used in the current protocol. 
The mean d-MPH plasma concentrations on Day 7 of Study KP415.109 are presented in Figure 1. 
The mean d-MPH trough concentration (Cmin; pre-dose on Day 7) was 3.3 ng/mL and the mean d-
MPH peak concentration (Cmax on Day 7) was 20.9 ng/mL at a median Tmax of 1.5 hr. The mean 
systemic exposure over the dosing interval (AUC0-24hr) for d-MPH was 208 ng•hr/mL and the mean 
terminal elimination plasma half-life (T1/2) of d-MPH was 8.9 hr. The mean accumulation ratios 
(Day 7/Day 1 ratios) for Cmin, Cmax and AUC0-24hr were 1.31, 1.20 and 1.34, respectively. The 
combination of 70%/30% KP415/d-MPH resulted in early peak d-MPH exposure followed by 
sustained d-MPH exposure, as desired for chronic, once-per-day treatment of ADHD in a pediatric 
population. The efficacy and safety of this combination in children 6-12 years old with ADHD will 
be studied in the study presented in this protocol. 


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Figure 1: Mean (N=10) d-Methylphenidate (d-MPH) Concentrations after the 7th Oral Daily 
Dose of 12 mg d-MPH and 56 mg KP415 Prodrug (Together Equivalent to 40 mg d-MPH) 
 
6. STUDY RATIONALE 
The current study will investigate the efficacy of KP415 compared to placebo and determine the 
onset and duration of the clinical effect of KP415 in treating children 6-12 years old with ADHD. 
7. STUDY OBJECTIVES 
7.1. Primary Objective 
To determine the efficacy of KP415 compared to placebo in treating children 6-12 years old with 
ADHD in a laboratory classroom setting. 
7.2. Secondary Objectives 
• To determine the onset and duration of the clinical effect of KP415 in treating ADHD in 
children 6-12 years old in a laboratory classroom setting.  
• To determine the safety and tolerability of KP415 compared to placebo in treating children 
6-12 years old with ADHD in a laboratory classroom setting. 


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8. INVESTIGATIONAL PLAN 
8.1. Study Design 
The study is a multicenter, dose-optimized, double-blind, randomized, placebo-controlled, parallel 
efficacy laboratory classroom study with KP415 in children with Attention-Deficit/Hyperactivity 
Disorder (ADHD). The study will consist of a Screening Period, an Open-Label Dose Optimization 
Phase, a Double-Blind Treatment Phase and a Follow-Up Visit, as follows: 
• Screening Period: Subjects will undergo a screening period up to 49 days prior to 
entering into the Open-Label Dose Optimization Phase. 
• Open-Label Dose Optimization Phase: During the Dose Optimization phase, subjects 
will be titrated to doses of 20, 30 or 40 mg KP415 based on tolerability and best 
individual dose-response in the opinion of the Investigator. 
• Double-Blind Treatment Phase: Eligible subjects will be randomized to receive single 
daily doses of KP415 or Placebo for 7 days according to a randomization schedule. The 
dose of KP415 given in the Treatment Phase will be the same as the optimized dose of 
KP415 at the end of the Dose Optimization Phase. All subjects will receive their 
assigned treatment daily for 7 days. The dose will be the same at each day of the 
Treatment Period. Efficacy and safety assessments will be performed after the last dose 
of the Treatment Period. 
• Follow-Up Visit: 3 ±2 days after administration of the last dose of the Treatment Phase, 
subjects will enter a Follow-Up Visit to evaluate safety parameters 
8.2. Study Duration 
Subjects will participate in the study as outpatients for up to 85 days, including up to 49 days of 
Screening; a 21-day (±3 days) Dose Optimization Phase, a 7-day Treatment Phase, and a Follow-
Up Visit (3 ±2 days after the administration of the last dose of the Treatment Phase). 
9. SUBJECT SELECTION 
9.1. Number of Subjects 
An appropriate number of subjects will enter the Screening Period to enroll approximately 176 
subjects in the Open-Label Dose Optimization Phase, and to randomize approximately 140 subjects 
in the Double-Blind Treatment Phase, with the intention to complete with approximately 126 
subjects. Subjects who terminate early in the Treatment Phase will not be replaced. 


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9.2. Study Population 
Children 6-12 years old with Attention-Deficit/Hyperactivity Disorder who meet the 
inclusion/exclusion criteria listed below. 
9.2.1. Inclusion Criteria (at Screening, except when noted otherwise) 
A subject will be eligible for inclusion in the study if all the following criteria apply: 
1. Subject must be at least 6 years old and less than 13 years old at the start of the Dose 
Optimization Phase (Day 0). 
2. Subject must have a body weight of at least 21 kg at Screening. 
3. Female subjects must agree, when 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. 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 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 of 12 years and older (including girls 
who will become 12 years or older 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”. 
4. Subject must be in general good health defined as the absence of any clinically relevant 
abnormalities as determined by the Investigator based on physical and neurological 
examinations, vital signs, ECGs, medical history, and clinical laboratory values 
(hematology, chemistry, and urinalysis) at Screening. If any of the hematology, 
chemistry, or urinalysis results are not within the laboratory's reference range, then the 
subject can be included only if the Investigator determines the deviations to be not 
clinically relevant. 
5. At least one parent/legal guardian of the subject must voluntary give written permission 
for him/her to participate in the study. 
6. Subject 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. 


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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 the Mini 
International Neuropsychiatric Interview for Children and Adolescents (MINI-KID). 
8. Subject must have a score of at least 3 (mildly 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 (see Section 12.1). 
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 Dose Optimization 
Phase (Day 0), and abstain from taking these to the end of the Follow-Up Visit or Early 
Termination; and wash out non-stimulant ADHD medications from 21 days prior to the 
start of the Dose Optimization Phase (Day 0), and abstain from taking these to the end 
of the Follow-Up Visit or Early Termination. 
10. An ADHD-Rating Scale-5 (ADHD-RS-5) total score (DuPaul et al. 2016) of at least 28 
at Visit 2 (Day 0). For subjects requiring washout of ADHD medications, this criterion 
refers to a score following washout (see Section 12.1). 
11. Subjects need to be able to perform at least the basic level of problems on the PERMP, 
based on a calibration assessment (Placement PERMP) performed at Visit 2 (Day 0). 
Based on the Placement PERMP, the level of math will be determined to be assigned 
during the practice laboratory classroom day at Visit 4. 
12. 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. If the 
subject is cared for by a caregiver for relevant parts of a school day, and if in this case, 
in the opinion of the Investigator, the caregiver of the subject is more suitable for certain 
assessments (for example, Conners 3-P and WREMB-R), the caregiver will need to 
agree to the applicable procedures and visits. 
13. Subject, parent/legal guardian and caregiver (if applicable) must be able to speak and 
understand English, and be able to communicate satisfactorily with the Investigator and 
study coordinator. 
14. Subject must be able to swallow size 3 capsules as demonstrated by easily swallowing 
a size 3 capsule at Screening. 
9.2.2. Exclusion Criteria (at Screening, except when noted otherwise) 
A subject who meets any of the following exclusion criteria will not be enrolled into the study: 


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1. If female, must not be pregnant or breastfeeding, and if of childbearing potential, must 
have a negative serum pregnancy test at Screening. In addition, a positive pregnancy test 
before the last dose of study drug will exclude a subject from further participation in the 
study. “Of childbearing potential” is defined in Section 14.8. 
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. 
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, 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. Past history of 
febrile seizure, drug-induced seizure, or alcohol withdrawal seizure is allowed. Subject 
taking anticonvulsants for seizure control currently or within the past 2 years before 
Screening is not eligible for study participation. 
6. Subject has a current (last month) psychiatric diagnosis other than specific phobia, motor 
skills disorders, oppositional defiant disorder, sleep disorders, elimination disorders, 
adjustment disorders, learning disorders, or communication disorders. Participants with 
school phobia or separation anxiety will not be eligible. 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. 
7. Subject has any history of attempted suicide or clinically significant suicidal ideation 
based on the C-SSRS assessment, in the opinion of the Investigator, at Screening or at 
any time before the last dose of study drug. 


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8. Subject has any clinically significant unstable medical abnormality, chronic disease, 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 drug absorption, distribution, metabolism, or excretion of study drug. Active 
medical conditions that are minor or well-controlled are not exclusionary if they do not 
affect risk to the subject or the study results. In cases in which the impact of the condition 
upon risk to the subject or study results is unclear, the medical monitor should be 
consulted. Any subject with a known cardiovascular disease or condition (even if 
controlled) must be discussed with the medical monitor during Screening. 
9. Subject has a history or presence of abnormal ECGs, which in the Investigator's opinion 
is clinically significant. Screening site ECGs will be centrally over-read, and eligibility 
will be determined by the Investigator based on the results of the over-read report. 
10. Subject has a history of, or currently has a malignancy, except for non-melanomatous 
skin cancer. 
11. 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. 
12. Subjects with a history of substance abuse or treatment (including alcohol) within 1 year 
prior to Screening. 
13. Subject shows evidence of substance or alcohol use or is currently using tobacco or other 
nicotine-containing products, or has a positive urine alcohol or urine drug screen at 
Screening. Subjects with a positive 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. 
14. Subject has a positive urine methylphenidate screen at the start of the Dose Optimization 
Phase (Day 0, Visit 2). 
15. Subject who has initiated Cognitive Behavioral Therapy (CBT) for the treatment of 
ADHD less than 1 month prior to Screening (subjects on stable CBT will be allowed), 
has initiated behavioral therapy (including school based interventions) less than 1 month 
prior to Screening, or is receiving behavioral therapy and in the opinion of the 
Investigator will not be able to follow a stable routine for the duration of the study. 
Unavoidable changes in school-based interventions that occur during study participation 


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will not be exclusionary, but should be documented by the Investigator, to the extent 
possible. 
16. Subject has participated in a classroom study within 6 months prior to the start of 
Screening, or has participated in any other clinical study with an investigational 
drug/product within 90 days prior to Screening, or is currently participating in another 
clinical trial. 
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 intolerance to adequate dose and 
duration of treatment with methylphenidate products. Judgment of adequate dose and 
duration is at the discretion of the Investigator. 
19. Subjects are using or planning to use prohibited drugs during the trial as specified in the 
protocol. 
20. Subject has a history of severe allergies or adverse drug reactions to more than one class 
of medications. 
21. Subject has a history of allergic reaction or a known or suspected sensitivity to 
methylphenidate or any substance that is contained in the study drug. 
22. Subject has any food allergies or dietary restrictions that are determined by the 
Investigator as too severe to be easily accommodated for during the study. 
23. Subject was home-schooled within 12 months prior to Screening. 
24. 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. 
25. 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. 
26. Subject's parent/legal guardian is an investigational site staff member or a relative of an 
investigational site staff member or a relative of an investigational site staff member. 
27. Subjects with a family member living in the same household participating in another 
ADHD clinical trial during the period of Screening through the Follow-Up Visit will be 


