Clinical trial NCT03659929
Conditions: Attention Deficit Hyperactivity Disorder
Sponsor: Arbor Pharmaceuticals, Inc.
Start date: 2018-09-18; Completion date: 2019-04-12
Enrollment: 320 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the AR19.004 study is to assess the efficacy of AR19 compared to placebo using the Adult ADHD Investigator Symptom Rating Scale (AISRS)

Detailed description:
This is a randomized, fixed-dose, double-blind, multicenter trial to investigate the safety and efficacy of AR19 in the treatment of ADHD in adults from 18 through 55 years of age. Safety parameters and therapeutic effect will be evaluated throughout the trial. A target of 312 subjects is set for enrollment. Once subjects are determined to meet all inclusion criteria and were screened, they will be randomized to 20 or 40 mg AR19 daily or placebo.

Arms: arm 1: Amphetamine Sulfate arm 2: Amphetamine Sulfate arm 3: Placebo, no active drug
Interventions: intervention 1: Amphetamine Sulfate intervention 2: Placebo
Intervention descriptions: intervention 1: active experimental AR19 intervention 2: Matching placebo

Protocol documents:
Prot_000.pdf: 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
A Multicenter, Fixed-Dose, Double-Blind, Randomized Study to Evaluate the Efficacy 
and Safety of AR19 (Amphetamine Sulfate) in Adult Subjects (Ages 18-55) with 
Attention Deficit Hyperactivity Disorder (ADHD)  
Protocol AR19.004 
 
Arbor Pharmaceuticals, LLC. 
6 Concourse Parkway, Suite 1800 
Atlanta, GA 30328 
 
Original Protocol Version:   
June 21, 2018 (Version 1.0) 
Protocol Amendment 1:   
July 18, 2018 
IND # 128294 
-Confidential- 
 
This clinical study will be conducted in accordance with the ethical principles outlined in 
the Declaration of Helsinki, Good Clinical Practices (International Conference on 
Harmonization Guideline E6), United States Code of Federal Regulations Title 21, and any 
local and/or federal regulations. 
This document and its contents are the property of and confidential to Arbor 
Pharmaceuticals, LLC. (Arbor). Any unauthorized copying or use of this document is 
prohibited. 
 
 
 


Arbor Pharmaceuticals, LLC. 
Clinical Study Protocol Amendment 1 
Protocol No. AR19.004 
18Jul2018 
 
Page 2 of 62 
 
STUDY CONTACTS 
Sponsor 
Name: Arbor Pharmaceuticals, LLC. (Arbor) 
Address: 6 Concourse Parkway, Suite 1800, Atlanta, GA 30328 
Monitor  
(Contract Research 
Organization)  
 
 
 
Sponsor’s Medical 
Expert 
 
 
 
 
 
Medical Monitor 
 
 
 
 
 
 
  
  
Product Safety 
(SAE Reporting) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




Arbor Pharmaceuticals, LLC. 
Clinical Study Protocol Amendment 1 
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18Jul2018 
 
Page 4 of 62 
INVESTIGATOR’S STATEMENT 
I have read the protocol, and I approve this document. I agree to conduct the study in 
accordance with the design and specific provision of this protocol and to comply with its 
obligations, subject to ethical and safety considerations and all applicable regulations (ICH, 
CFR, and IRB). I will provide copies of this protocol and access to all information furnished 
by Arbor to study personnel under my supervision. I will discuss this material with them to 
ensure they are fully informed about the study product and study procedures. I will let 
them know that this information is confidential, and that it may not be further disclosed to 
third parties. I understand that the study may be terminated or enrollment suspended at 
any time by Arbor or by me if it becomes necessary to protect the best interests of the 
study participants. 
Confidentiality Statement 
The confidential information in this document is provided to you as a Principal Investigator 
for review by you, your staff, and the applicable Institutional Review Board. Your 
acceptance of this document constitutes agreement that you will not disclose the 
information contained herein to others without written authorization from the Sponsor. 
Principal Investigator: 
 
 
 
 
 
 
 
 
 
Name (please print) 
 
Site Number 
 
 
 
Title 
 
 
 
 
 
Signature 
 
Date 
 


Arbor Pharmaceuticals, LLC. 
Clinical Study Protocol Amendment 1 
Protocol No. AR19.004 
18Jul2018 
 
Page 5 of 62 
Amendment #1: 
 
Changes made include clarifications on procedures, correction of typographical errors, and 
removal of PK processing information which will be detailed in the laboratory manual.  
Modified text is listed here in bold type.  Specifically: 
 
  Synopsis and Section 4.2: 
Exclusion Criteria #9 
 
WAS:   Has an ECG or clinical evidence of the following:   
• 
QTcF > 470 milliseconds (msec) for males, and > 450 msec for females 
 
IS:    Has ECG or clinical evidence of the following: 
• 
QTcF > 470 milliseconds (msec) for females, and > 450 msec for males 
 
Exclusion Criteria #12 
 
WAS: Has used prohibited drugs or agents (see Appendix B) within 30 days of the Baseline 
visit through Study Visit 7. (Stimulant medications are allowed until 7 days before the 
Baseline visit). Non-stimulant ADHD medications (guanfacine, bupropion, clonidine, and/or 
atomoxetine) are not allowed within 30 days of Visit 2 or at any time during the study. 
 
IS: 
 Has used prohibited drugs or agents (see Appendix B) within 28 days of the 
Baseline visit through Study Visit 7. (Stimulant medications are allowed until 7 days before 
the Baseline visit). Non-stimulant ADHD medications (guanfacine, bupropion, clonidine, 
and/or atomoxetine) are not allowed within 28 days of Visit 2 or at any time during the 
study.    
 
Exclusion Criteria #20 
  
WAS:  Note: subjects should be informed that they must not drink alcohol within 12 hours 
of screening and this should be confirmed prior to testing. 
 
IS:    Note:  subjects should be informed that alcohol consumed within 12 hours of 
screening may result in a positive test. 
 
 Section 5.9.1 Prior Medication 
 
WAS: Has used prohibited drugs or agents (see Appendix B) within 30 days of the Baseline 
visit through Study Visit 7. (Stimulant medications are allowed until 7 days before the 
Baseline visit). Non-stimulant ADHD medications (guanfacine, bupropion, clonidine, and/or 
atomoxetine) are not allowed within 30 days of Visit 2 or at any time during the study. 
 
IS: 
 Has used prohibited drugs or agents (see Appendix B) within 28 days of the 
Baseline visit through Study Visit 7. (Stimulant medications are allowed until 7 days before 
the Baseline visit). Non-stimulant ADHD medications (guanfacine, bupropion, clonidine, 


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18Jul2018 
 
Page 6 of 62 
and/or atomoxetine) are not allowed within 28 days of Visit 2 or at any time during the 
study.    
 
 Section 6.1.1 Screening Visit: 
 
WAS: CYP 2D6 genetic testing (analyzed only for randomized subjects who opt in)    
 
IS: 
 Statement removed (this procedure is performed at the Baseline Visit) 
 
 Section 11.3 Appendix C: 
 
WAS: Pharmacokinetic sample collection, processing, and shipment instructions with 
table 
 
IS:   
Appendix C removed (PK collection, processing, and shipment instructions will be 
detailed in the central laboratory manual) 
 
 Section 6.4.4 Hematology, Serum Chemistry and Urinalysis 
 
WAS:  CYP 2D6 genetic testing will be performed only at Screening (Visit 1) for those 
subjects who opt in.  Only randomized subjects who opt in will have their blood tested. 
 
IS:  CYP 2D6 genetic testing will be performed only at Baseline (Visit 2) for those 
randomized subjects who opt in. Subjects who opt out are still eligible for the study. 
 
 
 


Arbor Pharmaceuticals, LLC. 
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18Jul2018 
 
Page 7 of 62 
SYNOPSIS 
Protocol Title  
A Multicenter, Fixed-Dose, Double-Blind, Randomized Study to 
Evaluate the Efficacy and Safety of AR19 (Amphetamine 
Sulfate) in Adult Subjects (Ages 18-55) with Attention Deficit 
Hyperactivity Disorder (ADHD)  
Phase of 
Development 
Phase 3 
Investigators/Study 
Centers  
Approximately 30 investigators will enroll subjects at centers 
in the United States. 
Objectives   
Primary Objective: 
To assess the efficacy of AR19 compared to placebo using the 
Adult ADHD Investigator Rating Scale (AISRS) 
 
Secondary Objectives:    
 To assess efficacy using AISRS subscale scores 
 To assess global efficacy using the Clinical Global 
Impression of Severity (CGI-S) and Clinical Global 
Impression of Improvement (CGI-I)  
 To assess efficacy for treating executive function as 
measured by the Behavior Rating Inventory of 
Executive Function – Adult Version (BRIEF-A)  
 To investigate the safety and tolerability of AR19 in 
adult subjects ages 18-55 with ADHD 
Exploratory Objective 
 To assess efficacy for treating emotional dysregulation 
using established self-rated instruments for emotional 
dysregulation. To explore which facets of emotional 
dysregulation change with treatment using item and 
subscale analyses. 
 To assess exposure-response relationships using 
population pharmacokinetics 
Planned Number of 
Subjects 
312 
Study Design 
After Screening and Baseline evaluations are complete, eligible 
subjects will be randomized 1:1:1 to one of two fixed-dose 
groups in two divided doses (AR19 20 mg or AR19 40 mg) or 
placebo. Subjects unable to tolerate AR19 will be withdrawn 
from the trial. 
 
Subjects will begin dosing with double-blind study drug the 
morning following the Baseline visit. In order to maintain the 


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blind between the 10 mg and 20 mg capsules, a double-dummy 
technique will be utilized with matching placebo capsules. The 
first dose will be taken in the morning and the second dose 
will be taken 4 to 6 hours later. 
 
Subjects randomized to AR19 20 mg daily will be titrated in a 
blinded fashion according to the schedule below: 
Kit Dispensed 
at Visit/Day 
First Dose 
Second Dose 
Visit 2, Day 1 
20 mg 
Placebo 
10 mg 
 
20 mg 
Placebo 
10 mg 
Placebo 
Visit 3, Day 8 
20 mg 
Placebo 
10 mg 
 
20 mg 
Placebo 
10 mg 
 
Visit 4, Day 15 
20 mg 
Placebo 
10 mg 
 
20 mg 
Placebo 
10 mg 
 
Visit 5, Day 22 
20 mg 
Placebo 
10 mg 
 
20 mg 
Placebo 
10 mg 
 
Visit 6, Day 29 
20 mg 
Placebo 
10 mg 
 
20 mg 
Placebo 
10 mg 
 
 
Subjects randomized to AR19 40 mg daily will receive: 
Kit Dispensed 
at Visit/Day 
First Dose 
Second Dose 
Visit 2, Day 1 
20 mg 
Placebo 
10 mg 
 
20 mg 
Placebo 
10 mg 
Placebo 
Visit 3, Day 8 
20 mg 
Placebo 
10 mg 
 
20 mg 
Placebo 
10 mg 
 
Visit 4, Day 15 
20 mg 
 
10 mg 
Placebo 
20 mg 
Placebo 
10 mg 
 
Visit 5, Day 22 
20 mg 
 
10 mg 
Placebo 
20 mg 
 
10 mg 
Placebo 
Visit 6, Day 29 
20 mg 
 
10 mg 
Placebo 
20 mg 
 
10 mg 
Placebo 
 
Subjects randomized to placebo will receive the 10 mg and 
20 mg placebo capsules for the first and second dose for the 
duration of the trial (four capsules/day). 
 
Visit 7, Day 36: End of Study Visit 
 
Visit 8: Follow-up Phone Call 
 
 
 


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Inclusion: 
1. Is male or female between 18 and 55 years of age, 
inclusive, at the time of Screening.  
2. Meets criteria for diagnosis of ADHD using Conners' 
Adult ADHD Diagnostic Interview for DSM-IV™ adapted 
for DSM-5™ (CAADID). 
3. Has an AISRS total score of ≥26 at Visit 2. 
4. Has a clinician-administered CGI-S score of 4 or greater 
at Visit 2. 
5. In the clinical judgment of the Investigator, the subject 
needs pharmacological treatment for ADHD.  
6. Must read and write English at a level sufficient to 
provide written informed consent and to complete 
study-related materials. 
7. For subjects currently on a stable dose of allowed 
non-ADHD medication, there will be no expected 
changes in subject’s medications during the study with 
the exception of medications listed in Section 5.9.2.  
8. Males and females who are fertile and sexually active 
with a partner of the opposite sex must adhere to 
contraception requirements for the duration of the 
study as follows: 
o Females of childbearing potential must agree to 
be abstinent or to use highly effective forms of 
contraception. 
o Females of non-childbearing potential, defined 
as surgically sterile (status post hysterectomy, 
bilateral oophorectomy, or bilateral tubal 
ligation) or post-menopausal for at least 
12 months do not require contraception during 
the study.  
o Males, including males who are surgically sterile, 
with female partners of childbearing potential, 
must agree to be abstinent or else use a 
medically acceptable form of contraception from 
screening through the end of study.  
Exclusion: 
1. Has a primary psychiatric diagnosis other than ADHD. 
2. Has any other current secondary or co-morbid medical, 
psychiatric, or social condition which, in the opinion of 
the investigator, might compromise subject safety, or is 
likely to interfere with protocol compliance or to 
confound the assessment of safety or efficacy.   
3. Has a history or current symptoms of bipolar disorder, 


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schizophrenia or psychotic disorder. 
4. Has clinically significant cognitive impairment in the 
clinical judgment of the Investigator. 
5. Has a Body Mass Index of <17 or ≥39 kg/m2. 
6. Has a Screening or Baseline blood pressure of 
≥139 mmHg systolic or of ≥89 mmHg diastolic. 
7. Is pregnant or breastfeeding, or is planning to become 
pregnant during the study. 
8. Has a history of any of the following disorders:   
 seizure disorder (excluding a history of isolated 
febrile seizures <6 years old),  
 Inadequately or not treated hypertension is defined 
as a subject who has blood pressure indicative of 
Stage 2 hypertension (systolic pressure ≥140 mmHg 
or diastolic pressure ≥90 mmHg). Subjects who are 
adequately treated must be on a stable dose of 
antihypertensive medications for 3 months prior to 
screening and their antihypertensive medications 
are not anticipated to change. Blood pressure will 
be taken in triplicate, and the average will be used 
for evaluating entry criteria. 
 Untreated thyroid disease. Subjects with a history of 
thyroid disease who have been on a stable dose of 
thyroid hormone for at least three months are 
eligible to participate if their thyroid-stimulating 
hormone (TSH) level does not fall in the excluded 
range, shown below in 14. 
 Glaucoma  
 Tourette’s disorder, or chronic tics.   
9. 
Has ECG or clinical evidence of the following:   
 QTcF > 470 milliseconds (msec) for females, and > 
450 msec for males 
 Atrial or ventricular hypertrophy 
 Intraventricular conduction defects other than 
incomplete right bundle branch block in the 
absence of other heart disease  
 Myocardial infarct, ischemia, or symptomatic 
coronary artery disease within 1 year prior to the 
Screening Visit 
 Clinically significant atrial or ventricular 
dysrhythmia; the heart must be in predominantly 
normal sinus rhythm 
 Second or third degree atrioventricular block 
 Heart failure 


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 Functionally significant cardiac structural 
abnormality or valvular disease 
 Cardiomyopathy 
 Any other cardiovascular condition that the 
Investigator feels may predispose the subject to 
cardiovascular events (e.g., myocardial infarction, 
stroke) or arrhythmia 
 
10. Known family history of sudden cardiac death in the 
absence of pre-existing heart disease. 
11. Use of any psychotropic medication within 30 days of 
the Baseline visit except for ADHD medication. 
(Sedative hypnotics prescribed as a sleep aid at a stable 
dose for at least 30 days prior to Baseline, at bedtime 
only, are allowed during the study).  
12. Has used prohibited drugs or agents (see Appendix B) 
within 28 days of the Baseline visit through Study 
Visit 7. (Stimulant medications are allowed until 7 days 
before the Baseline visit). Non-stimulant ADHD 
medications (guanfacine, bupropion, clonidine, and/or 
atomoxetine) are not allowed within 28 days of Visit 2 
or at any time during the study. 
13. Has received an investigational drug within 60 days of 
the Screening visit. 
14. Has an abnormal laboratory test value, vital sign, or 
other exam finding at Screening or Baseline that, in the 
opinion of the Investigator, warrants exclusion from the 
study. In addition, subjects with laboratory values listed 
below are considered exclusionary: 
 Serum aspartate transaminase (AST) or alanine 
transaminase (ALT) >1.5 × upper limit of normal 
(ULN) 
 Serum total bilirubin >1.5 × ULN unless due to 
Gilbert’s Syndrome 
 Serum creatinine > 1.3 × ULN 
 Glycosylated hemoglobin (HbA1c) ≥7.0%. 
 TSH <0.9 × lower limit of normal (LLN) or TSH 
>1.2 × ULN 
15. Reports a history of hypersensitivity or intolerance to 
any formulation of amphetamine. 
16. Reports a history of poor therapeutic response to any 
formulation of amphetamine or methylphenidate despite a 
clearly adequate trial (including dose and duration).  
17. Is unable to swallow medication in capsule form. 


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18. Is unable or unwilling to follow directions of study staff 
or comply with all the testing and requirements of the 
protocol. 
19. Has a positive urine drug result at Screening (with the 
exception of current ADHD stimulant therapy, if any).  
Note: subjects should be informed that they should not 
participate in the trial or submit to urine drug testing if 
they are using any controlled or recreational drug (other 
than a prescribed stimulant for ADHD), and non-use 
should be confirmed prior to testing.  
20. Has a positive blood alcohol level at Screening. Note:  
subjects should be informed that alcohol consumed 
within 12 hours of screening may result in a positive 
test. 
21. Has current or known history of drug or alcohol abuse 
within the past 12 months. 
22. Has a history of human immunodeficiency virus (HIV), 
hepatitis B, or untreated hepatitis C infection. Note: 
Subjects with a history of hepatitis C infection who have 
been treated and whose HCV RNA is currently 
undetectable are not excluded.  
23. Has a score of ≥2 for suicidal ideation, or any self-
injurious behavior in the past year using the Columbia 
Suicide Severity Rating Scale at Baseline. 
Randomization 
 
Study subjects will be randomized to AR19 or placebo at Study 
Visit 2.  
Treatments 
AR19 (amphetamine sulfate) 20 mg or 40 mg or matching 
placebo daily (4 capsules per day) 


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Criteria for 
Evaluation 
Change in ADHD symptoms will be assessed using the 
following: 
 
Adult ADHD Investigator Rating Scale (AISRS) 
 
Clinical Global Impression of Severity (CGI-S)  
 
Clinical Global Impression of Improvement (CGI-I)  
 
Behavior Rating Inventory of Executive Function for 
Adults (BRIEF-A) 
 
Difficulties in Emotional Regulation Scale (DERS) 
 
Affective Style Questionnaire (ASQ) 
Safety will be assessed using: 
 
Blood pressure and pulse measurements 
 
Weight 
 
Electrocardiograms (ECGs) 
 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Laboratory assessments 
 
Adverse event monitoring 
 
Statistical Methods  
 
Sample Size: 
Approximately 87 patients per treatment group will provide 
approximately 90% power to detect a 7.0-point difference in 
mean change from Baseline to Visit 7 in the AISRS total score 
between one of the AR19 doses and placebo with a standard 
deviation of 13.0 and Type I error of 0.025 using a two-sample 
t test. To account for an approximate 20% dropout rate, a total 
of 104 subjects will be randomized to each of the three 
treatment groups for a total of 312 randomized subjects. 
 
Statistical Methods: 
All continuous study assessments will be summarized by 
treatment and time point using descriptive statistics (n, mean, 
median, standard deviation, minimum, and maximum). All 
categorical study assessments will be summarized by 
treatment and time point using frequency counts and 
percentages. Hypothesis testing, unless otherwise indicated, 
will be two-sided and performed at the 5% significance level. 
Full details will be included in a statistical analysis plan (SAP). 
 
The primary efficacy endpoint is change from Baseline in 
AISRS total score at Visit 7. A Bonferroni adjustment will be 
utilized for the primary efficacy analysis where each AR19 
dose will be tested against placebo separately using an alpha 


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of 0.025 for each test. No other adjustments for multiplicity 
will be applied to any other endpoints or comparisons. 
 
Analysis Populations: 
Three populations will be defined for data analysis: the Safety 
Population, the Full Analysis Set Population, and the Per 
Protocol Population. 
 
Safety Population: 
All subjects who are randomized and receive at least one dose 
of study medication will be included in the Safety Population. 
The Safety Population is the primary analysis population for 
safety assessments. Results will be presented “as treated.” 
 
Full Analysis Set (FAS) Population: 
All subjects who are randomized, receive at least one dose of 
study medication, and have one or more post-baseline 
on-treatment primary efficacy assessment(s) will be included 
in the FAS Population. The FAS Population is the primary 
analysis population for clinical efficacy. Results will be 
presented “as randomized.” 
 
Per Protocol (PP) Population: 
All subjects who are in the FAS population and who do not 
have any major protocol deviations will be included in the PP 
Population. The PP Population will be used as a sensitivity 
analysis for clinical efficacy. 
 
Efficacy Analysis: 
Primary: 
The primary efficacy variable, change from Baseline in AISRS 
at Visit 7, will be compared between each of the two different 
AR19 dose groups and the placebo group using a restricted 
maximum likelihood (REML)-based mixed model for repeated 
measures (MMRM). This model will include fixed effects for 
treatment, week, baseline AISRS, and the treatment-by-week 
interaction. Study week will be included in the model as a 
categorical variable. Within this model, pairwise comparisons 
(using least squares [LS] mean contrasts) will be made to 
compare AISRS at Visit 7 for each AR19 dose level with 
placebo separately (primary efficacy outcome). Treatments 
will also be compared at other weeks as secondary analyses. If 
differences between baseline characteristics exist between the 
three treatment groups in this comparison, it will be 
investigated whether adjustment for these characteristics is 


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clinically relevant and necessary as a sensitivity analysis.   
 