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excluded. Subjects with a family member living in the same household participating in 
the current clinical trial during the administration of study drug (Visits 2 to 6) will be 
excluded. Different subjects from the same family are allowed in this trial if they are in 
different cohorts, and there is no overlap in time from Visit 2 to Visit 6. 
28. Subject is, in the opinion of the Investigator, unsuitable in any other way to participate 
in this study. 
9.2.3. Eligibility Criteria (End of Dose Optimization Phase) 
Subjects will need to meet the following additional eligibility criteria at the end of the Dose 
Optimization Phase in order to enter into the Double-Blind Treatment Phase: 
1. A reduction of ≥30% reduction of ADHD-RS-5 from baseline (Day 0) during the Open-
Label Dose Optimization Phase. 
2. A CGI-I score of 1 or 2 points (“Very Much Improved” or “Much Improved”) at the end 
of the Open-Label Dose Optimization Phase. 
3. Acceptable tolerability of the optimized KP415 dose experienced during the Dose 
Optimization Phase. 
These assessments will be made based on the days before Visit 5 while still taking study drug (and 
NOT based on the 2 days of no study drug before Visit 5) 
9.2.4. Rescreening 
Subjects who are screened outside the screening window may be rescreened for participation in a 
later cohort. Subjects who received any dose of study drug and are terminated early or are not 
eligible to continue in the Treatment Phase, are not eligible to participate in another cohort of the 
study (and will not be rescreened). 
10. STUDY TREATMENTS 
10.1. KP415 Dose Optimization 
In the Open-Label Dose Optimization Phase, daily treatments of 20, 30 and 40 mg open-label 
KP415 capsules will be administered (one capsule/day), for the titration to an optimal daily KP415 
dose based on tolerability and best individual dose-response in the opinion of the Investigator. At 
Visits 4 and 5, study drug will be administered at the school site by study staff on the morning of 
the abbreviated laboratory classroom days. Two days before Visit 5, subjects must not take study 
drug. On the other days of the Dose Optimization Phase, the medication will be taken in the morning 
at home. The dose taken at the school site at Visit 5 will be the last dose of unblinded study drug. 


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Subjects will begin taking open-label KP415 at home the morning following Visit 2. The starting 
dose of KP415 (Days 1-7 ±3 days) will be 30 mg/day. KP415 dose adjustments, if needed, will be 
performed at approximately weekly intervals between visits (at Visits 3 and 4). Actual visit dates 
may deviate from exactly being spaced 7 days apart such that the total duration of the Dose 
Optimization Phase ranges between 18 and 24 days (21 ±3 days). The daily doses of KP415 used 
in the Dose Optimization Phase will be 20, 30 and 40 mg (dose optimization range of ≥20 and ≤40 
mg). At Visits 3 and 4, 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 KP415 dose should be increased, decreased, or remain the 
same for the next week of dosing. If subjects experience symptoms of intolerance during the at-
home treatment, they must contact the clinical site, and, at the discretion of the Investigator, their 
KP415 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. 
At Visit 5, the Investigator will evaluate the eligibility criteria (see Section 9.2.3) for continuation 
into the subsequent Double-Blind Treatment Phase. For subjects eligible for the Treatment Phase, 
the optimal daily KP415 dose will be used as the daily KP415 dose (or matching placebo) in the 
Treatment Phase. 
10.2. Study Drug Administration in the Double-Blind Treatment Phase 
The following treatments will be administered in the Double-Blind Treatment Phase: 
• Treatment A: one KP415 capsule (test product) once daily for 7 days. 
• Treatment B: one matching placebo capsule once daily for 7 days. 
The dose of KP415 will be determined by the optimal dose of KP415 at the end of the Dose 
Optimization Phase, either 20, 30 or 40 mg/day KP415 or matching placebo. 
During the Treatment Phase, blinded study medications of each treatment will be administered from 
Sunday (the day after Visit 5) to Saturday (Visit 6). On Saturday (Visit 6), the blinded doses of each 
study drug will be administered at the school site by study staff on the morning of the test laboratory 
classroom day. On the other days, the medication will be taken in the morning at home. Double-
blind study drug will be taken orally with 240 mL water and additional water may be given if needed 
10.3. Treatment Assignment/Randomization 
Open-Label Dose Optimization Phase: All eligible subjects will start on a dose of 30 mg/day 
open-label KP415 and the KP415 dose will be titrated to either 20, 30 or 40 mg/day based on 
tolerability and best individual dose-response in the opinion of the Investigator. 
Double-Blind Treatment Phase: Subjects able to tolerate at least 20 mg/day of KP415 and with 


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an adequate dose-response during the Dose Optimization Phase (see eligibility criteria in Section 
9.2.3) will be randomized on Day 21 (Visit 5) of the Treatment Period on a 1:1 basis to a treatment 
of KP415 (Treatment A) or placebo (Treatment B). Randomization will be stratified by study site. 
10.4. Blinding 
Open-Label Dose Optimization Phase: the KP415 dose levels during the Dose Optimization 
Phase including the optimized KP415 dose at the end of the Dose Optimization Phase will not be 
blinded. 
Double-Blind Treatment Phase: the treatment with study drug, either active KP415 or placebo, 
will be blinded during the Double-Blind Treatment Phase. Neither the subject, the Investigator, or 
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 
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 patient’s treatment 
assignment is essential for the clinical management or welfare of the patient, the Investigator should 
contact the ARO’s Medical Monitor (or designee). Prior to unblinding the patient’s treatment 
assignment, the Investigator should assess the relationship of an adverse event to the administration 
of the study drug (Yes or No). The Investigator must then contact the ARO’s Medical Monitor to 
unblind an individual patient’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 an SAE is reported, the ARO’s Medical 
Monitor (or designee) may unblind the treatment assignment for an individual subject for expedited 
regulatory reporting requirements. 
10.5. Compliance 
All study drug will be recorded by each site’s pharmacy staff member or Investigator-delegated 
employee. A record of the study drug accountability will be prepared and kept by the clinical site. 
11. STUDY PROCEDURES 
The study will consist of a Screening Visit, an Open-Label Dose Optimization Phase, a Double-
Blinded Treatment Phase, and a Follow-Up Visit. 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:  


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11.1. Screening Procedures 
Subjects will complete the screening visit (Visit 1) within 49 days of starting the Open-Label Dose 
Optimization Phase (Visit 2). Prior to conducting any study-related activities including screening 
procedures, written or verbal assent and the Health Insurance Portability and Accountability Act 
(HIPAA) authorization must be signed and dated by the parent/legal guardian. 
The following procedures will be performed at the Screening Visit: 
1. Permission and HIPAA authorization by one parent/legal guardian of the subject. 
2. Written or verbal assent by the subject. 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. 
3. ADHD Diagnosis and Confirmation 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 confirmed by the 
Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-
KID). 
4. Perform the clinician-administered Clinical Global Impressions–Severity (CGI-S) 
scale assessment. Subjects must have a CGI-S score of at least 3 (mildly ill) for further 
study participation. 
5. Subject demographics including date of birth, sex, race, and ethnicity. 
6. Administer a size 3 capsule orally with 240 mL of water (Capsule Swallowing Test). 
The capsule may not contain any active drug substance. Subjects must be able to easily 
swallow the size 3 capsule to be eligible for further study participation. 
7. Review of inclusion/exclusion criteria to determine study eligibility. 
8. Record medical history including chronic conditions, relevant surgical procedures 
(with start date), medications, and history of alcohol and recreational drug use. 
9. A complete physical examination. 
10. Body weight, height, and BMI. 
11. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood 
pressure, and oral temperature). 
12. Perform the Columbia Suicide Severity Rating Scale (C-SSRS) assessment, 


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“Children’s Baseline/Screening” version. Subjects with a history of attempted suicide 
or clinically significant suicidal ideation based on the C-SSRS assessment, in the 
opinion of the Investigator 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. 
13. 12-lead electrocardiogram (ECG) after subject has been in supine position for a 
minimum of 3 minutes. 
14. Clinical laboratory tests (chemistry, hematology and urinalysis) will be obtained. 
Clinical laboratory measurements may be repeated at the discretion of the Investigator. 
15. At Screening, urine samples will be tested for alcohol and drugs of abuse 
(amphetamines, methamphetamines, benzodiazepines, barbiturates, cannabinoids, 
cocaine, opioids including oxycodone). If the urine test is positive for alcohol or drugs 
of abuse 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 at Screening may test positive for ADHD medications such 
as amphetamines and methamphetamines. These medications must be washed out by 
Day 0. 
16. At Screening, urine samples will be tested for methylphenidate. If the urine test is 
positive for methylphenidate 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 at Screening may test positive for 
methylphenidate. Since these medications must be washed out by Day 0, the 
methylphenidate screen must test negative on Day 0 (Visit 2) for subjects to be eligible 
to continue in the study. 
17. Serum β-human chorionic gonadotropin (β-hCG) pregnancy test for all female subjects 
of childbearing potential. A positive pregnancy test will exclude a subject from further 
participation in the study. “Of childbearing potential” is defined in Section 14.8. 
18. Review of concomitant medications, treatment and/or therapies including treatment for 
ADHD. 
After subjects complete the screening procedures and are considered eligible to take part in the 
clinical study, they will be instructed to return to the clinic at Visit 2 to begin the Open-Label Dose 
Optimization Phase. In addition, they will be instructed with the date on which to begin wash out 
of any ADHD and other medications prior to Day 0 (Visit 2). See Section 12.1 for the medications 
that are prohibited and their associated time frames, including the days that they are prohibited 
before Day 0 (Visit 2), i.e., washout days for subjects taking the medications. 