Secondary and Exploratory: 
The number and percentage of subjects who have each 
category of the CGI-S and CGI-I at each time point will be 
presented by treatment group. Cochran-Mantel-Haenszel row 
mean score tests will be used to compare the treatment 
groups. CGI-S and CGI-I results will also be summarized 
treating the responses as continuous values. A MMRM will be 
utilized to compare treatments at each time point. The model 
will include fixed effects for treatment, week, and the 
treatment-by-week interaction.   
 
BRIEF-A, DERS, and ASQ scale scores will be summarized 
descriptively over time utilizing observed and change from 
baseline scores. Treatments will be compared at each time 
point utilizing MMRM models on change from baseline scores. 
The model will include fixed effects for treatment, week, 
baseline value, and the treatment-by-week interaction. 
 
 
Safety Analysis: 
The nature, frequency, and severity of adverse events, 
including serious adverse events and adverse events leading to 
discontinuation, will be summarized descriptively by 
treatment group. Vital signs, ECGs, and clinical laboratory test 
results will be summarized using actual and change from 
baseline values. C-SSRS data will be listed. 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition of Term 
ADHD 
Attention Deficit Hyperactivity Disorder 
AISRS 
Adult ADHD Investigator Rating Scale 
AE/SAE 
Adverse Event/Serious Adverse Event 
ASQ 
Affective Style Questionnaire  
BL 
Baseline 
BRIEF-A 
Behavior Rating Inventory of Executive Function – Adult Version 
CAADID 
Conners' Adult ADHD Diagnostic Interview for DSM-IV™ 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression of Improvement  
CGI-S 
Clinical Global Impression of Severity 
CNS 
Central Nervous System 
C-SSRS 
Columbia Suicide Severity Rating Scale  
CYP 
Cytochrome P450 
DERS 
Difficulties in Emotional Regulation Scale 
DSM-5™  
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ET 
Early Termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
IR 
Immediate Release 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LLN 
Lower Limit of Normal 
MINI 
Mini International Neuropsychiatric Interview for Adults 
PFC 
Prefrontal Cortex  
MMRM 
Mixed Model for Repeated Measures 
SAP 
Statistical Analysis Plan 
ULN 
Upper Limit of Normal 


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TABLE OF CONTENTS 
1 
INTRODUCTION ...................................................................................................... 20 
1.1 
Background ............................................................................................ 20 
1.1.1 
Attention Deficit Hyperactivity Disorder (ADHD) ..................................... 20 
1.1.2 
Overview of Current ADHD Treatments ................................................... 20 
1.1.3 
Rationale for Development of AR19 in ADHD Adults ................................. 21 
1.2 
Mechanism of Action.................................................................................... 21 
1.3 
Rationale for Dose Selection ......................................................................... 21 
2 
STUDY OBJECTIVES ................................................................................................. 23 
2.1 
Primary Objective ........................................................................................ 23 
2.2 
Secondary Objectives ................................................................................... 23 
2.3 
Exploratory Objective .................................................................................. 23 
3 
INVESTIGATIONAL PLAN ........................................................................................ 23 
3.1 
Description of Overall Study Design and Plan ................................................ 23 
3.2 
Endpoints .................................................................................................... 24 
3.2.1 
Efficacy Endpoints .................................................................................. 24 
3.2.2 
Safety Endpoints ..................................................................................... 24 
3.2.3 
Exploratory Endpoints ............................................................................ 24 
4 
STUDY POPULATION ............................................................................................... 25 
4.1 
Inclusion Criteria .................................................................................... 25 
4.2 
Exclusion Criteria ........................................................................................ 26 
4.3 
Removal of Subjects from Therapy or Assessment ......................................... 28 
5 
CLINICAL TRIAL MATERIALS .................................................................................. 29 
5.1 
Description of Clinical Trial Material ............................................................ 29 
5.2 
Packaging, Storage, and Dispensing of Study Drug ......................................... 29 
5.3 
Administration ............................................................................................ 30 
5.4 
Randomization and Blinding Procedures ...................................................... 31 
5.5 
Emergency Unblinding of a Randomization Code .......................................... 32 
5.6 
Study Drug Adjustments .............................................................................. 32 
5.7 
Drug Accountability ..................................................................................... 32 
5.8 
Treatment Compliance ................................................................................. 33 
5.9 
Prior, Concomitant, and Prohibited Medications ........................................... 33 
5.9.1 
Prior Medications ................................................................................... 33 
5.9.2 
Concomitant Therapy .............................................................................. 33 
5.9.3 
Prohibited Medications ........................................................................... 34 
6 
CLINICAL EVALUATIONS ......................................................................................... 34 
6.1 
Study Procedures ........................................................................................ 34 
6.1.1 
Screening Visit – Study Visit 1 (Day -30 to -1) ........................................... 38 
6.1.2 
Baseline – Study Visit 2 (Day 1) ............................................................... 39 
6.1.3 
Treatment Period – Day 2 to Day 36 (±2) ................................................. 40 
6.1.4 
End of Study – Visit 7/Day 36 .................................................................. 40 
6.1.5 
Early Termination ................................................................................... 41 
6.1.6 
Unscheduled Visit ................................................................................... 41 
6.1.7 
Post-Withdrawal Follow-Up Telephone Call – Visit 8 ................................ 42 
6.2 
Description of Assessments .......................................................................... 42 
6.2.1 
Baseline Characteristics .......................................................................... 42 
6.2.1.1 
Demography ............................................................................... 42 
6.2.2 
Medical History ....................................................................................... 42 
6.2.3 
Efficacy Parameters ................................................................................ 42 
6.2.3.1 
Primary Efficacy Variable ............................................................. 42 
6.2.3.2 
Secondary Efficacy Variables ........................................................ 43 


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6.2.3.3 
Exploratory Endpoints ................................................................. 43 
6.3 
Assessments ................................................................................................ 43 
6.3.1 
Adult ADHD Investigator Rating Scale (AISRS) ......................................... 43 
6.3.2 
Clinical Global Impression Scales (CGI) .................................................... 43 
6.3.3 
Mini International Neuropsychiatric Interview 7.0.2 (MINI)...................... 44 
6.3.4 
Conners’ Adult ADHD Diagnostic Interview for DSM-IVTM (CAADID) .......... 44 
6.3.5 
Behavior Rating Inventory of Executive Function–Adult Version (BRIEF-A)44 
6.3.6 
Difficulties in Emotional Regulation Scale (DERS) ..................................... 44 
6.3.7 
Affective Style Questionnaire (ASQ) ......................................................... 44 
6.4 
Safety Parameters/Assessments .................................................................. 44 
6.4.1 
Physical Examination .............................................................................. 45 
6.4.2 
Vital Signs ............................................................................................... 45 
6.4.3 
Electrocardiography ............................................................................... 45 
6.4.4 
Hematology, Serum Chemistry and Urinalysis .......................................... 45 
6.4.5 
Pregnancy Test and Contraceptives for Females of Child-Bearing Potential 46 
6.4.6 
Drugs of Abuse Testing ............................................................................ 46 
6.4.7 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................... 46 
7 
ADVERSE EVENTS ................................................................................................... 47 
7.1 
Definition of an Adverse Event ..................................................................... 47 
7.2 
Definition of a Serious Adverse Event (SAE) .................................................. 47 
7.3 
Collection of Adverse Events ........................................................................ 48 
7.4 
Assessment of Adverse Events ..................................................................... 48 
7.4.1 
Assessment of Adverse Event Severity ..................................................... 48 
7.4.2 
Assessment of Adverse Event Relatedness ............................................... 49 
7.4.3 
Recording of AEs and SAEs ...................................................................... 49 
7.5 
Reporting of Serious Adverse Events ............................................................ 50 
7.5.1 
Serious Adverse Event Notification .......................................................... 50 
7.5.2 
SAE Expedited Reporting......................................................................... 50 
7.6 
Procedures for Reporting Pregnancy Exposure and Birth Events ................... 50 
7.7 
Emergency Unblinding ................................................................................. 51 
7.8 
Follow-up of AEs and SAEs ........................................................................... 51 
8 
STUDY ADMINISTRATION ....................................................................................... 51 
8.1 
Quality Assurance/Quality Control ............................................................... 51 
8.1.1 
Direct Access to Source/Data Documents ................................................. 51 
8.1.2 
Periodic Monitoring ................................................................................ 51 
8.1.3 
Audit and Inspection ............................................................................... 51 
8.1.4 
Confidentiality of Subject Data ................................................................. 52 
8.2 
Data Handling and Record Keeping .............................................................. 52 
8.2.1 
Electronic Case Report Forms (eCRFs) ..................................................... 52 
8.2.2 
Study Records Retention ......................................................................... 52 
8.3 
Termination of the Study ............................................................................. 52 
9 
STATISTICAL ANALYSES ......................................................................................... 53 
9.1 
Determination of Sample Size ....................................................................... 53 
9.2 
General Methodology ................................................................................... 53 
9.3 
Subject Populations for Statistical Analysis ................................................... 53 
9.3.1 
Safety Population .................................................................................... 53 
9.3.2 
Full Analysis Set (FAS) Population ........................................................... 53 
9.3.3 
Per Protocol Population .......................................................................... 54 
9.4 
Primary Efficacy Analysis ............................................................................. 54 
9.5 
Secondary Efficacy Analyses......................................................................... 54 
9.6 
Exploratory Endpoints ................................................................................. 55 


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9.7 
Handling of Drop-Outs or Missing Data ......................................................... 55 
9.8 
Safety Analyses ............................................................................................ 55 
9.8.1 
Adverse Events ....................................................................................... 55 
9.8.2 
Clinical Laboratory Assessments.............................................................. 56 
9.8.3 
Vital Signs and ECGs ................................................................................ 56 
9.8.4 
Other Safety Variables ............................................................................. 56 
10 ETHICS, LEGAL, AND ADMINISTRATIVE ASPECTS .................................................... 56 
10.1 
Institutional Review Board........................................................................... 56 
10.2 
Ethical Conduct of the Study ......................................................................... 57 
10.3 
Subject Information and Informed Consent ................................................... 57 
11 APPENDICES ........................................................................................................... 58 
11.1 
Appendix A .................................................................................................. 58 
11.2 
Appendix B .................................................................................................. 59 
12 REFERENCES .......................................................................................................... 61 
 
List of In-Text Tables 
Table 5.3.1 
Titration Scheme for 20 mg Daily Dose ........................................................................ 31 
Table 5.3.2 
Titration Scheme for 40 mg Daily Dose ........................................................................ 31 
Table 6.1.1 
Schedule of Events ................................................................................................................. 35 
 
 
 