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Before or on the day during the screening period that subjects 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”). 
Rescreening: Subjects who are screened outside the screening window may be rescreened for 
participation in a later cohort. Subjects who received any dose of study drug and are terminated 
early or are not eligible to continue in the Treatment Phase, are not eligible to participate in another 
cohort of the study (and will not be rescreened). 
11.2. Open-Label Dose Optimization Phase (Visit 2-5) 
Subjects who meet the inclusion/exclusion criteria during Screening, will enter into the Open-Label 
Dose Optimization Phase (Visit 2-5). The subjects will undergo the following procedures during 
these visits. 
11.2.1. Visit 2 (Day 0) 
The following procedures will be performed at Visit 2: 
1.  Review of inclusion/exclusion criteria to determine whether subjects continue to meet 
study eligibility. 
2. A Placement Permanent Product Measure of Performance (PERMP) will be performed 
to assure that subjects can complete at least the basic level of math problems and to 
determine the appropriate level of math to be assigned during the practice laboratory 
classroom day at Visit 4. Subjects must be able to perform at least the basic level of 
problems to enroll in the trial. 
3. Update medical history. 
4. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood 
pressure, and oral temperature). 
5. Perform the Columbia Suicide Severity Rating Scale (C-SSRS), “Children’s Since Last 
Visit” version. Subjects with clinically significant suicidal ideation based on the C-
SSRS assessment, in the opinion of the Investigator, 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. 
6. Perform the ADHD-Rating Scale-5 (ADHD-RS-5) score (DuPaul et al. 2016) 
assessment (baseline assessment). Subjects needs to have an ADHD-RS-5 total score of 
at least 28 for further study participation. For subjects requiring washout of ADHD 
medications, this criterion refers to a score following washout of at least 5 days. 


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7. Perform the clinician-administered Clinical Global Impressions–Severity (CGI-S) scale 
assessment (baseline assessment). Subjects must have a CGI-S score of at least 3 (mildly 
ill) for further study participation. For subjects requiring washout of ADHD 
medications, this criterion refers to a score following washout of at least 5 days. 
8. Perform the Clinical Global Impressions–Improvement (CGI-I) scale assessment. 
9. Perform the Conners 3-P baseline assessment. The parent/guardian/caregiver will assess 
the subject’s ADHD symptoms using the Conners 3-P questionnaire based on the 
subject’s functioning on the days before Visit 2 (and since washout of ADHD 
medications, if applicable). 
10. Perform the Weekly Rating of Evening and Morning Behavior - Revised (WREMB-R) 
assessment. The Investigator or designee will fill in the WREMB-R questionnaire based 
on an interview with the parent/guardian/caregiver. The scoring will be based on the 
subject’s morning and evening functioning on the days before Visit 2 (and after washout 
of ADHD medications, if applicable). 
11. Urine samples will be tested for methylphenidate. If the urine test is positive 
methylphenidate on Day 0, the subject will be excluded from study participation. 
12. Urine pregnancy test for all female subjects of childbearing potential. A positive 
pregnancy test at Screening will exclude a subject from further participation in the study. 
“Of childbearing potential” is defined in Section 14.8. 
13. Review of concomitant medications, treatment and/or therapies. 
14. Assessment and review of Adverse Events, and the subject’s parent/guardian will be 
instructed to contact the study site for the reporting of AEs during the dosing periods at 
home. 
15. Provide subject with the starting dose of 30 mg KP415 to begin the Dose Optimization 
Phase (Days 1-7 ±3 days). KP415 dose adjustments, if needed, will be performed at 
approximately weekly intervals between visits (at Visits 3 and 4). Actual visit dates may 
deviate from exactly being spaced 7 days apart such that the total duration of the Dose 
Optimization Phase ranges between 18 and 24 days (21 ±3 days). 
11.2.2. Visit 3 (Day 7 ±3 days) 
The following procedures will be performed at Visit 3: 
1. Record the number of returned and administered capsules of unblinded study drug for 
drug accountability and compliance. 


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2. Review of inclusion/exclusion criteria to determine whether subjects continue to meet 
study eligibility. 
3. Update medical history. 
4. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood 
pressure, and oral temperature). 
5. Perform the Columbia Suicide Severity Rating Scale (C-SSRS), “Children’s Since Last 
Visit” version. Subjects with clinically significant suicidal ideation based on the C-
SSRS assessment, in the opinion of the Investigator, 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. 
6. Perform the ADHD-Rating Scale-5 (ADHD-RS-5) score (DuPaul et al. 2016) 
assessment. 
7. Perform the clinician-administered Clinical Global Impressions–Severity (CGI-S) scale 
assessment. 
8. Perform the Clinical Global Impressions–Improvement (CGI-I) scale assessment. 
9. Perform the Conners 3-P Assessment. The parent/guardian/caregiver will assess the 
subject’s changes in ADHD symptoms using the Conners 3-P questionnaire. 
10. KP415 dosing and dose adjustments, if needed, will be performed at weekly intervals ± 
3 days. At Visit 3, based on the CGI, 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 KP415 dose should be 
increased, decreased, or remain the same for the next week of titration. At any day during 
the Dose Optimization Phase, the daily dose will be either 20, 30 or 40 mg KP415.  
11. Assessment and review of Adverse Events, and the subject’s parent/guardian will be 
instructed to contact the study site for the reporting of AEs during the dosing periods at 
home. 
12. Review of concomitant medications, treatment and/or therapies. 
11.2.3. Visit 4 (Day 14 ±3 days) 
If possible, study site staff will contact the parent/guardian 1 day before Visit 4 to remind them that 
subjects must come to Visit 4 without taking the study drug since it will be administered by study 
staff at Visit 4. 


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The following procedures will be performed at Visit 4: 
1. Record the number of returned and administered capsules of unblinded study drug for 
drug accountability and compliance. 
2. Review of inclusion/exclusion criteria to determine whether subjects continue to meet 
study eligibility. 
3. Update medical history. 
4. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood 
pressure, and oral temperature). 
5. Perform the Columbia Suicide Severity Rating Scale (C-SSRS), “Children’s Since Last 
Visit” version. Subjects with clinically significant suicidal ideation based on the C-
SSRS assessment, in the opinion of the Investigator 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. 
6. Perform the ADHD-Rating Scale-5 (ADHD-RS-5) score (DuPaul et al. 2016) 
assessment. This assessment may be obtained by phone within 48 hours before the visit. 
7. Perform the clinician-administered Clinical Global Impressions–Severity (CGI-S) scale 
assessment. This assessment may be obtained by phone within 48 hours before the visit. 
8. Perform the Clinical Global Impressions–Improvement (CGI-I) scale assessment. This 
assessment may be obtained by phone within 48 hours before the visit. 
9. Administer the open-label KP415 dose at the laboratory school by study staff. The 
capsule with study drug will be swallowed with approximately 240 mL of water. 
Additional water may be given if needed. 
10. Each subject will complete an abbreviated practice laboratory classroom session with 
SKAMP and PERMP assessments at pre-dose and at 0.5, 1, and 2 hours post-dose. 
11. Perform the Conners 3-P Assessment. The parent/guardian/caregiver will assess the 
subject’s changes in ADHD symptoms using the Conners 3-P questionnaire. The 
questionnaire form may be provided to the parent/guardian/caregiver at the previous 
visit, and be filled in by the parent/guardian/caregiver before coming to this visit. 
12. KP415 dosing and dose adjustments, if needed, will be performed at weekly intervals 
±3 days. At Visit 4, based on the CGI, interview with the parent/guardian/caregiver, and 
safety data, the Investigator will evaluate the subject’s therapeutic responses and 


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tolerability to treatment, and decide whether the current KP415 dose should be 
increased, decreased, or remain the same for the next week of titration. At any day during 
the Dose Optimization Phase, the daily dose will be either 20, 30 or 40 mg KP415. 
13. Assessment and review of Adverse Events, and the subject’s parent/guardian will be 
instructed to contact the study site for the reporting of AEs during the dosing periods at 
home. 
14. Review of concomitant medications, treatment and/or therapies. 
11.2.4. Visit 5 (Day 21 ±3 days) 
Two days before Visit 5, subjects must not take any study drug (this is important for obtaining a 
baseline of the SKAMP/PERMP scores). At Visit 5, subjects will be administered unblinded study 
drug at the study site (this is the last dose of unblinded study drug). If possible, study site staff will 
contact the parent/guardian 3 days before Visit 5 to remind them that subjects must abstain of taking 
study drug on the 2 days before Visit 5, and come to Visit 5 without taking the study drug since it 
will be administered by study staff at Visit 5. 
The following procedures will be performed at Visit 5: 
1. Record the number of returned and administered capsules of unblinded study drug for 
drug accountability and compliance.  
2. Update medical history. 
3. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood 
pressure, and oral temperature). 
4. Urine pregnancy test for all female subjects of childbearing potential. A positive 
pregnancy test will exclude a subject from further participation in the study. “Of 
childbearing potential” is defined in Section 14.8. 
5. Urine samples will be tested for methylphenidate. 
6. Perform the Columbia Suicide Severity Rating Scale (C-SSRS) assessment, “Children’s 
Since Last Visit” version. Subjects with clinically significant suicidal ideation based on 
the C-SSRS assessment, in the opinion of the Investigator, 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. 
7. Administer the open-label KP415 dose at the laboratory school by study staff. The 
capsule with study drug will be swallowed with approximately 240 mL of water. 