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1 
INTRODUCTION 
1.1 
Background 
1.1.1 Attention Deficit Hyperactivity Disorder (ADHD) 
Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder which 
typically presents in childhood. As defined in the Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition (DSM-5™), ADHD is characterized by pervasive and 
impairing symptoms of inattention, hyperactivity, and impulsivity which begin in 
childhood.1 ADHD often persists into adulthood with one-half to two-thirds of child 
patients continuing to be symptomatic adults. The estimated prevalence of ADHD in adults 
in the United States is 4.4%.2 ADHD causes significant impairment in patients throughout 
the lifespan. Adults with ADHD are more likely to quit a job or be fired, have auto accidents, 
experience sudden changes in personal or career goals, and have higher perceived social 
and emotional stress.3,4 
Specific etiology of this disorder is unknown, and there is no single diagnostic test. It is 
apparent that the prefrontal cortex (PFC) plays a significant role in maintaining executive 
function, and that patients with ADHD appear to have less-than-adequate PFC activity, 
resulting in an overall inability to regulate impulsive behavior.5 Adequate diagnosis 
requires the use not only of medical but also of special psychological, educational, and 
social resources. Learning may or may not be impaired. The diagnosis must be based upon 
a complete history and evaluation of the patient and not solely on the presence of the 
required number of DSM-5™ characteristics. 
The core symptoms used to diagnose ADHD in adults are inattention and hyperactivity-
impulsivity. It has, however, been recognized for decades that many adult ADHD patients 
experience clinically significant levels of emotional dysregulation.6 Items pertaining to 
emotional dysregulation are contained in certain domains of several existing tools, 
including the Behavior Rating Inventory of Executive Function—Adult Version (BRIEF-A), 
Difficulties in Emotion Regulation Scale (DERS), and Affective Style Questionnaire (ASQ).7  8, 
9  
1.1.2 Overview of Current ADHD Treatments 
Controlled clinical trials have consistently demonstrated that stimulants (amphetamine 
and methylphenidate) substantially reduce the characteristic symptoms and functional 
impairment of patients with ADHD.10,11 Stimulants have a large effect size, with a mean of 
0.73 to 0.96 in placebo-controlled adult ADHD trials.12  
Amphetamine and methylphenidate both contain chiral centers that give rise to distinct 
enantiomeric forms. Amphetamine, in particular, exists as dextro- and levo-amphetamine 
isomers that have different pharmacokinetic and neuropharmacological properties. Several 
products have been marketed containing different proportions of each isomer. Dexedrine, 
for example, consists of pure d-amphetamine; while mixed amphetamine salts such as 
Adderall consist of a ratio of approximately 3:1 d-amphetamine to l-amphetamine. 


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Benzedrine, a product first marketed in 1933, consisted of a racemic mixture of 
approximately 50% d-amphetamine and 50% l-amphetamine.  
Evekeo® is a marketed immediate-release (IR) formulation of amphetamine sulfate 
indicated for narcolepsy, ADHD, and exogenous obesity.13 Amphetamine is a 
sympathomimetic amine with central nervous system (CNS) stimulant activity and is a 1:1 
racemic mix of d-amphetamine and l-amphetamine. The l-isomer is more potent than the 
d-isomer in cardiovascular activity but less potent in causing CNS excitatory effects. 
In response to the growing misuse of amphetamines, including by intranasal 
administration, AR19 is an abuse-deterrent formulation of a 1:1 racemic mixture of d- to 
l-amphetamine sulfate.14,15 Enhancements to the current IR formulation of Evekeo® are 
intended to achieve a level of deterrence against abuse when the formulation is 
manipulated and administered by unintended routes (e.g., intranasal, intravenous). The 
abuse-deterrent capabilities of AR19 are attributed to pellets within the capsule that confer 
abuse-deterrent properties.   
 
. 
1.1.3 Rationale for Development of AR19 in ADHD Adults 
Racemic amphetamine was the first stimulant studied for treatment of behavioral 
disorders in children in 1937.16 However, only one study has been conducted to date 
documenting the efficacy of a 50% d-amphetamine and 50% l-amphetamine compound 
(Evekeo®) in the treatment of ADHD.   
This study was conducted in children ages 6 to 12 years and demonstrated efficacy 
beginning at 45 minutes and continuing through 10 hours after administration of a single 
dose.17 No studies evaluating the effects of this mixture of d:l amphetamine have been 
completed in adults. The current study will test the safety and efficacy of this composition 
(AR19) in adult subjects 18 through 55 years old with ADHD. 
1.2 
Mechanism of Action 
Amphetamine is a CNS stimulant. The mode of therapeutic action in humans is not 
completely understood. Amphetamine is thought to block the reuptake of norepinephrine 
and dopamine into the presynaptic neuron and increase the release of these monoamines 
into the extraneuronal space.18 
1.3 
Rationale for Dose Selection  
AR19 will be available in 10 mg and 20 mg strengths for this study. 
Although there is limited information regarding dosing of amphetamine-based IR products 
in adults, the Food and Drug Administration (FDA) has approved several extended-release 
amphetamine-based products for the treatment of ADHD in adults.19,20    


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In the Evekeo® children classroom study, the median optimized daily dose was 20 mg. In 
general, adults have lower systemic exposure to amphetamines when receiving the same 
fixed dosage and formulation.21  
For one longer-acting amphetamine mixed salt formulation, the maximum dosage was 
50 mg (31.3 mg amphetamine equivalents).20 The maximum daily dose of 40 mg that will 
be used in this study has 29.3 amphetamine equivalents. AR19 is a 50-50 mixture of d- and 
l-amphetamine, it is anticipated that the side effect profile of the 40 mg dose should not be 
substantially greater. Therefore, the 20 and 40 mg daily doses used in this study are 
expected to show efficacy and establish the safety profile of AR19 in adults.   
AR19 will be given twice daily: the first dose on awakening and the second dose four to 
six hours later. The double-dummy technique will be utilized in order to maintain the blind 
between the 10 mg and 20 mg capsules and matching placebo.  
In adults, the starting dose will be 10 mg once daily the first week and 10 mg twice per day 
the second week. In subsequent weeks, subjects randomized to 10 mg twice per day (20 mg 
daily) will remain on that dose until the final visit, while subjects randomized to 20 mg 
twice per day will be raised in increments of 10 mg/week with completion of titration at 
Visit 5 (Week 4) and remain on their randomized dose (40 mg/day) for the final visit. 
Subjects who experience unacceptable tolerability will be discontinued. 
The efficacy and safety profile of amphetamine is well established, and recent studies 
continue to support the safe and effective use of amphetamine for the treatment of ADHD.  
The use of amphetamine in the treatment of ADHD is endorsed by professional medical 
organizations including the National Institute for Health and Care Excellence and the 
European Network Adult ADHD.22,23   
There are no published professional guidelines for the treatment of adult ADHD by 
professional organizations in the United States. 
Evekeo® is indicated for children and adolescents 3 years and older. The most common 
side effects in the Medication Guide include headache, stomach pain, insomnia, decreased 
appetite, dry mouth, nervousness, and dizziness. For a full list of side effects, refer to the 
Evekeo® label and Medication Guide.13 
The most commonly reported adverse reactions from placebo-controlled trials of two 
extended-release amphetamine-based products in adults with incidence greater than or 
equal to 5% and at least twice the incidence of placebo included decreased appetite, 
decreased weight, nausea, dry mouth, diarrhea, insomnia, anxiety, anorexia, dizziness, 
increased heart rate, and tachycardia.19,20 
Amphetamine should be given cautiously to subjects with a history of drug dependence or 
alcoholism. Chronic abusive use can lead to marked tolerance and psychological 
dependence, with varying degrees of abnormal behavior. 
Sudden deaths, stroke, and myocardial infarction have been reported in adults taking 
stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult 


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cases is also unknown, adults have a greater likelihood than children of having serious 
structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, 
coronary artery disease, or other serious cardiac problems. Adults with such abnormalities 
should also generally not be treated with stimulant drugs.13  
Use of stimulants may cause treatment-emergent psychotic or manic symptoms in patients 
with no prior history or exacerbation of symptoms in patients with pre-existing psychiatric 
illness. Clinical evaluation for bipolar disorder is recommended prior to stimulant use. 
Patients beginning treatment for ADHD should be monitored for the appearance or 
worsening of aggressive behavior or hostility. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to assess the efficacy of AR19 compared to placebo 
using the Adult ADHD Investigator Rating Scale (AISRS). 
 
2.2 
Secondary Objectives   
 To assess efficacy using AISRS hyperactive and inattentive subscale scores 
 To assess global efficacy using the Clinical Global Impression of Severity (CGI-S) and 
Clinical Global Impression of Improvement (CGI-I)  
 To assess efficacy for treating executive function as measured by the BRIEF-A  
 To investigate the safety and tolerability of AR19 in adult subjects ages 18 through 
55 with ADHD 
 
2.3 
Exploratory Objective 
 To assess efficacy for treating emotional dysregulation using established self-rated 
instruments for emotional dysregulation. To explore which facets of emotional 
dysregulation change with treatment using item and subscale analyses.   
 To assess exposure-response relationships using population pharmacokinetics 
 
3 
INVESTIGATIONAL PLAN 
3.1 
Description of Overall Study Design and Plan 
This randomized, fixed-dose, double-blind, multi-center trial investigates the safety and 
efficacy of AR19 in the treatment of ADHD in adults from 18 through 55 years of age. 
Safety parameters and therapeutic effect will be evaluated throughout the trial. 
Subjects will be randomized to 20 or 40 mg AR19 daily or placebo in a 1:1:1 ratio in this 
fixed dose study. The expected drop-out rate is projected at 20%. 
The study will consist of: 
 A 30-day Screening period and Baseline evaluation 


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 Titration with AR19 for 4 weeks to 20 or 40 mg daily dose or placebo 
 At least two weeks at a stable dose of AR19 or placebo 
 Post Withdrawal Follow Up phone call at Visit 8 
 
Study visits will be conducted according to the Schedule of Assessments (Table 6.1.1). 
Subjects who have signed an informed consent form (ICF) and who satisfy the 
inclusion/exclusion criteria will receive study drug twice daily, once in the morning and 
again four to six hours later. Study medication dosing will start at 10 mg/day and will be 
titrated in weekly intervals in 10-mg increments to 20 or 40 mg/day, depending on 
randomization. 
It is anticipated that approximately 30 sites will participate in the study. Subject enrollment 
will continue until approximately 312 subjects are enrolled. 
3.2 
Endpoints 
3.2.1 Efficacy Endpoints 
The primary efficacy endpoint is the change in the AISRS total score at Visit 7 compared to 
Visit 2 (Baseline) with AR19 vs placebo. 
Secondary efficacy endpoints include the change in AISRS subscale scores (Inattention 
subscale and Hyperactivity/Impulsivity subscale), CGI-S, CGI-I, and executive function as 
measured by the BRIEF-A. 
3.2.2 Safety Endpoints 
All subjects who enter the study will be assessed for safety. Safety will be monitored by 
adverse events (AEs) assessed at each visit. In addition, the Columbia Suicide Severity 
Rating Scale (C-SSRS)24 will be administered at Baseline and all subsequent scheduled 
visits to assess emergent suicidal thoughts or behaviors. Medical history will capture all 
medical conditions at Visits 1 (Screening) and 2 (Baseline). Physical examinations and 
clinical laboratory tests will be conducted at Screening and at Visit 7 (End of Study) and 
also can be conducted at any subsequent visit as deemed necessary by the Principal 
Investigator. Safety will be assessed by the following measures throughout the study: 
 Vital sign changes 
 Changes in weight 
 Incidence and severity of AEs 
 Incidence of clinically significant changes from Baseline in the C-SSRS 
 Electrocardiogram (ECG) changes 
 Laboratory values 
 
3.2.3 Exploratory Endpoints 
Items pertaining to emotional dysregulation are contained in certain domains of several 
existing tools, including the BRIEF-A, DERS, and ASQ, which will be used in this study. We 
hypothesize that AR19 treatment will improve emotional dysregulation based on prior 


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studies of stimulant medications. In addition to assessing efficacy, as indicated by the total 
scores on each instrument, which facets of emotional dysregulation change with treatment 
using item and subscale analyses will also be explored. 
In addition, exposure-response relationships will be explored using population 
pharmacokinetics. 
4 
STUDY POPULATION 
Approximately 312 adult subjects (male or female) with a diagnosis of ADHD per DSM-5TM 
criteria will be enrolled. Subjects must be 18 to 55 years old, inclusive, at the time of 
Screening.   
Subjects who satisfy the inclusion/exclusion criteria will undergo a 7-day washout of 
previous ADHD stimulant medications, and AR19 or placebo will then be initiated at 
10 mg/day the morning after Visit 2. Depending on treatment group, the daily dose will be 
increased in 10-mg increments every week to 20 or 40 mg/day. The study duration from 
first dose of study drug to the follow-up visit is expected to be approximately 6 weeks. 
Subjects will be monitored for safety and for therapeutic response to AR19 treatment. 
Safety and clinical response assessments will be performed at each visit or more frequently 
if clinically indicated.  
Each subject must meet all the inclusion criteria and none of the exclusion criteria to be 
eligible for enrollment in the study. Waivers to inclusion/exclusion criteria will NOT be 
granted. 
4.1 
Inclusion Criteria 
A subject may be enrolled in the study if he/she meets all the following criteria: 
1. Is male or female between 18 and 55 years of age, inclusive, at the time of Screening.  
2. Meets criteria for diagnosis of ADHD using Conners' Adult ADHD Diagnostic 
Interview for DSM-IV™ adapted for DSM-5™ (CAADID). 
3. Has an AISRS total score of ≥26 at Visit 2. 
4. Has a clinician-administered CGI-S score of 4 or greater at Visit 2. 
5. In the clinical judgment of the Investigator, the subject needs pharmacological 
treatment for ADHD.  
6. Must read and write English at a level sufficient to provide written informed consent 
and to complete study-related materials. 
7. For subjects currently on a stable dose of allowed non-ADHD medication, there will 
be no expected changes in subject’s medications during the study with the exception 
of medications listed in Section 5.9.2.  
8. Males and females who are fertile and sexually active with a partner of the opposite 
sex must adhere to contraception requirements for the duration of the study as 
follows: 
o Females of childbearing potential must agree to be abstinent or to use highly 
effective forms of contraception. 


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o Females of non-childbearing potential, defined as surgically sterile (status 
post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or 
post-menopausal for at least 12 months do not require contraception during 
the study.  
o Males, including males who are surgically sterile, with female partners of 
childbearing potential, must agree to be abstinent or else use a medically 
acceptable form of contraception from screening through the end of study.  
 
4.2 
Exclusion Criteria 
A subject will be excluded from study participation if he/she meets one or more of the 
following criteria: 
1. Has a primary psychiatric diagnosis other than ADHD. 
2. Has any other current secondary or co-morbid medical, psychiatric, or social 
condition which, in the opinion of the investigator, might compromise subject safety, 
or is likely to interfere with protocol compliance or to confound the assessment of 
safety or efficacy.   
3. Has a history or current symptoms of bipolar disorder, schizophrenia, or psychotic 
disorder. 
4. Has clinically significant cognitive impairment in the clinical judgment of the 
Investigator. 
5. Has a Body Mass Index of <17 or ≥39 kg/m2. 
6. Has a Screening or Baseline blood pressure of ≥139 mmHg systolic or ≥89 mmHg 
diastolic. 
7. Is pregnant or breastfeeding, or is planning to become pregnant during the study. 
8. Has a history of any of the following disorders:   
 seizure disorder (excluding a history of isolate febrile seizures <6 years old),  
 Inadequately or not treated hypertension is defined as a subject who has blood 
pressure indicative of Stage 2 hypertension (systolic pressure ≥140 mmHg or 
diastolic pressure ≥90 mmHg). Subjects who are adequately treated must be on 
a stable dose of antihypertensive medications for 3 months prior to screening 
and their antihypertensive medications are not anticipated to change. Blood 
pressure will be taken in triplicate, and the average will be used for evaluating 
entry criteria. 
 Untreated thyroid disease. Subjects with a history of thyroid disease who have 
been on a stable dose of thyroid hormone for at least three months are eligible to 
participate if their thyroid-stimulating hormone (TSH) does not fall in the 
excluded range, shown below in 14. 
 Glaucoma  
 Tourette’s disorder, or chronic tics.   
9. 
Has ECG or clinical evidence of the following:   
 QTcF > 470 milliseconds (msec) for females, and > 450 msec for males 
 Atrial or ventricular hypertrophy 


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 Intraventricular conduction defects other than incomplete right bundle branch 
block in the absence of other heart disease  
 Myocardial infarct, ischemia, or symptomatic coronary artery disease within 1 
year prior to the Screening Visit 
 Clinically significant atrial or ventricular dysrhythmia; the heart must be in 
predominantly normal sinus rhythm 
 Second or third degree atrioventricular block 
 Heart failure 
 Functionally significant cardiac structural abnormality or valvular disease 
 Cardiomyopathy 
 Any other cardiovascular condition that the Investigator feels may predispose 
the subject to cardiovascular events (e.g. myocardial infarction, stroke) or 
arrhythmia 
 
10. Known family history of sudden cardiac death in the absence of pre-existing heart 
disease. 
11. Use of any psychotropic medication within 30 days of the Baseline visit except for 
ADHD medication. (Sedative hypnotics prescribed as a sleep aid at a stable dose for 
at least 30 days prior to Baseline, at bedtime only, are allowed during the study.)  
12. Has used prohibited drugs or agents (see Appendix B) within 30 days of the Baseline 
visit through Study Visit 7. (Stimulant medications are allowed until 7 days before 
the Baseline visit.) Non-stimulant ADHD medications (guanfacine, bupropion, 
clonidine, and/or atomoxetine) are not allowed within 30 days of Visit 2 or at any 
time during the study. 
13. Has received an investigational drug within 60 days of the Screening visit. 
14. Has an abnormal laboratory test value, vital sign, or other exam finding at Screening 
or Baseline that, in the opinion of the Investigator, warrants exclusion from the 
study. In addition, subjects with laboratory values listed below are considered 
exclusionary: 
 Serum aspartate transaminase (AST) or alanine transaminase (ALT) >1.5 × 
upper limit of normal (ULN) 
 Serum total bilirubin >1.5 × ULN unless due to Gilbert’s Syndrome 
 Serum creatinine >1.3 × ULN 
 Glycosylated hemoglobin (HbA1c) ≥7.0%. 
 TSH <0.9 × lower limit of normal (LLN) or TSH >1.2 × ULN 
15. Reports a history of hypersensitivity or intolerance to any formulation of 
amphetamine. 
16. Reports a history of poor therapeutic response to any formulation of amphetamine 
or methylphenidate despite a clearly adequate trial (including dose and duration).  
17. Is unable to swallow medication in capsule form. 
18. Is unable or unwilling to follow directions of study staff or comply with all the 
testing and requirements of the protocol. 
19. Has a positive urine drug result at Screening (with the exception of current ADHD 
stimulant therapy, if any). Note: subjects should be informed that they should not 


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participate in the trial or submit to urine drug testing if they are using any controlled or 
recreational drug (other than a prescribed stimulant for ADHD), and non-use should be 
confirmed prior to testing.  
20. Has a positive blood alcohol level at Screening. Note:  subjects should be informed 
that alcohol consumed within 12 hours of screening may result in a positive test. 
21. Has current or known history of drug or alcohol abuse within the past 12 months. 
22. Has a history of human immunodeficiency virus (HIV), hepatitis B, or untreated 
hepatitis C infection. Note: subjects with a history of hepatitis C infection who have 
been treated and whose HCV RNA is currently undetectable are not excluded.  
23. Has a score of ≥2 for suicidal ideation, or any self-injurious behavior in the past year 
using the Columbia Suicide Severity Rating Scale at Baseline. 
4.3 
Removal of Subjects from Therapy or Assessment 
Any subject who withdraws from the study prior to completing the treatment period will 
be considered to have "prematurely discontinued" study participation. Subjects may 
withdraw or be withdrawn from the study for the following reasons: 
 
The subject wishes to discontinue study participation 
 
An adverse event or serious adverse event that imposes an unacceptable risk to the 
subject’s health to continue in the study 
 
Major protocol deviations (e.g. failed to meet entry criteria, did not adhere to 
protocol requirements and/or impact integrity of subject level data) 
 
The subject is unable to tolerate 20 or 40 mg daily dose, depending on 
randomization 
 
Lost to follow up 
 
The subject becomes pregnant. If subjects are to withdraw due to pregnancy, the 
procedures in Section 7.6 should be followed  
 
The sponsor decides to terminate the study. 
Although a subject is not obliged to give his/her reason for withdrawing prematurely, the 
Investigator will make a reasonable effort to obtain the reason while fully respecting the 
subject’s rights. The procedures described for Early Termination (Section 6.1.5) will be 
performed, if possible. Every effort will be made to contact a subject who fails to attend a 
study visit, or does not respond by telephone, to ensure that the subject is in satisfactory 
health. The Medical Monitor will be informed of removal or early withdrawal of a subject 
from the study. 
Withdrawn subjects will not be replaced. 
If modifications in the experimental design, dosages, subject selection, etc. are indicated or 
required, such changes will be instituted only following consultation between the Sponsor 
and the Investigator and will be accomplished through formal amendments to this protocol 
and approval by the appropriate review committees. 
This study may be discontinued at any time if, in the opinion of the Principal Investigator or 
the Sponsor, continuation of the study represents a significant medical risk to participating 
subjects. 