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Additional water may be given if needed. This dose will be the last dose of unblinded 
study drug in the Dose Optimization Phase. 
8. Each subject will complete an abbreviated practice laboratory classroom session with 
SKAMP and PERMP assessments at pre-dose and at 0.5, 1, and 2 hours post-dose. The 
pre-dose SKAMP and PERMP assessments will be recorded as the baseline for these 
assessments. 
9. Perform the ADHD-Rating Scale-5 (ADHD-RS-5) score (DuPaul et al. 2016) 
assessment. This assessment may be obtained by phone within 48 hours before the visit. 
This assessment will be made based on the days before Visit 5 while still taking study 
drug (and NOT based on the 2 days of no study drug before Visit 5). 
10. Perform the clinician-administered Clinical Global Impressions–Severity (CGI-S) scale 
assessment. This assessment may be obtained by phone within 48 hours before the visit. 
This assessment will be made based on the days before Visit 5 while still taking study 
drug (and NOT based on the 2 days of no study drug before Visit 5). 
11. Perform the Clinical Global Impressions–Improvement (CGI-I) scale assessment. This 
assessment may be obtained by phone within 48 hours before the visit. This assessment 
will be made based on the days before Visit 5 while still taking study drug (and NOT 
based on the 2 days of no study drug before Visit 5). 
12. Perform the Conners 3-P Assessment. At this visit, the parent/guardian/caregiver will 
assess the subject’s changes in ADHD symptoms using the Conners 3-P questionnaire 
based on the subject’s functioning on the days before Visit 5 while still taking study 
drug (and NOT based on the 2 days of no study drug before Visit 5). The questionnaire 
form may be provided to the parent/guardian/caregiver at the previous visit, and be filled 
in by the parent/guardian/caregiver before coming to this visit. 
13. Perform the Weekly Rating of Evening and Morning Behavior - Revised (WREMB-R) 
assessment. The Investigator or designee will fill in the WREMB-R questionnaire based 
on an interview with the parent/guardian/caregiver. The scoring will be based on the 
subject’s morning and evening functioning on the days before Visit 5 while still taking 
study drug (and NOT based on the 2 days of no study drug before Visit 5). 
15. The Investigator will evaluate the eligibility criteria (see Section 9.2.3) for continuation 
into the subsequent Double-Blind Treatment Phase. For subjects eligible for the 
Treatment Phase, the optimal daily KP415 dose will be used as the daily KP415 dose 
(or matching placebo) in the Treatment Phase. 
14. Randomize subjects on a 1:1 basis to a treatment of KP415 (Treatment A) or placebo 


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(Treatment B). The appropriate blinded study drug to be taken at home once-a-day in 
the morning on each of the following 6 days (Days 22-27 ±3 days) will be dispensed to 
the subjects. 
15. Assessment and review of Adverse Events, and the subject’s parent/guardian will be 
instructed to contact the study site for the reporting of AEs during the dosing periods at 
home. 
16. Review of concomitant medications, treatment and/or therapies. 
11.2.5. Unscheduled Visits 
At the discretion of the Investigator, subjects may be asked to come to the clinical site for an 
unscheduled visit. Unscheduled visits can occur at any time during the Dose Optimization Phase, 
between Visits 2, 3, 4 and 5. Examples of reasons to conduct an unscheduled visit: 
• If subjects experience an Adverse Event during the at-home treatment, they must contact 
the clinical site, and, at the discretion of the Investigator, further in-person medical 
evaluation and review is needed. 
• If subjects experience symptoms of intolerance during the at-home treatment with study 
drug or have complaints about increases in ADHD symptoms, they must contact the clinical 
site, and, at the discretion of the Investigator, their KP415 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). 
3. Assessment and review of Adverse Events. 
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 Adverse Events): 
a. Physical examination 


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b. 12-lead ECG after subject has been in supine position for a minimum of 3 
minutes 
c. C-SSRS, “Children’s Since Last Visit” version. Subjects with clinically 
significant suicidal ideation based on the C-SSRS assessment, in the opinion of 
the Investigator, 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 
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 unblinded 
KP415 drug: 
a. Perform the CGI-I scale assessment. 
b. Perform the Conners 3-P Assessment. The parent/guardian/caregiver will assess 
the subject’s changes in ADHD symptoms using the Conners 3-P questionnaire. 
c. If needed, perform a KP415 dose adjustments: based on the CGI, 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 KP415 dose should be increased, decreased, or remain the same. At 
any day during the Dose Optimization Phase, the daily dose will be either 20, 30 
or 40 mg KP415. 
If a subject meets withdrawal criteria during the Unscheduled Visit, the subject will be withdrawn 
and Early Termination procedures will be completed (see Section 11.4). 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 Unscheduled Visit do not need to be repeated. 
11.3. Treatment Phase: Days 22-27 & Visit 6 (Day 28) 
On Days 22-27 ±3 days, subjects will take double-blind study drug at home under supervision of 
parent or legal guardian. Subject’s parent/guardian will contact the study site for the reporting of 
AEs during the dosing period at home. 
The final dose of double-blind study drug will be administered on the 7th day of the double-blind 
Treatment Phase (Day 28 ±3 days; Visit 6) at the laboratory school by study staff. On Day 28 ±3 
days (Visit 6), each subject will complete a full-length laboratory classroom day with efficacy 
assessments at pre-dose and post-dose study drug.  
The following procedures will occur on Day 28 ± 3 days (Visit 6) of the study: 
1. Record the number of returned and administered capsules of blinded study drug for drug 
accountability and compliance. 


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2. Vital signs (respiratory rate, pulse rate, blood pressure, and oral temperature) after 
subject has been sitting for a minimum of 3 minutes, will be collected at any time before 
dosing. 
3. Perform the Columbia Suicide Severity Rating Scale (C-SSRS) assessment, “Children’s 
Since Last Visit” version. At Visit 6, if a subject has clinically significant suicidal 
ideation based on the C-SSRS assessment, in the opinion of the Investigator, further 
evaluation and/or preventive intervention steps for suicidal behavior will be taken, at the 
discretion of the Investigator. 
4. Perform the Weekly Rating of Evening and Morning Behavior - Revised (WREMB-R) 
assessment. The Investigator or designee will fill in the WREMB-R questionnaire based 
on an interview with the parent/guardian/caregiver. The scoring will be based on the 
subject’s morning and evening functioning on the days before Visit 6 while taking 
blinded study drug. 
5. Each subject will complete a full-length laboratory classroom day with efficacy 
assessments, as listed below. 
6. Perform the Conners 3-P Assessment. At Visit 6, the parent/guardian/caregiver will 
assess the subject’s changes in ADHD symptoms using the Conners 3-P questionnaire. 
7. Administer the final dose of the double-blind study drug on the 7th day of the Double-
Blind Treatment Phase at the laboratory school by study staff. The capsule with study 
drug will be swallowed with approximately 240 mL of water. Additional water may be 
given if needed, and the volume of additional water will be recorded. 
8. Perform the (SKAMP) Swanson, Kotkin, Agler, M-Flynn, and Pelham score 
assessments at pre-dose and at 0.5, 1, 2, 4, 8, 10, 12 and 13 hours post-dose on the full 
classroom day. 
9. Perform the Permanent Product Measure of Performance (PERMP) score assessment 
at pre-dose and at 0.5, 1, 2, 4, 8, 10, 12 and 13 hours post-dose on the full classroom 
day. 
10. Review of concomitant medications, treatment and/or therapies. 
11. Assessment and review of Adverse Events. 
11.4. Early Termination Visit 
Early Termination (ET) from the study is defined as withdrawal during the Dose Optimization 
Phase or Treatment Phase after at least one dose of study drug is administered. For subjects who 


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withdraw early from the study, the Investigator should make every effort to perform all ET 
procedures before discharging the subject from the research clinic. 
The following procedures will be performed at ET visits: 
1. Complete physical examination. 
2. Body weight. 
3. Vital signs (respiratory rate, pulse rate, blood pressure, and oral temperature) after subject 
has been sitting for a minimum of 3 minutes. 
4. 12-lead ECG after subject has been in supine position for a minimum of 3 minutes. 
5. Clinical laboratory tests (chemistry, hematology and urinalysis). 
6. Urine pregnancy test for all female subjects of childbearing potential. “Of childbearing 
potential” is defined in Section 14.8. 
7. Assessment of the Columbia Suicide Severity Rating Scale (C-SSRS), “Children’s Since 
Last Visit” version. If a subject has clinically significant suicidal ideation based on the C-
SSRS assessment, in the opinion of the Investigator, further evaluation and/or preventive 
intervention steps for suicidal behavior will be taken, at the discretion of the Investigator. 
8. Review of concomitant medications, treatment and/or therapies. 
9. Assessment and review of Adverse Events. 
Subjects will be discharged from the study clinic when the Investigator determines that the subjects 
are medically stable and, if possible, after all ET procedures are completed. 
Subjects who withdraw early from the study and complete the above ET procedures will not return 
for a Follow-Up Visit. Therefore, the ET Visit is the EOS for these subjects. 
11.5. Follow-Up Visit 
Subjects who complete the all phases of the study from the Open-Label Dose Optimization Phase 
through the Treatment Phase will return in 3 ±2 days after the administration of the last dose of 
study drug for the Follow-Up Visit. 
The following procedures will be completed during the Follow-Up Visit: 
1. Complete physical examination. 
2. Body weight. 


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3. Update medical history. 
4. Vital signs after a minimum of 3 minutes of rest (respiratory rate, pulse rate, blood pressure, 
and oral temperature). 
5. 12-lead ECG after subject has been in supine position for a minimum of 3 minutes. 
6. Clinical laboratory tests (chemistry, hematology and urinalysis). 
7. Urine pregnancy test for all female subjects of childbearing potential. “Of childbearing 
potential” is defined in Section 14.8. 
8. Assessment of the Columbia Suicide Severity Rating Scale (C-SSRS), “Children’s Since 
Last Visit” version. If a subject has clinically significant suicidal ideation based on the C-
SSRS assessment, in the opinion of the Investigator, further evaluation and/or preventive 
intervention steps for suicidal behavior will be taken, at the discretion of the Investigator. 
9. Review of concomitant medications, treatment and/or therapies. 
10. Assessment and review of adverse events. 
The Follow-Up Visit is the EOS for subjects who will undergo the Follow-Up procedures. 
11.6. End of Study (EOS) 
The End of Study (EOS) is either the Follow-Up Visit for subjects who complete the Treatment 
Phase, or the Early Termination Visit for subjects who withdraw early from the study. 
12. CONCOMITANT MEDICATIONS AND RESTRICTIONS 
Subjects will adhere to the following restrictions before and after administration of study drug, as 
specified: 
12.1. Medication Restrictions 
• Stimulant ADHD medications (with the exception of study drug), including herbal 
medications, are prohibited from 5 days prior to the start of the Dose Optimization Phase 
(Day 0) to the end of the Follow-Up Visit or Early Termination Visit. These include: 
methylphenidate, amphetamine, Ritalin®, Ritalin® SR, Metadate® ER, Concerta®, 
dextromethylphenidate, Focalin®, dextroamphetamine, Dexedrine®, Adderall®. 
• Non-Stimulant ADHD medications are prohibited from 21 days prior to the start of the Dose 
Optimization Phase (Day 0) to the end of the Follow-Up Visit or Early Termination Visit. 
These include: Atomoxetine, guanfacine, clonidine; and SSRIs such as fluoxetine and 


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paroxetine. 
• The following medications are prohibited from 21 days prior to the start of the Dose 
Optimization Phase (Day 0) to the end of the Follow-Up Visit or Early Termination Visit: 
o Tricyclic antidepressants. 
o Monoamine oxidase inhibitors (MAOIs) 
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 Coumarin anticoagulants 
 
• Sedative hypnotics/sleep enhancers (with the exception of melatonin) are prohibited from 
14 days prior to the start of the Dose Optimization Phase (Day 0) to the end of the Follow-
Up Visit or Early Termination Visit. 
• Melatonin is allowed if subjects have taken it for more than 30 days before the start of the 
Dose Optimization Phase (Day 0) and are on a stable dose. Otherwise, melatonin is 
prohibited from 5 days prior to Day 0 to the end of the Follow-Up Visit or Early Termination 
Visit. 
Medications allowed during the course of the study include nasal steroids, bronchodilators, 
acetaminophen and nonsteroidal anti-inflammatory medications; non-sedating antihistamines such 
as cetirizine, loratadine, and fexofenadine; mometasone; and approved courses of prescription and 
nonprescription medications for the treatment of acute illnesses. 
12.2. General Restrictions 
Female subjects must agree when 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. 
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 14 days after the last dose of study drug has been taken. 
“Of childbearing potential” is defined in Section 14.8. 