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Arbor retains the right to terminate the study at an individual study site or at all study sites 
for administrative reasons such as, but not limited to: unacceptable subject accrual, failure 
of the Principal Investigator to conduct the study according to protocol, or failure to 
complete study case report forms (CRFs) or maintain study records satisfactorily. 
5 
CLINICAL TRIAL MATERIALS 
5.1 
Description of Clinical Trial Material 
It is the responsibility of the Sponsor to ensure that study drug provided for this study is 
manufactured under Good Manufacturing Practices (GMP) and is suitable for human use. 
AR19 contains amphetamine sulfate, which is a white crystalline powder that is freely 
soluble in water. AR19 has a molecular weight of 368.49 and is provided as 10 mg and 
20 mg capsules in this study. Each capsule also contains the following inactive ingredients: 
polyethylene oxide, polyethylene glycol, starch, citric acid, α-tocopherol, hypromellose, 
water, and talc. Placebo is identical to AR19, except it contains no active medication.  
The following will be supplied by the Sponsor: 
 10 mg and 20 mg AR19 capsules 
 Placebo capsules identical in appearance to AR19 at both dosage levels 
Arbor will provide sufficient quantities of AR19 and matching placebo to allow for 
completion of the study. The lot numbers and expiration dates of the study medications 
will be recorded in the final study report.  
Records will be maintained indicating the receipt and dispensation of all medication 
supplies. At the conclusion of the study, all unused study medication will be returned to the 
Sponsor’s designee for destruction. 
5.2 
Packaging, Storage, and Dispensing of Study Drug 
AR19 and placebo will be provided as capsules in weekly blister cards in blinded 
packaging. Since AR19 10 mg and 20 mg strengths are two different colored capsules, the 
double-dummy technique will be utilized to maintain the blind. Double-blinded AR19 and 
placebo at each dose level will have identical appearance and taste. Each weekly blister 
card will contain a total of 36 capsules to have a 7-day supply plus 2 extra days. 
The placebo is made of pharmaceutical excipients in capsule form. Placebo capsules are 
identical in formulation, taste, and appearance to AR19, but lack the active ingredient 
amphetamine sulfate. 
Study drug labels will contain information to meet the applicable regulatory requirements.   
All study drug supplies must be stored in accordance with the manufacturer’s instructions 
at room temperature between 68˚F to 77˚F (20˚C to 25˚C), as defined in the United States 
Pharmacopeia (USP). Until dispensed to the subject, the study drug will be stored in a 
securely locked area, accessible to authorized personnel only. Study drug contains 


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amphetamine sulfate, a Schedule II federally controlled substance, and should be stored in 
accordance with federal, state, and local regulations. 
The dispensing pharmacist or designated qualified individual will be responsible for 
dispensing study drug and documenting important information on the appropriate drug 
accountability records at the time of dispensing, such as but not limited to: date dispensed, 
number of capsules, medication identifier or batch number, and subject identification 
number. The dispensing pharmacist or designated qualified individual will be responsible 
for providing the subject with the correct blister card in the appropriate strength(s).   
Arbor Pharmaceuticals or designee will provide detailed dispensing instructions prior to 
study conduct. 
5.3 
Administration 
The following dosing procedures will be followed:   
 The dosing regimen will be two capsules twice daily. All subjects will be instructed 
to take their first dose (two different colored capsules) of study medication in the 
morning. The second dose (two different colored capsules) should be taken four to 
six hours later. 
 Study medication will be administered orally by swallowing the capsules.  
 Study drug can be taken with or without food. 
This study is a fixed dose regimen. Dose adjustments are not allowed during the study.  
After Screening and Baseline evaluations are complete, eligible subjects will be randomized 
1:1:1 to one of two fixed-dose groups (AR19 10 mg p.o. b.i.d. or AR19 20 mg p.o. b.i.d.) or 
placebo.  
Subjects unable to tolerate their AR19 dose at any time during study drug administration 
will be withdrawn from the trial. 
Subjects will begin dosing with double-blind study drug the morning following the Baseline 
visit. The first dose will be taken in the morning (2 capsules) and the second dose 
(2 capsules) will be taken 4 to 6 hours later. 
 


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Table 5.3.1 Titration Scheme for 20 mg Daily Dose 
 
 
 
 
 
 
 
 
 
Table 5.3.2 Titration Scheme for 40 mg Daily Dose 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects randomized to placebo will receive the 10 mg and 20 mg placebo capsules for the 
first and second dose (4 capsules/day) during the trial.    
 
Visit 7, Day 36: End of Study Visit 
 
Visit 8: Follow-up Phone Call  
 
5.4 
Randomization and Blinding Procedures 
All study medication will be supplied in weekly blister packs and will be similar in color, 
smell, taste, and appearance, thereby enabling double-blind conditions. 
Enrollment will occur at Visit 2, upon randomization, after all screening procedures have 
been performed and eligibility for the study is confirmed at the Baseline Visit.  
Kit Assigned 
on Visit/Day 
First Dose 
Second Dose 
Visit 2, Day 1  
20 mg 
Placebo 
10 mg  
 
20 mg 
Placebo 
10 mg 
Placebo 
Visit 3, Day 8 
20 mg 
Placebo 
10 mg 
 
20 mg 
Placebo 
10 mg 
 
Visit 4, Day 15 
20 mg 
Placebo 
10 mg 
20 mg 
Placebo 
10 mg 
 
Visit 5, Day 22 
20 mg 
Placebo 
10 mg 
20 mg 
Placebo 
10 mg 
Visit 6, Day 29 
20 mg 
Placebo 
10 mg 
20 mg 
Placebo 
10 mg 
 
Kit Assigned 
on Visit/Day 
First Dose 
Second Dose 
Visit 2, Day 1  
20 mg 
Placebo 
10 mg  
 
20 mg 
Placebo 
10 mg 
Placebo 
Visit 3, Day 8 
20 mg 
Placebo 
10 mg 
 
20 mg 
Placebo 
10 mg 
 
Visit 4, Day 15 
20 mg 
10 mg 
Placebo 
20 mg 
Placebo 
10 mg 
 
Visit 5, Day 22 
20 mg 
10 mg 
Placebo 
20 mg 
10 mg 
Placebo 
Visit 6, Day 29 
20 mg 
10 mg 
Placebo 
20 mg 
10 mg 
Placebo 


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For the randomization of subjects, the Investigator or delegated designee will complete the 
randomization electronic case report form (eCRF), which is integrated with the study 
interactive web response system (IWRS). The IWRS will assign subjects to a treatment 
group (placebo, 20 mg, or 40 mg AR19/day) based on the pre-defined randomization list. 
Randomization will occur via IWRS at Visit 2, if a subject meets all inclusion and no 
exclusion criteria. Subjects will be randomized 1:1:1 to placebo or 20 or 40 mg AR19/day. 
Randomization will take place according to a fixed schedule using a permuted block design 
with no stratification by clinical site.   
5.5 
Emergency Unblinding of a Randomization Code 
Unblinding should occur only when knowing the treatment assignment has a bearing on 
the medical treatment or evaluation of a subject. Whenever possible, the need to unblind 
should be discussed with the Medical Monitor prior to unblinding. In the event of an 
emergency, the Investigator, Pharmacist, or designated qualified individual may obtain the 
subject’s blinded treatment via IWRS. If an individual designated to perform emergency 
unblinding does not have access to the IWRS, Sponsor designee may be contacted and can 
perform the unblinding for that individual. 
A subsequent written report, including all pertinent details, must be submitted to the 
Medical Monitor within 1 business day of the unblinding. Whenever possible, the blind of 
the subject should be maintained. 
If an Investigator, site personnel performing assessments, or subject is unblinded, the 
subject must be withdrawn from the study, and procedures accompanying withdrawal 
should be performed.   
5.6 
Study Drug Adjustments  
Subjects who cannot tolerate their daily dose of AR19 (up to 20 or 40 mg daily) will be 
discontinued from the study. Study drug dose adjustments are not allowed during this fixed 
dose study. 
5.7 
Drug Accountability 
The Investigator or designee will verify and acknowledge receipt of study drug. All study 
medication must be stored in a secure area under the proper storage requirements with 
limited access (i.e., restricted to the Investigator or designees). Study medication 
designated for this clinical study must not be taken by anyone other than those enrolled in 
this specific investigation and may not be utilized for any laboratory or animal research. All 
study medication dispensed to subjects must be accurately recorded on the Drug 
Accountability Record maintained at the study center. Subjects should be instructed to 
return all study medication dispensed to them (including any unused capsules and blister 
cards) at each study visit. 
Drug accountability will be performed at each study visit starting with Study Visit 3. At 
each visit, subjects should return all unused medication dispensed to them at the prior 
visit. All study medication and blister cards will be retained at the site for study monitor 


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verification. All study medication should be stored at the study site until further instruction 
from the study monitor. 
The Investigator is responsible for returning all unused or partially used study medication 
to the Sponsor’s designee at the end of the study. The Investigator must verify that all 
unused or partially used study medication supplies have been returned by the subject and 
that no remaining supplies are in the Investigator’s possession at the time of study 
discontinuation.  
Arbor or designee will provide detailed drug accountability instructions at the start of the 
study. 
5.8 
Treatment Compliance 
Subject training at the Baseline Visit (Visit 2) and subsequent ongoing retraining regarding 
proper dosing of study medication will occur to ensure subject compliance. Beginning with 
Visit 3, study staff will assess compliance at every study visit to confirm that the subject is 
taking study medication according to the protocol. Compliance is defined as taking 80% to 
100% of study medication for the duration of the study. 
5.9 
Prior, Concomitant, and Prohibited Medications 
5.9.1 Prior Medications  
Subjects who were taking a prescription psychotropic medication other than a stimulant or 
sedative hypnotic at the time of Screening are not eligible for the study. Subjects who have 
recently taken prescription psychotropic medications for ADHD (except stimulants or 
sedative hypnotics) are eligible, if the psychotropic medication will be discontinued at least 
28 days prior to the Baseline Visit. Any non-study ADHD stimulant medication must be 
discontinued at least 7 days prior to the Baseline Visit 2. Subjects must not have 
participated in any other clinical study in which an investigational drug was administered 
within 60 days of the Screening Visit and must not participate in other investigational trials 
during this study. 
5.9.2 Concomitant Therapy 
Information on concomitant medications will be collected at each study visit through the 
Post Withdrawal Follow-Up Phone Call (Visit 8) or early termination.  
Intermittent use of acetaminophen or non-steroidal anti-inflammatory medications is 
allowed. Use of non-sedating antihistamines, including Zyrtec, Claritin, and Allegra, as well 
as Nasonex will also be allowed during the trial. Acetaminophen is permitted for control of 
fever or pain, if needed. Short courses of prescription and non-prescription medications for 
treatment of acute illnesses such as the common cold, viral illnesses, and ear infections are 
permitted, provided they do not contain the medications listed in Appendix B of the 
protocol.   
If a subject discontinues from the study early, study drug is to be discontinued for at least 
24 hours prior to his/her beginning new ADHD therapy. 


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5.9.3 Prohibited Medications  
Use of psychotropic medications, including but not limited to anticonvulsant, 
antidepressant, anxiolytic, and antipsychotic medications, is not allowed during the study, 
except for sedative hypnotics used at a stable dose at bedtime only, for at least 30 days prior 
to Baseline Visit 2. Stimulants (other than study drug) must be discontinued 7 days prior to 
Baseline Visit 2. Non-stimulant ADHD medications (guanfacine, bupropion, clonidine, 
and/or atomoxetine) are not allowed within 30 days of Visit 2 or at any time during the 
study. Prescription or non-prescription cold and/or allergy medications and herbal 
preparations with sedative effects (such as first-generation antihistamines) or with 
stimulant or pressor effects (such as pseudoephedrine or ephedrine) are also prohibited. 
Systemic corticosteroids are prohibited; inhaled or topical corticosteroids are not 
prohibited.  Subjects are not to use an investigational medication from another trial during 
the study or for the 60 days prior to study start. Prohibited concomitant medications can be 
resumed after Study Visit 8. 
A list of concurrent medication classes that are excluded can be found in Appendix B. 
6 
CLINICAL EVALUATIONS 
6.1 
Study Procedures 
A detailed schedule of events is located in Table 6.1.1.  
Approximately 312 adult subjects, aged 18 to 55 years inclusive at Screening, with a 
diagnosis of ADHD per DSM-5™ criteria will be eligible for participation in this study. A 
maximum of 50 mL of blood will be drawn from subjects throughout the study duration.   






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AISRS = Adult ADHD Investigator Rating Scale; ASQ = Affective Style Questionnaire; BL = baseline; BMI = body mass index; BRIEF-A = Behavior Rating 
Inventory of Executive Function – Adult Version; CAADID = Conners Adult ADHD Diagnostic Interview for DSM-IV; CGI-I = Clinical Global Impression of 
Improvement; CGI-S = Clinical Global Impression of Severity; C-SSRS = Columbia Suicide Severity Rating Scale; CYP = cytochrome P450; DERS = Difficulties 
in Emotion Regulation Scale; DSM-5™ = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; ECG = electrocardiogram; FU = follow-up; 
HbA1c = glycosylated hemoglobin; MINI = Mini International Neuropsychiatric Interview for Adults; PK = pharmacokinetic 
 


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6.1.1 Screening Visit – Study Visit 1 (Day -30 to -1) 
Before any study-specific procedures are performed, the subject must receive an 
explanation of all study procedures and must sign and date an Institutional Review Board 
(IRB)-approved written informed consent form. A subject ID number will be assigned at the 
Screening Visit (Visit 1), for any subject who signs an ICF.  
The timing of the Screening Visit must take into account planned absences at the clinical 
site and the timing of the study visits according to the Schedule of Events Table 6.1.1. 
The Screening Visit may be split into more than one calendar day if needed, if all required 
assessments are performed within 30 days of Baseline (Visit 2). 
Diagnosis of ADHD based on DSM-5™ criteria and the CAADID will be confirmed for all 
subjects at entry by a physician or mental health profession (Master’s level or higher), 
having at least five years of experience using ADHD rating scales for assessment of ADHD 
and also using the DSM for assessment of psychiatric disorders. A MINI-7.0.2 will be 
administered on all subjects to assist in screening for other mental health disorders that 
may be exclusionary.  
Following confirmation of appropriate age at the Screening Visit, a diagnosis of ADHD 
consistent with DSM-5™ criteria will be confirmed prior to the evaluation of other inclusion 
and exclusion criteria.   
During the Screening Period, the following activities will be performed: 
 Obtain subject informed consent 
 Review of inclusion/exclusion criteria 
 Review of medical history 
 Review of medication history (ADHD stimulant medication should be discontinued 
7 days prior to the Baseline Visit) 
 Demographics 
 Completion of the following diagnostic criteria for ADHD performed by a physician 
or mental health professional (Master’s Level or higher) with the required 
experience as outlined above: 
o CAADID 
o DSM-5™ Diagnoses 
 Mini International Neuropsychiatric Interview (MINI) 7.0.2 
 AISRS 
 CGI-S 
 C-SSRS Baseline Visit version 
 Height, body weight, and body mass index (BMI) 
 Blood pressure and pulse (in triplicate via automated machine), respiratory rate, 
and temperature 
 Resting 12-lead ECG 
 Physical examination 
 Laboratory tests (see Appendix A) 


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o Serum chemistry panel (including serum pregnancy test for females of 
child-bearing potential) 
o Hematology 
o Urinalysis 
o Urine drug screen for drugs of abuse testing (performed at the site) 
o Blood alcohol level 
o HbA1c 
 
Blood and urine samples MUST be drawn after all other assessments are completed. 
 
6.1.2 Baseline – Study Visit 2 (Day 1) 
Once the subject is determined to be initially eligible during Screening, the Baseline (Study 
Visit 2, Day 1) evaluations will be completed. The timing of the Baseline Visit (Day 1) must 
take into account the need for study visits to occur according to the Schedule of 
Assessments (see Table 6.1.1).  
If the subject continues to meet eligibility criteria at the Baseline Visit (Day 1), enrollment 
of the subject into the study will be performed by randomizing the subject through the 
integrated IWRS/eCRF. Double-blind study medication will be dispensed by the site 
pharmacy or designated, qualified study personnel (see Section 5.2). 
Subjects will be instructed to start taking study medication on the morning of Day 2 with 
the first dose administered in the morning and the second dose four to six hours later. 
Subjects will be instructed to return all unused study medication with blister card at the 
next scheduled study visit.  
The following activities will be performed pre-randomization: 
 Review of inclusion/exclusion criteria 
 Review of medical history 
 Body weight 
 Blood pressure and pulse (in triplicate via automated machine) 
 C-SSRS since last visit 
 AISRS 
 BRIEF-A 
 CGI-S 
 DERS 
 ASQ 
 Concomitant medications assessment 
 Urine pregnancy test for females of child-bearing potential  
 Urine drug screen for drugs of abuse testing, performed at site 
 eCRF entry for randomization  
 
The following activities will be performed post-randomization: 
 Cytochrome P450 (CYP) 2D6 genetic testing will be performed only for those 
randomized subjects who opt in. Subjects who opt out are still eligible for the study. 


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 Study drug dispensing and study medication training  
 
6.1.3 Treatment Period – Day 2 to Day 36 (±2) 
Enrolled subjects will begin taking study medication at home the morning following the 
Baseline Visit at 10 mg/day or placebo. From Day 2 through Day 36 (±2) inclusive, subjects 
will swallow study medication (2 capsules) once daily in the morning with or without food, 
and again four to six hours later. The dosing regimen will be twice daily for the duration of 
the study (4 capsules/day). 
The following activities will be performed at each visit: 
 Blood pressure and pulse (in triplicate via automated machine)  
 AISRS 
 CGI-S 
 CGI-I 
 Follow-up C-SSRS 
 Adverse events assessment 
 Concomitant medications assessment 
 Pharmacokinetic sampling* (Visit 6 only) 
 Urine pregnancy test for females of child-bearing potential (Visits 4 and 6 only) 
 eCRF entry for study drug assignment 
 Study drug accountability and study medication training 
 Dispense study drug 
 
*Blood for pharmacokinetics (Visit 6 only) MUST be drawn after efficacy and safety 
assessments are completed. Subjects should be instructed to record accurate dosing history 
(date/time) on their dosing card for the day prior to and day of their study visit. 
 
6.1.4 End of Study – Visit 7/Day 36 
The following activities will be performed during Study Visit 7 / End of Study: 
 Blood pressure and pulse (in triplicate via automated machine) 
 Body weight 
 AISRS 
 BRIEF-A 
 DERS 
 ASQ 
 CGI-S 
 CGI-I 
 Follow-up C-SSRS 
 Resting 12-lead ECG  
 Physical Examination 
 Laboratory tests 
o Pharmacokinetic sampling 
o Serum chemistry panel  
o Hematology  


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o Urinalysis 
o Urine pregnancy test for females of child-bearing potential 
 AE assessment 
 Concomitant medications assessment 
 eCRF entry for study completion  
 Study drug accountability  
 
Blood and urine samples MUST be drawn after efficacy and safety assessments are 
completed. 
 
6.1.5 Early Termination 
Every effort should be made to have subjects who withdraw early from the trial return to 
the site to complete an Early Termination Visit and return any unused study drug. 
The following activities should be performed: 
 Blood pressure and pulse (in triplicate via automated machine) 
 Body weight 
 Physical examination 
 Resting 12-lead ECG  
 Laboratory tests  
o Serum chemistry panel  
o Hematology 
o Urinalysis 
o Urine pregnancy test for females of child-bearing potential 
 AISRS 
 BRIEF-A 
 DERS 
 ASQ 
 CGI-S 
 CGI-I 
 Follow-up C-SSRS 
 AE assessment 
 Concomitant medications assessment 
 eCRF entry for early withdrawal 
 Study drug accountability  
 
6.1.6 Unscheduled Visit 
Unscheduled visits are allowed if a safety concern is identified.  
The following activities may be performed, including but not limited to: 
 Blood pressure and pulse (in triplicate via automated machine), respiratory rate, 
and temperature 
 Physical examination, including body weight 
 Resting 12-lead ECG 
 Laboratory tests (see Appendix A) 


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o Serum chemistry panel 
o Hematology 
o Urinalysis 
o Urine pregnancy test for females of child-bearing potential 
 Any other safety assessments per Investigator’s clinical judgment 
 AE assessment 
 Concomitant medications assessment 
 Study drug accountability and study medication training, if needed 
6.1.7 Post-Withdrawal Follow-Up Telephone Call – Visit 8  
The following activities will be performed during a follow-up telephone call, 
7 + 2 days after Visit 7, for subjects who complete the study: 
 AE assessment 
 Concomitant medications assessment 
6.2 
Description of Assessments 
Safety and efficacy evaluations will be performed during the study. The schedule of these 
procedures is described in Table 6.1.1. 
6.2.1 Baseline Characteristics 
6.2.1.1 Demography 
Information relating to the subject’s gender, age, race, and weight/height will be collected 
at screening and recorded on the appropriate eCRF page. 
6.2.2 
Medical History 
The medical history of each subject will be collected and recorded on the appropriate eCRF 
page. This history will also include any abnormalities found during the physical 
examination conducted at the Screening Visit. History of prior and concomitant 
medications will be recorded as indicated in Section 5.9. 
6.2.3 
Efficacy Parameters 
As much as possible, the same individual should perform a given efficacy assessment at 
every visit when the assessment is required. Efficacy will be assessed by the following 
measures collected during the study: 
6.2.3.1 Primary Efficacy Variable 
The primary efficacy endpoint is the change in AISRS total score from Visit 2 (Baseline) to 
Visit 7 (End of Study) in AR19 treated subjects compared to placebo.  


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6.2.3.2 Secondary Efficacy Variables 
 CGI-S at Visit 7 compared to Baseline 
 CGI-I at Visit 7 
 Changes from Baseline of AISRS subscale scores compared to Visit 7 
 Changes from Baseline of the BRIEF-A, subscales, indices, and composites compared 
to Visit 7 
 
6.2.3.3 Exploratory Endpoints 
Items pertaining to emotional dysregulation are contained in certain domains of several 
existing tools, including the BRIEF-A, DERS, and ASQ, which will be used in this study.   
Exposure-response relationships using population pharmacokinetics will be explored. A 
nonlinear mixed-effect modeling approach will be used for population pharmacokinetic 
analysis. To aid the population pharmacokinetic analysis, two blood plasma samples will be 
collected from all subjects. Error! Reference source not found. provides instructions on 
processing and shipment of samples to the central laboratory. The samples collected will 
include pre-dose up to approximately 6 hours following drug administration on planned 
subject visit days (Visit 6 and Visit 7). Subjects should be instructed to record accurate 
dosing history (date/time) on their dosing card for the day prior to and day of their study 
visit. Additional AR19 concentration vs time data may be pooled from other studies and 
included in population pharmacokinetic analysis. Covariates such as age, weight, liver 
function (AST and ALT), CYP 2D6 metabolizer status, and race and their effect on AR19 
pharmacokinetic parameters will be explored. The developed population pharmacokinetic 
model will be used to conduct exposure-response analysis. 
 
6.3 
Assessments 
6.3.1 Adult ADHD Investigator Rating Scale (AISRS) 
The AISRS is a validated 18-item scale that corresponds directly to the 18 ADHD items in 
the Diagnostic and Statistical Manual of Mental Disorders.25 It includes adult prompts for 
each item. The AISRS will be used to determine trial eligibility. An AISRS assessment will be 
completed at Study Visits 1 through 7. The Investigator or other designated, qualified 
individual from the study research team will complete the assessment. 
6.3.2 Clinical Global Impression Scales (CGI) 
The Clinical Global Impression Scales are used to measure features associated with ADHD. 
A global assessment of disease severity (CGI-S) will be completed at Study Visits 1 through 
7. A global assessment of disease improvement (CGI-I) relative to baseline will be 
completed at Study Visits 3 through 7. The Investigator or designated, qualified individual 
from the study site will perform the assessment. 