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13. INVESTIGATIONAL PRODUCT 
13.1. Active Pharmaceutical Ingredients 
The chemical name of the KP415 prodrug 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. It is a single d-methylphenidate 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. 
13.2. Clinical Trial Material 
The capsules of study drug (KP415 capsules) with contain two active pharmaceutical ingredients: 
d-methylphenidate hydrochloride as the immediate release (IR) d-methylphenidate component, and 
KP415 prodrug as the extended release (ER) d-methylphenidate component. In terms of d-MPH 
equivalent amounts, all capsule strengths contain 30% of d-MPH (IR component) and 70% of d-
MPH from the KP415 prodrug. The total equivalent amount of d-methylphenidate (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. 
Total 
d-MPH 
dose 1 
(mg) 
d-MPH 2 
 
 
(mg) 
KP415 
Prodrug 3 
 
(mg) 
20 
6 
28 (14) 
30 
9 
42 (21) 
40 
12 
56 (28) 
1. Based on the d-MPH amount plus the equivalent amount of d-MPH as KP415 prodrug. 
2. The dose of d-MPH is expressed in terms of d-methylphenidate hydrochloride. 
3. The dose of KP415 prodrug is expressed in terms of KP415 chloride. The amount of d-MPH hydrochloride 
equimolar to each KP415 prodrug dose is listed between parentheses. 
 
Unblinded capsules with 20, 30 and 40 mg KP415 will be used in the Open-Label Dose 
Optimization Phase; capsules of 20, 30 and 40 mg KP415 blinded versus placebo capsules will be 
used in the Double-Blind Treatment Phase. All study drug will be supplied by the Sponsor (or 
designee). The Sponsor (or designee) will supply sufficient quantities of KP415 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. 
All other drug products needed for the conduct of the study will be commercially available products 
obtained by each research site. 


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13.3. Pharmaceutical Formulation 
KP415 and placebo are provided in size 3 capsules consisting of an opaque white hydroxypropyl 
methylcellulose (HPMC) capsule shell without markings. Besides KP415 drug substance, each 
capsule of double-blind study drug contains the following inactive ingredients: microcrystalline 
cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate. The placebo capsules 
contain microcrystalline cellulose. 
13.4. Packaging and Labeling 
The KP415 capsules for the Open-Label Dose Optimization Phase, and the KP415 and placebo 
capsules for the Double-Blind Treatment Phase will be packaged and labeled appropriately. 
13.4.1. Open-Label Dose Optimization Phase 
Unblinded KP415 capsules will be packaged as bottles with 10 capsules. One bottle contains enough 
drug supply for one subject, for at least 7 days of dosing in the Open-Label Dose Optimization 
Phase (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. 
13.4.2. Double-Blind Treatment Phase 
Blinded study medication will be packaged and numbered as a kit for each subject based on the 
randomization scheme. The patient randomization number assigned by the interactive web response 
system or similar system/process will correspond to the number on the kit. 
Each kit for the Double-Blind Treatment Phase will consist of 1 bottle with 10 capsules of study 
drug and 1 bottle with 1 capsule of study drug. The bottle with 10 capsules contains enough drug 
supply for 6 days of dosing at home in the Double-Blind Treatment Phase (1 capsule/day every 
morning) and 4 extra capsules to cover the potential loss of capsules or extra dosing days before the 
next visit. The bottle with 1 capsule contains the capsule that will be administered in the research 
clinic in the morning of the laboratory classroom day on Day 7 (Visit 6). This is the last and final 
dose of study drug. 
Each bottle with 10 capsules will be dispensed to the subjects at Visit 5 with instructions on how to 
administer the study drug. The number on the bottle will be recorded in the Electronic Data Capture 
(EDC) system for the study. The bottle with 1 capsule will be labeled with the same number, and 
will be kept at the research clinic until administration. 
The bottles of study drug will be labeled according to the appropriate FDA regulations. 


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13.5. Dispensing Procedures 
13.5.1. Open-Label Dose Optimization Phase 
Unblinded bottles of drug supply will be dispensed at each visit as follows: 
• Visit 2: At Visit 2, subjects will be dispensed an unblinded bottle with 10 capsules of 30 mg 
KP415 (starting dose). 
• Visit 3: Subjects will return to the research clinic after 7 ±3 days for Visit 3 with unused 
study drug, and will be dispensed either a bottle with 30 mg KP415 (same daily dose as 
Week 1), with 20 mg KP415 (dose level decrease from Week 1), or with 40 mg KP415 
(dose level increase from Week 1). 
• Visit 4: Subjects will return to the research clinic after 7 ±3 days for Visit 4 with unused 
study drug, and will be dispensed either a bottle with 20, 30 or 40 mg KP415 (same daily 
dose as Week 2, or either dose level decrease or increase from Week 2). 
At Visits 2, 3 and 4, a bottle will be dispensed to the subject’s parent or 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 unblinded study drug for drug accountability and compliance. 
At Visits 4 and 5, subjects will be administered unblinded study drug at the study site. During the 2 
days before Visit 5, subjects will not take any study drug. 
13.5.2. Double-Blind Treatment Phase 
Blinded bottles of drug supply (KP415 capsules or matching placebo) will be dispensed at each visit 
as follows: 
• Visit 5: Subjects will return to the research clinic after 7 ±3 days after Visit 4, with unused, 
unblinded study drug.  
o At Visit 5, subjects will be administered unblinded study drug at the study site (this 
is the last dose of unblinded study drug). During the 2 days before Visit 5, subjects 
will not take any study drug (this is important for obtaining a baseline of the 
SKAMP/PERMP scores). 
o At Visit 5, subjects will be assigned double-blind study drug by the interactive web 
response system or similar system/process. The assigned study drug will consist of 
one of the following: 20, 30 or 40 mg KP415 capsules or placebo capsules. The 
bottle (bottle with 10 capsules) will be dispensed to the study subject’s parent or 


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guardian with instructions when and how to administer study drug while at home, 
starting on the day after Visit 5 (Day 22). On Days 22-27, subjects will take study 
drug at home under supervision of parent or legal guardian. 
• Visit 6: Subject’s parent or guardian will be instructed to return for Visit 6 with unused 
study drug. The final dose of study drug will be administered on the last day of the Double-
Blind Treatment Phase (Visit 6) at the laboratory school by study staff. One capsule from 
the second bottle in the drug supply kit (bottle with 1 capsule) will be used for 
administration. Special care will be taken to assure that subjects receive the same assigned 
study drug, during the days at home and at the laboratory classroom day. 
At each visit, a bottle will be dispensed to the subject’s parent or 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 unblinded 
(at Visit 5) and blinded (at Visit 6) study drug for drug accountability and compliance. 
In the event that subjects report 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 interactive 
web response system or similar system/process. All efforts will be made to ensure subjects receive 
daily doses of double-blind study drug for at least 7 days during the Double-Blind Treatment Phase. 
The Investigator will not supply study drug to anyone other than those named as sub-investigators 
on FDA Form 1572, designated site staff, and subjects in the study. 
13.6. 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. 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. 


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13.7. Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for each subject, in 
both the Dose Optimization Phase and the Treatment Phase, 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. 
14. SAFETY AND EFFICACY ASSESSMENTS 
14.1. Medical History 
A complete medical history will be obtained at the Screening Visit including the recording of 
demographic data (date of birth, sex, age, race, ethnicity), 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. 
14.2. Physical Examination 
A complete physical examination including body weight (lbs or kg) will be completed for all 
subjects at Screening, and at Early Termination (if possible) or Follow-Up. The complete physical 
examination will include a review of the subject’s general appearance, skin, head and neck (eyes, 
ears, nose, mouth, and throat), lymph nodes, thyroid, musculoskeletal/extremities, cardiovascular 
system, lungs, abdomen and a brief examination of the neurological system. 
Height will be recorded in inches (in) or centimeters (cm) with the subject’s shoes removed. Body 
weight will be measured in pounds (lbs) or kilograms (kg); subjects will remain in their normal 
clothing with shoes and jacket (and/or outer clothing) removed. 
14.3. ADHD Diagnosis and Severity Assessments 
At Screening, eligible subjects must meet the inclusion criteria for a primary diagnosis of ADHD 
by 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 the Mini International Neuropsychiatric Interview for Children 
and Adolescents (MINI-KID). 
The following scales will be used during the Open-Label Dose Optimization Phase to globally 
assess the changes in ADHD severity from week to week: 
• ADHD-Rating Scale-5 (ADHD-RS-5): The ADHD-RS-5 is an 18-item scale based on 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) (American 
Psychiatric Association 2013) criteria of ADHD that rates symptoms on a 4-point scale. 


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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-5 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 inattentiveness. Scores will be obtained during 
a clinician-directed interview with the parent/guardian/caregiver at each visit in the Dose 
Optimization Phase. 
• 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 scored from 1 (very 
much improved) to 7 (very much worse). 
The following scale will be used to assess the effect of open-label KP415 during the Open-Label 
Dose Optimization Phase and the efficacy of KP415 versus placebo during the Double-Blind 
Treatment Phase: 
• Conners 3rd Edition-Parent (Conners 3-P): The Conners 3-P (short form) is a 43-item 
parent/guardian/caregiver 
report 
that 
provides 
evaluation 
of 
inattention, 
hyperactivity/impulsivity, learning problems, executive functioning, aggression, and peer 
relationships. The parent/guardian/caregiver will assess changes in ADHD symptoms via 
the Conners 3-P questionnaire at baseline (Visit 2, Day 0) and at each visit during the Dose-
Optimization and the Treatment Phase. 
• Weekly Rating of Evening and Morning Behavior - Revised (WREMB-R) Scale: The 
11-item WREMB-R questionnaire is a parent-rated questionnaire that was developed to 
assess behaviors for their severity during the morning hours (3 items) and evening hours (8 
items) (Carlson 2007). The possible score for each item ranges from 0 (no difficulty) to 3 (a 
lot of difficulty). The Investigator or designee will obtain the scores for the WREMB-R 
questionnaire by interviewing the parent/guardian/caregiver at Visits 2, 5 and 6. The 
assessment at Visit 2 is the baseline assessment (after washout of ADHD medications, if 
applicable); the assessments at Visits 5 and 6 are evaluations at the end of the Dose 
Optimization and Treatment Phase, respectively. 
The following scales will be used to assess the efficacy of KP415 versus placebo during the Double-
Blind Treatment Phase: 
• Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP): Rating scale will be 
performed at Visit 4, Visit 5, and Visit 6. 


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The SKAMP scale is a validated rating of subjective impairment of classroom behaviors. It 
is comprised of 13 items (grouped under the subcategories of attention, deportment, quality 
of work, and compliance) on which subjects are rated according to a 7-point scale (0 = 
normal to 6 = maximal impairment) by trained study personnel (Swanson 1999). The 
SKAMP-Combined (SKAMP-C) score is obtained by summing the rating values for each 
of the 13 items. The SKAMP-Deportment (SKAMP-D) score is a measure of behavior and 
comprises of 4 items. The SKAMP-Attention (SKAMP-A) score is a measure of attention 
and comprises 4 items. The Higher SKAMP scores signify greater impairment. The 
SKAMP-C score will be used in the primary efficacy endpoint. 
• Permanent Product Measure of Performance (PERMP): Rating scale will be performed 
at Visit 4, Visit 5, and Visit 6. A Placement PERMP will be performed at Visit 2 (Day 0) to 
assure that subjects can complete at least the basic level of math problems and to determine 
the appropriate level of math to be assigned during the practice laboratory classroom day at 
Visit 4. Based on the practice laboratory classroom day at Visit 4, the final level of math for 
each subject will be determined for use in the remainder of the study (Visits 5 and 6). 
The PERMP is an individually calibrated five-page mathematics worksheet consisting of 
400 problems. Subjects will be instructed by site staff to work at their seats and complete as 
many problems as possible in 10 minutes. Performance will be evaluated using two scores: 
The number of problems attempted (PERMP-A) and the number of problems correct 
(PERMP-C). 
14.4. Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidal ideation will be assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS, 
Pediatric Version) (Posner et al. 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 visits of 
the Dose Optimization Phase (Visits 2, 3, 4 and 5), at Visit 6, and at Follow-Up or Early 
Termination. 
Subjects with a history of attempted suicide or clinically significant suicidal ideation based on the 
C-SSRS assessment, in the opinion of the Investigator, at Screening or 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. 
14.5. Vital Signs 
Vital sign measurements will be obtained 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. Vital signs will be collected 
once at each visit. On the full laboratory classroom day (Day 28 ±3 days, Visit 6), vital signs will 


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be collected at any time before dosing. 
14.6. 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. The QT interval corrected for heart rate will be calculated with Fridericia’s 
formula (QTcF). ECGs will be obtained at Screening, and at Early Termination or Follow-Up. ECG 
recordings will be evaluated by skilled readers operating from a centralized ECG laboratory. One 
reader should read all the ECG recordings from a given subject. 
14.7. Clinical Laboratory Measurements 
All clinical laboratory samples will be sent to a central laboratory for analysis. Up to approximately 
40 mL of blood will be collected for clinical chemistries, hematology, and pregnancy test (if 
applicable) from each subject during the study. Clinical Laboratory Measurements will be 
performed during the Screening Period and at Follow-Up or Early Termination. Clinical Laboratory 
Measurements may be repeated at the discretion of the Investigator. 
The Clinical Laboratory evaluations will consist of the following: 
• Total Hematology as well as differential and Coagulation: red blood cell count, white 
blood cell count with differential (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils), hemoglobin, hematocrit and platelets, Prothrombin Time (PT) and Partial 
Thromboplastin Time (PTT). 
• 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, 
thyroid stimulating hormone (TSH), and uric acid. TSH will be measured at Screening 
only (to evaluate the exclusion criterion for subjects with uncontrolled thyroid disease). 
• Urinalysis: microanalysis for specific gravity, pH, protein, glucose, ketones, blood, 
nitrites, leukocytes. If positive for blood, protein or nitrites, a microscopic examination 
will be performed. 
• Urine Screen for Alcohol Drugs of Abuse: At Screening (Visit 1) and Day 0 (Visit 2), 
urine samples will be tested for alcohol and drugs of abuse (amphetamines, 
methamphetamines, benzodiazepines, barbiturates, cannabinoids, cocaine, opioids 
including oxycodone). If the urine test is positive for alcohol and drugs of abuse 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 


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screen at Screening may test positive for ADHD medications such as amphetamines, and 
methamphetamines. The alcohol and drugs of abuse urine screen at Visit 2 is performed 
to document the results and, if applicable, to record whether subjects have washed out 
their ADHD medications before Visit 2  
• Urine Screen for Methylphenidate: At Screening (Visit 1), on Day 0 (Visit 2), and at Visit 
5, before administration of study drug, urine samples will be tested for methylphenidate. 
A urine dipstick (e.g., NarcoCheck®) will be used to screen for the presence of 
methylphenidate in the urine. If a subject's current ADHD medication at Screening 
contains MPH, the urine screen at Screening may test positive for MPH. Since all ADHD 
medications must be washed out by Day 0, they must test negative on Day 0 (Visit 2) for 
subjects to be eligible to continue in the study. The MPH urine screen at Visit 5 is 
performed to document whether subjects have abstained from their unblinded study 
medication starting 2 days before Visit 5. 
14.8. Pregnancy Test 
Pregnancy Tests: will be performed for all female subjects of childbearing potential. A serum β-
hCG pregnancy test will be performed at Screening. A urine pregnancy test will be performed at 
Visit 2 (Day 0), Visit 5 (Day 21), and at Follow-Up or Early Termination. A positive pregnancy test 
before the last dose of study drug will exclude a subject from further participation in the study. A 
positive urine pregnancy test will be confirmed with a serum β-hCG pregnancy test. 
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 of 12 years and older (including 
girls who will become 12 years or older 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”. 
14.9. Adverse Event Assessments 
Adverse Events will be assessed and recorded from Day 1 through either Follow-Up or Early 
Termination. While subjects are in the laboratory classroom after administration of study drug (Visit 
6), AEs will be monitored continuously by study staff. During administration of study drug away 
from the research clinic, subject’s parent/guardian will be instructed to contact the study site for the 
reporting of AEs during the dosing period at home. In addition, study staff will inquire 
parent/guardian during the next study visit about AEs during the dosing period at home. Definitions 
and details of AE reporting and documentation are listed in Section 18. 


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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. 
• 
Sponsor request for early termination of the study. 
• 
Positive pregnancy test (tested in females of childbearing potential). 
• 
Out-of-range vital signs, at the discretion of the Investigator. In order to ensure accuracy, 
out-of-range vital signs may be repeated once, at least 2 minutes after an abnormal 
finding. 
• 
For other reasons (e.g., significant protocol violation, non-compliance, overdose). 
 
If a subject is withdrawn from treatment due to an adverse event, 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. 
If a subject meets withdrawal criteria during the Open-Label Dose Optimization Phase or the 
Double-Blind Treatment Phase, the subject will be withdrawn and Early Termination procedures 
will be completed. 
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 Open-Label Dose 
Optimization Phase or the Double-Blind Treatment Phase do not need to be repeated. 
15.2. Replacement of Subjects  
Subjects who withdraw from the study during the Double-Blind Treatment Phase will not be 
replaced. Subjects who withdraw from the study during the Open-Label Dose Optimization Phase 
may be replaced. 
16. EFFICACY ENDPOINTS 
The following endpoints will be used to determine efficacy: 


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16.1. Primary Efficacy Variable: 
• Average of the change from baseline (measured at Visit 5) of the SKAMP-C scores collected 
across the laboratory classroom day at Visit 6. 
16.2. Secondary Efficacy Variables:  
• Change from baseline (measured at Visit 5) of the SKAMP-C scores measured at each time 
point on the laboratory classroom day at Visit 6. The serial measures at different times post-
dosing will be used to determine onset and duration of the clinical effect of KP415. 
• Change from baseline of the scores measured at each time point and the average of the 
scores collected across the laboratory classroom day at Visit 6, for the following endpoints: 
o SKAMP-D and SKAMP-A scores 
o PERMP scores 
o PERMP-A and PERMP-C scores 
• WREMB-R scores (total score, and morning and evening subscore) at Baseline (Visit 2), 
Visit 5 and Visit 6. 
16.3. Safety Endpoints: 
The occurrence of Treatment-Emergent Adverse Events (TEAEs) will be assessed starting 
following the first dose of open-label drug (KP415), and ending with the Follow-Up Visit or Early 
Termination Visit. Additional safety evaluations will include physical examinations, vital signs, as 
well as height and weight, ECG Parameters, clinical laboratory tests, and a follow-up C-SSRS 
administered at each study visit. AEs during the Open-Label Dose Optimization Phase and the 
Double-Blind Treatment Phase will be will be reported and analyzed separately. 
17. STATISTICAL CONSIDERATIONS 
This section summarizes the statistical considerations for this protocol. Details will be provided in 
the Statistical Analysis Plan for Protocol No: KP415.E01 (SAP_KP) prior to the primary endpoint 
database lock and unblinding of the trial. 
17.1. Statistical Hypotheses 
17.1.1. Primary Efficacy Endpoint(s):  
The primary efficacy endpoint will be the mean change from the baseline measurement at Visit 5 
and SKAMP-C scores (∆𝑆𝐾𝐴𝑀𝑃−𝐶
̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅) collected across the laboratory classroom day at Visit 6. 


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17.1.2. Secondary Efficacy Endpoints 
The following is a list of the secondary endpoints: 
 
• ∆𝑆𝐾𝐴𝑀𝑃−𝐶
̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅ scores at each time point on the laboratory classroom day at Visit 6. The 
serial measures at different times post-dosing will be used to determine onset and duration 
of the clinical effect of KP415. 
• The mean change from baseline at each time point collected across the laboratory classroom 
day at Visit 6 for the following endpoints: 
o SKAMP-D and SKAMP-A scores 
o PERMP scores 
o PERMP-A and PERMP-C scores 
• WREMB-R scores (total score, and morning and evening subscore)  
 
17.2. Sample Size Calculation 
Test Treatment does not have Carry-over Effect: The primary hypothesis is that the test drug is 
superior (change in SKAMP-C from baseline measured at Visit 5 are lower) when compared to 
placebo. The null and alternative hypotheses are as follows: 
 
𝐻0: ∆𝑆𝐾𝐴𝑀𝑃−𝐶
̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅𝑐𝑜𝑛𝑡𝑟𝑜𝑙−∆𝑆𝐾𝐴𝑀𝑃−𝐶
̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅𝑡𝑒𝑠𝑡= 0 
𝐻𝐴: ∆𝑆𝐾𝐴𝑀𝑃−𝐶
̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅𝑐𝑜𝑛𝑡𝑟𝑜𝑙−∆𝑆𝐾𝐴𝑀𝑃−𝐶
̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅̅𝑡𝑒𝑠𝑡≠0 
Studies of this type often have a clinically and statistically relevant (p <0.05) interaction effect 
between treatment and time. Therefore, if the interaction between treatment and time is statistically 
relevant, then the hypothesis test will be based on the interaction effect. If the interaction is not 
statistically relevant, then the hypothesis test will be based on just the treatment main effect. 
Drug efficacy studies are sized to be able to detect at least the Minimum Clinically Important 
Difference (MCID). MCID has not been established for the SKAMP-C scores. However, Rai et al. 
(Rai et. al. 2015) noted “0.5 standard deviations has been suggested to correspond to the MCID in 
a number of studies“. Biederman et al. (Biederman et al. 2007) also noted, in a similar study on 
lisdexamfetamine dimesylate, “Previous studies of amphetamine products using the SKAMP-D to 
assess efficacy in children with ADHD have disclosed an effect size of greater than .50.” Therefore, 
the SD is assumed to be 1 and the MCID is assumed to be 0.5. 


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Therefore, assuming a mean difference between test and control for SKAMP-C of 0.5 units and a 
standard deviation (SD) of 1.0, 126 subjects would need to complete the study, assuming 80% 
power when testing a significance level of  = 0.05 (2-sided two-sample z-test). Figure 2 shows the 
change in the detectable effect size with a range and SD’s. The figure shows that even if the SD is 
50% greater than expected, the minimum detectable effect size changes from -0.5 to -.0.7. Given 
previous studies of amphetamine products using ∆𝑆𝐾𝐴𝑀𝑃−𝐶 in a classroom setting showed 
differences of greater than 1 with SD’s close to 1 (McCracken et al. 2003; Biederman et al. 2007; 
Swanson et al. 1998). 


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Figure 2: Change in Effect Sizes for a Range of Standard Deviations 
 
 
The samples sizes are based on the Two Sample Z-Test assuming Equal Variance module in PASS 
Version 15.0.3. 
Assuming an approximate 10% dropout during the Double-Blind Treatment Phase, 140 subjects are 
planned to be randomized in the Double-Blind Treatment Phase. Assuming an approximate 20% 
dropout during the Open-Label Dose Optimization Phase, 176 subjects are planned to be enrolled 
in the Open-Label Dose Optimization Phase. 


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17.3. Populations for Analysis 
There are three populations in this study: 
Intent-to-Treat (ITT) Population: All randomized subjects who receive at least one dose of 
double-blind study medication and have at least one post-dose SKAMP-C assessments at Visit 
6. 
Per-Protocol (PP) Population: ITT subjects who received the morning dose of double-blind 
study medication at the laboratory test session, who have all 8 post-dose SKAMP-C assessments 
at Visit 6, who did not miss more than 2 days of therapy during the Double-Blind Treatment 
Phase, and did not use prohibited medications during the Double-Blind Treatment Period. 
Overall Safety Population: All subjects who entered the Open-Label Dose Optimization phase 
and received at least one dose of open-label study medication and had at least one post-dose 
safety assessment. This will include subjects who were randomized as well as those subjects 
who were never randomized. This population will be used for safety analyses. 
17.4. Statistical Analyses 
17.4.1. General Approach 
Analysis Populations: All baseline analyses will be performed using the ITT, PP and Overall Safety 
populations. All efficacy analyses will be performed using both the ITT and PP populations. All 
safety analyses will use the Overall Safety Population. 
Descriptive Statistics: For descriptive statistics, the following will be reported: 
• Continuous data: n, mean, standard deviation, median and interquartile range, minimum 
and maximum 
• Categorical: n/N, percentage of total per arm and 95% confidence interval per category 
• Binary: n/N, percentage per arm and 95% confidence interval 
 
Missing Data: The following applies to the primary and secondary efficacy endpoint and safety 
analyses. If there is < 5% of patients with outcome data points missing, then no additional sensitivity 
analyses will be performed. If there are ≥ 5% of patients with missing outcome data, then the 
missingness will be assessed. If the outcome data is considered to missing at random (MAR), no 
additional steps will be taken to handle the missing data (see SAP for details). If the outcome data 
is Not Missing at Random (NMAR), a sensitivity analysis using a pattern-mixture model (see SAP 
for details) will be performed. 
If there is < 5% of patients with covariate data values missing, then no additional sensitivity analyses 
will be performed. If there are  5% of patients with missing covariate data values, then the 
missingness will be assessed. If the covariate data is considered to be MAR, a sensitivity analyses 


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using multiple imputation methods (see SAP for details) will be performed. If the covariate data is 
NMAR, alternative imputation methods such as pattern mixture model will be assessed (see SAP 
for details). 
Any change to the data analysis methods described in the protocol will require an amendment only 
if it changes a principal feature of the protocol. Before unblinding of the aggregate database, minor 
modifications or clarifications to the data analysis methods may be described and justified in the 
statistical analysis plan. Any retrospective or exploratory analyses not defined by the protocol or 
the statistical analysis plan will be explained in the clinical study report. 
17.4.2. Analysis of the Primary Efficacy Endpoint 
The primary efficacy endpoint treatment effect is the SKAMP-C scores over the day during Visit 
6. Though the SKAMP questionnaire uses the Likert scale, the SKAMP-C, which aggregates the 
scores from all the domains, will be treated as a continuous measure. 
The estimate of the difference between test and control will be based on a repeated measures 
analysis using a Mixed-Effect Model Repeated Measure (MMRM) model where: 
• Time, treatment and the interaction of time and treatment are the fixed effects. Site will be 
included as a fixed effect. If site effect is not statistically significant, it will be removed 
from the model. 
• Subject is the random effect. 
 
Prior to conducting any analyses, we will be looking at the distribution of data. The outcome data 
will be assessed for normality using Shapiro-Wilk (SW) test. If there is evidence of a lack of 
normality, several normalizing transformations will be considered. See SAP for details. Point 
estimates for each treatment group and treatment mean group differences (KP415 – Placebo) will 
be presented with standard errors and 95% confidence intervals An unstructured (co)variance 
structure shared across treatment groups will be specified to model the within-subject errors. If the 
p-value for interaction between treatment and baseline covariate is not < 0.05, then that covariate 
will be dropped from the model and the analysis will be re-run. Model fit will be assessed using 
graphical and quantitative methods. See SAP for details. 
Studies of this type often have a clinically and statistically relevant (p <0.05) interaction effect 
between treatment and time. Therefore, if the interaction between treatment and time are statistically 
relevant, then the hypothesis test will be based on the interaction effect. If the interaction is not 
statistically relevant, then the hypothesis test will be based on just the treatment main effect. 
17.4.3. Analysis of the Secondary Endpoints 
The secondary endpoint analyses described in this section will be performed if the primary endpoint 


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hypothesis test is significant. If the primary endpoint hypothesis test is not significant, only the 
descriptive statistics will be provided. 
SKAMP-C measured at each time point at Visit 6: The same MMRM model developed for the 
primary efficacy endpoint will be used to estimate the least square means and their corresponding 
95% confidence interval for each time and treatment combination. Differences in least square means 
between the treatment arms and unadjusted p-values will be reported for each time point. 
Onset of clinical effect is defined as the earliest post-dose time point at which the difference between 
KP415 and Placebo is statistically significant (p<0.05) between KP415 and placebo as measured 
by the SKAMP-C Score. The duration of the treatment effect is defined as the length of the time 
interval, such that statistical significance was reached at each time point of this interval. 
All other secondary endpoints: The remaining secondary endpoints will be treated as continuous 
data. The overall interaction effect of treatment and time or the treatment effect if the interaction is 
significant and the individual time point estimates will be determined using the same model analysis 
methods and output described for the SKAMP-C endpoint. 
17.4.4. Sensitivity Analyses 
As a sensitivity analysis, the interaction of treatment and unbalanced baseline covariates identified 
in the baseline characteristic analysis will be included in the primary and secondary models. If the 
p-value for interaction between treatment and baseline covariate is not significant (p ≥0.01), then 
that covariate will be dropped from the model and the analysis will be re-run. 
17.4.5. Safety Analysis 
All analyses of safety will be conducted on the Overall Safety Population. The safety assessment 
will be based on adverse events, physical exams, vital signs, ECG parameters, clinical laboratory 
tests and C-SSRS scores. 
Adverse events will be coded in accordance with the Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse events with new onset during the study between the initiation of study drug 
and 5 days after the last dose of study drug will be considered treatment-emergent (TEAEs). This 
will include any AE with onset prior to initiation of study drug and increased severity after the 
treatment initiation. 
TEAEs will be summarized by system organ class and preferred term, and by treatment. This will 
include overall incidence rates (regardless of severity and relationship to study drug) and incidence 
rates for moderate or severe adverse events. A summary of serious adverse events and adverse 
events leading to early discontinuation from the study will be summarized by treatment. 
Safety laboratory tests and vital signs will be summarized by post-treatment change from baseline 


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for each of the parameters using descriptive statistics by treatment group. Those subjects with 
significant laboratory abnormalities will be identified in data listings. Additional safety parameters 
will be summarized in data listings. See Section 18 for more information on safety data. 
17.4.6. Baseline Descriptive Statistics 
The key baseline characteristics (see the Statistical Analysis Plan (SAP) for list of baseline 
characteristics) will summarized descriptively per treatment arm and the two arms will be compared 
statistically. For continuous variables, the data will be assessed as to whether they are normally 
distributed using the Shapiro-Wilk test (SW). If this is no evidence of lack of normality (SW 
p>0.05), then the two arms will be compared using the t-test with unequal variances. If SW indicates 
that there is evidence that the variable is not normally distributed (SW p < 0.05), then the non-
parametric Wilcoxon rank sum test will be used to compare the two arms. For binary and categorical 
variables, the chi-square test will be used for the comparison between the two arms.  
As a sensitivity analysis, if there is evidence of a difference in baseline characteristics (p <0.01), 
and the difference is considered clinically relevant by the Principal Investigator of the study, the 
primary and secondary efficacy endpoint analyses will include these variables as covariates. 
17.4.7. Planned Interim Analyses  
There are no planned interim analyses. 
17.4.8. Sub-Group Analyses 
The subgroup analyses described in this section will be performed if the primary endpoint is 
significant. If the primary endpoint is not significant, then only the descriptive statistics will be 
provided. 
The primary efficacy endpoint model and analysis methods along with the safety endpoints and 
analyses will be used to analyze any subgroups such as site, dose, age and gender. Please see the 
SAP for the list of subgroup and further details about the analyses. 
17.4.9. Tabulation of Individual Participant Data 
A listing of date and type of each subject’s TEAE will be provided. 
17.4.10. 
Exploratory Analyses 
Changes in ADHD severity will be compared from week to week in the ITT and PP Population 
based on ADHD-RS-5, CGI-S, CGI-I, and Conners 3-P. Please see the SAP for further details about 
the analyses. 


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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 Adverse Events 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 visit or the Early Termination 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. Adverse events 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. AE Grading  
Adverse Events shall be graded with regard to severity according to criteria defined in the Common 
Terminology Criteria for Adverse Events v4.0 (CTCAE). Grade refers to the severity of the AE. 
The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE 
based on this general guideline. 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activity of Daily Living (ADL). 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 


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Grade 5 
Death related to AE. 
18.1.4. AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following: 
1. Definitely - 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. Probably - 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 unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
3. 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. 
4. Unrelated - An event that can be determined with certainty to have no relationship to the 
study drug. 
18.2. Serious Adverse Events 
A Serious Adverse Event (SAE) is defined as any AE occurring at any dose that results in any of 
the following outcomes: 
• Death 
• A life-threatening adverse experience 
• 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. 
 
Note that AEs of Grade 3 due to hospitalization or prolongation of a hospitalization, and Grade 4 
and Grade 5 per CTCAE grading criteria are classified as SAEs. 
18.2.1. Serious Adverse Event Reporting 
Within 24 hours after a SAE detection, observation, or report of occurrence (regardless of the 


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relationship to test article), the Investigator or designee will enter the SAE into the electronic 
database. The investigator/qualified designee will enter the required information regarding the SAE 
into the appropriate module of the eCRF, which will automatically result in distribution of the 
information to the appropriate sponsor contact. If the EDC system is temporarily unavailable, the 
event, including the investigator-determined causality to study drug, should be reported via a paper 
back-up SAE form to the appropriate sponsor contact. Upon return of the availability of EDC 
system, the SAE information must be entered into the eCRF.  
If EDC is not functional, a paper SAE form will be utilized and provided to the following contact: 
DCRI Safety Surveillance 
DCRISafetysurveillance@duke.edu 
Fax: 919-668-7138 
Telephone: 919-668-8624 
 
These SAE reports must contain the following information: 
1. Study name/number 
2. Study Drug 
3. Investigator details (name, phone, fax, e-mail) 
4. Subject Number 
5. Subject Demographics 
6. Clinical Event 
7. Description 
a. Date of onset 
b. Treatment (drug, dose, dosage form) 
c. AE Relationship to study drug 
d. Action taken regarding study drug in direct relationship to the 
AE 
e. Criteria for “Serious” applicable to the AE 
8. Cause of death (whether or not the death was related to study drug) 
9. Autopsy findings (if available) 
 
Any SAE that occurs during the study should be recorded by each clinical site, and reported to the 
ARO. The ARO will notify the Sponsor by the end of the next business day after SAE notification 
receipt from the site. 
SAEs considered definitely, probably, or possibly related to study drug shall also be classified by 
Sponsor as being “expected” or “unexpected.” An unexpected event is one that is not listed in the 
investigator’s brochure (KP415). 
The person responsible for the study shall ensure the study has been carried out in accordance with 
local pharmacovigilance regulations. 


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All serious event reporting by Sponsor will adhere to 21 CFR 312.32 for IND drugs (7-day or 15-
day alerts) and 21 CFR 314.80 for marketed drugs (15-day alerts). Unexpected fatal or life-
threatening SAEs considered related to the study drug should be reported to the FDA by Sponsor 
with an IND Safety report within 7 days. The Institutional Review Board (IRB) will be notified of 
the 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 electronic Case Report Form (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. 
For SAEs that occur during the study, the assessment, treatment, and follow up shall be performed 
for up to at least 30 days after last dose for events considered definitely, probably, or possibly related 
to study drug, and continued 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, i.e., 
>40 mg KP415. Notifications of known incidences of subjects taking more than one capsule of 
study drug per day (irrespective of the dose size) will be provided by each study site to the ARO. 
The ARO will notify the sponsor before the end of the next business day after ARO’s notification 
receipt from the site. If there is an associated AE or SAE, the site is to report the event on the 
electronic case report form within 24 hours. 
Known signs and symptoms after acute overdosage of d-MPH, resulting principally from 
overstimulation of the central nervous system and from excessive sympathomimetic effects, include 
vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by 
coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, 
tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous 
membranes (Concerta® Extended Release Package Insert 2008, Focalin® Package Insert 2017, 
Focalin® XR Package Insert 2015, Ritalin® and Ritalin-SR® Package Insert 2015). Rhabdomyolysis 
has also been reported (Ritalin® and Ritalin-SR® Package Insert 2015). 
19. PREGNANCY 
Females with a positive pregnancy test will terminate the study early. The initial report of a 
pregnancy during the study will be provided by the site to the ARO. The ARO will notify the 


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Sponsor before the end of the next business day after ARO’s notification by the site, and ARO will 
report to the IRB within a time frame after the incident identification as required by the IRB. 
All pregnancies will be followed to at least the completion/termination of the pregnancy. The 
Investigator will document the subject visits accordingly and record the information in the clinical 
site’s source documents. If the pregnancy continues to delivery, the outcome (health of the infant), 
in addition to the maternal health status, must be included in the report. 
Pregnancy will not be considered an AE or SAE; any pregnancy complication or termination of a 
pregnancy for medical reasons will be recorded as an AE or SAE. 
20. 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 serious adverse events 
4. Improper breaking of the blind 
5. Multiple visits missed or outside permissible windows 
6. Materially inadequate record keeping 
7. Intentional deviation from protocol, Good Clinical Practice, or regulations by study 
personnel 
8. Subject repeated non-compliance with study requirements 
 
It is the Site Investigator’s responsibility to report to the IRB any Protocol Violation(s) according 
to the IRB’s policy. A copy of the IRB submission will be filed in the site’s regulatory binder and 
in the Sponsor’s files at the ARO. 
21. DATA MANAGEMENT AND RECORD KEEPING 
21.1. Data Management 
Data will be recorded at the site on eCRFs. All entries on a eCRF are ultimately the responsibility 
of the Site Investigator, who is expected to review each form for completeness, accuracy and 
legibility before signing. All forms must be filled out by using black ink. Errors should be lined out 
but not obliterated and the correction inserted, initialed and dated. An eCRF must be completed for 
each participant for whom parental permission was obtained and who has given written or verbal 
assent. The eCRFs and source documents must be made available to the Sponsor and/or its 
representatives. 


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21.2. Record Keeping 
The Site Investigators and Academic Research Organization (ARO) 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, and monitor visit 
logs.  
The Site Investigators, their affiliated Institutions and the ARO should maintain the trial documents 
as required by the applicable regulations, and should take measures to prevent accidental or 
premature destruction of documents. Clinical trial documents must be kept in the clinical site’s and 
ARO’s archives until written authorization is obtained from the Sponsor. 
21.3. Access to Source Data/Documents 
The Site Investigators and ARO 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. 
22. QUALITY CONTROL AND QUALITY ASSURANCE 
Sponsor and/or Sponsor’s representatives will perform quality control and quality assurance checks 
of this clinical trial that it sponsors. Before the enrollment of any patient in this study, personnel of 
the ARO will review with the Site Investigators and site personnel the appropriate documents and 
processes to conduct the trial including the protocol, Investigator’s Brochure, eCRFs and 
procedures for their completion, the informed consent process, and the procedure for reporting 
SAEs. Site visits will be performed by CRAs from the ARO, or—as needed--other ARO personnel 
and/or other Sponsor personnel and/or representatives. During these visits, information recorded on 
the eCRFs will be verified against source documents and requests for clarification or correction 
may be made. After the eCRF data is entered by the site, ARO personnel will review for safety 
information, completeness, accuracy, and logical consistency. Computer programs that identify data 
inconsistencies may be used to help monitor the clinical trial. If necessary, requests for clarification 
or correction will be sent to Site Investigators. 
The ARO and Sponsor agree to be responsible for implementing and maintaining quality control 
and quality assurance systems with written standard operating procedures to ensure that the clinical 
trial is conducted and data are generated, documented, and reported in compliance with the protocol 
and accepted standards of Good Clinical Practice (GCP) per the International Council for 
Harmonisation (ICH E6(R2)). 


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23. 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: 
http://www.wma.net/en/30publications/10policies/b3/17c.pdf 
24. INSURANCE 
24.1. 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 Site Investigators and the other collaborators from 
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 Site Investigators by the ARO. 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 Site Investigators by the ARO. 


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