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6.3.3 Mini International Neuropsychiatric Interview 7.0.2 (MINI) 
The MINI is a short, structured diagnostic interview developed for DSM-5™. It assesses the 
15 most common psychiatric diagnoses and can be completed in about 15 minutes.26 The 
MINI will be completed at Screening. 
6.3.4 Conners’ Adult ADHD Diagnostic Interview for DSM-IVTM (CAADID) 
The CAADID is a structured interview that assesses childhood and adult ADHD symptoms. 
Although the version used was designed for DSM-IVTM, it can be adapted to make an ADHD 
diagnosis using DSM-5™ criteria. 
6.3.5 Behavior Rating Inventory of Executive Function–Adult Version (BRIEF-A) 
The BRIEF-A is a standardized measure designed to assess adult executive functioning and 
self-regulation.7 It is composed of 75 items and 9 clinical scales which include: Inhibit, 
Self-Monitor, Plan/Organize, Shift, Initiate, Task Monitor, Emotional Control, Working 
Memory, and Organization of Materials. The clinical scales compose two indexes: 
Behavioral Regulation (BRI) and Metacognition (MI), and these indexes form the overall 
summary score, the Global Executive Composite (GEC).  
6.3.6 Difficulties in Emotional Regulation Scale (DERS) 
The DERS is a validated non-disease state scale consisting of 39 items. These items are 
grouped to reflect difficulties in: a) awareness and understanding of emotions; 
b) acceptance of emotions; c) ability to engage in goal directed behavior and refrain from 
impulsive behavior while experiencing negative emotions; and d) access to emotional 
regulation strategies perceived as effective.8 
6.3.7 Affective Style Questionnaire (ASQ) 
The ASQ is a 20-item questionnaire used to measure individual styles in emotional 
regulation. The styles assessed in this instrument are: a) suppression and other strategies 
to conceal or avoid emotion; b) more able to access emotional information in adaptive 
problem solving (i.e., to be better able to modulate emotional experience and expression 
according to contextual demands); and c) reflecting comfort and non-defensiveness in 
response to arousing emotional responses, thus tolerating the aroused emotional 
response.9   
6.4 
Safety Parameters/Assessments 
All subjects who enter the study will be assessed for safety. Safety will be monitored by AEs 
assessed at each post-dose visit. In addition, the C-SSRS will be administered at Screening 
and all subsequent scheduled visits to assess emergent suicidal thoughts or behaviors. 
Medical history will capture all medical conditions at Visits 1 (Screening) and 2 (Baseline). 
Physical examinations and clinical laboratory tests will be conducted at Visit 1 (Screening) 
and Visit 7 (End of Study), and at an Early Termination Visit, if necessary and can be 
conducted at any post-dose visit, if the Principal Investigator deems it necessary. 


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The following will be assessed throughout the study according to the Schedule of Events 
Table 6.1.1: 
 Incidence and severity of AEs (see Section 7). 
 Incidence of clinically significant changes from Baseline in the C-SSRS. 
6.4.1 Physical Examination 
A full physical examination will be performed at Visits 1 (Screening), 7 (End of Study), and 
at an Early Termination Visit, if necessary. This will include physical examination of the 
following body areas and systems: head and neck, abdominal, chest, cardiovascular, heart, 
respiratory, musculoskeletal, skin, neurological, and endocrine. This assessment is optional 
at unscheduled visits, per the Investigator’s discretion. 
Body weight will also be measured at Screening (Visit 1), Baseline (Visit 2), and at the End 
of Study (Visit 7) or at the Early Termination Visit, if necessary.  
6.4.2 Vital Signs 
Blood pressure and pulse will be assessed at all study visits and will be taken using 
automated machines programmed to take 3 consecutive readings (at least 2 minutes 
apart). Subjects should be comfortably seated for at least a few minutes prior to blood 
pressure readings. Respiratory rate, height for BMI, and temperature will be measured at 
Screening (Visit 1) only.  
6.4.3 Electrocardiography 
A 12-lead ECG will be recorded at Screening (Visit 1), End of Study (Visit 7) and at an Early 
Termination Visit (if necessary) by the Investigator or other designated, qualified 
individual from the study site. The ECGs will be assessed by a central reader(s). ECGs can 
be performed at unscheduled visits, per the Investigator’s discretion. 
6.4.4 Hematology, Serum Chemistry and Urinalysis 
At Screening (Visit 1), End of Study (Visit 7) and at an Early Termination Visit (if 
necessary), laboratory tests will include a non-fasting serum chemistry panel, hematology 
(complete blood count), and urinalysis. Laboratory assessments are optional at 
Unscheduled Visits. For a complete list of laboratory tests, please see Appendix A. 
CYP 2D6 genetic testing will be performed only at Baseline (Visit 2) for those randomized 
subjects who opt in. Subjects who opt out are still eligible for the study. During the trial, 
CYP 2D6 testing results will be blinded to the subject and investigative site in order 
to ensure protocol efficacy and safety assessments remain unbiased. 
Detailed sample collection, handling, processing, and shipment instructions will be 
provided by Sponsor’s laboratory designee prior to the start of the study.  


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6.4.5 Pregnancy Test and Contraceptives for Females of Child-Bearing Potential 
At the Screening Visit (Visit 1), a serum pregnancy test will be performed for all female 
subjects of child-bearing potential.  
Urine dipstick pregnancy tests will be performed onsite at Visit 2 (Baseline) and Visits 4, 6, 
and 7 (End of Study) or early termination visit (if necessary) and may be performed at any 
time during study participation, if pregnancy is suspected. If positive, confirmation should 
be performed via a serum pregnancy test. 
Moreover, females of child bearing potential must agree to use adequate birth control 
methods to prevent pregnancy throughout the study. Examples of medically highly 
effective forms of birth control include:  
 Surgical sterility (via vasectomy, hysterectomy, or bilateral ligation) or post-
menopausal females  
 Sexual partner is sterile, or of the same sex  
 Implants of levonorgestrel in females  
 Oral contraceptive (combined or progesterone only) in females  
 Double-barrier method (any combination of physical and chemical methods) 
 Intrauterine device in females, or other method with published data showing that 
the lowest expected failure rate is less than 1% per year  
 Complete abstinence from penile-vaginal intercourse 
 
6.4.6 Drugs of Abuse Testing 
A urine test for drugs of abuse will be performed at the site during Visit 1 (Screening) and 
Visit 2 (Baseline). The following drugs will be included: amphetamine, barbituates, 
benzodiazepenes, cocaine, opiates, methadone, methamphetamine, and phencyclidine 
(PCP).  
6.4.7 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a brief, Investigator-administered questionnaire that provides for the 
identification, quantification, and standardized assessment of the occurrences and severity 
of suicidal ideation and behavior.28  
The Baseline version of the C-SSRS will be administered to all subjects at the Screening 
Visit. The “Since Last Visit” version will be used at all subsequent study visits (and Early 
Termination, if necessary). The Investigator or other designated, qualified individual at the 
clinical site will perform these assessments. 


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7 
ADVERSE EVENTS  
7.1 
Definition of an Adverse Event 
An AE is defined as “any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.” An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product. This includes any newly occurring event or 
previous condition that has increased in severity or frequency since the administration of 
study drug. 
Adverse events will be identified at the times indicated in the schedule by asking the 
subject a neutral question such as: "How have you been feeling since your last visit?" 
Adverse events may also be reported spontaneously at any time. Any adverse or 
unexpected events, signs, or symptoms will be fully recorded on the AE form in the eCRF 
including details of onset, resolution, frequency, severity (as defined below), seriousness, 
relationship to the drug, effect on the study drug, treatments administered, and outcome. 
Any AE that occurs during the study will be followed, whenever possible, until it returns to 
the baseline condition or becomes stable with no further change expected. 
Beginning with the first dose of study drug on Day 2, all AEs occurring up to study 
completion, must be recorded in the eCRF. All changes in health occurring prior to study 
drug dosing should be recorded as medical history. 
7.2 
Definition of a Serious Adverse Event (SAE) 
An SAE is any event or reaction that fulfills one or more of the following outcomes: 
 Results in death 
 Is life threatening. This means that the patient is at risk of death at the time of the 
event; it does not mean that the event hypothetically might have caused death if it 
were more severe 
 Requires inpatient hospitalization or prolongs an existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Results in a congenital defect or birth defect 
 Is an important medical event that may not be immediately life threatening or result 
in death or hospitalization but that may jeopardize the patient or require 
intervention to prevent one of the above outcomes. 
Medical and scientific judgment should be exercised in deciding whether a case is serious.   
All SAEs must be recorded on the eCRF adverse event form as “serious” and submitted 
promptly during the study. All SAEs should be monitored until they are resolved or are 
clearly determined to be due to a subject’s stable or chronic condition or intercurrent 
illness. 


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Reports for hospitalization for elective procedures do not need to be reported as SAEs, if 
there are no precipitating signs/symptoms or worsening of a pre-existing condition that 
necessitated the procedure. However, SAEs must be reported for any complications 
resulting from a procedure that prolonged the hospitalization.  
Serious adverse events should be reported as outlined in Section 7.5. 
7.3 
Collection of Adverse Events 
The collection of AE information will start with the first dose of study drug (Day 2) and 
continue through the post-withdrawal follow-up phone call (i.e., 7 days after Visit 7). The 
collection of SAE information will start with the first dose of study drug (Day 2) and 
continue 30 days after the subject’s last dose of study drug. For subjects who terminate 
early, all AEs and SAEs should be treated as medically appropriate. Should a subject have 
an ongoing SAE at the last study contact or has an SAE within 30 days after Visit 7, the 
subject will continue to be followed as specified in Section 7.8. 
To detect the occurrence of AEs and SAEs, the physician should use non-direct neutral 
questioning of the subject at each post-dose clinical visit. Information of AEs and SAEs may 
also be given voluntarily by the subject at any time during the study.   
7.4 
Assessment of Adverse Events 
The Investigator will assess each AE according to severity and relatedness to study drug. 
7.4.1 Assessment of Adverse Event Severity 
The following guidelines for rating severity of AEs should be used: 
Mild: Awareness of signs or symptoms, but easily tolerated; are of minor irritant type; no 
loss of time from normal activities; symptoms would not require medication or a medical 
evaluation; signs and symptoms may be transient, disappearing during continued 
treatment with study medication.  
Moderate: Discomfort enough to cause interference with usual activities; the study 
medication may have been interrupted. 
Severe: Incapacitating with inability to do work or do usual activities; signs and symptoms 
may be of systemic nature or require medical evaluation; the study drug may have been 
stopped, and treatment for the event may be required. 
The term “severe” is often used to describe the intensity of a specific event, as in mild, 
moderate, or severe myocardial infarction; the event itself, however, may be of relatively 
minor medical significance, such as severe headache. This is not the same as serious, which 
is based on subject/event outcome or action criteria usually associated with events that 
pose a threat to a subject’s life or functioning. The Investigator must decide whether each 
AE meets the definition of an SAE. 


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7.4.2 Assessment of Adverse Event Relatedness 
The relatedness of an AE to study medication will be determined by the Investigator using 
the following definitions: 
Related: The AE is clearly related to the study drug. This assessment means there is 
evidence to suggest a clear, causal relationship between the study drug and the AE. 
Possibly Related: The AE may be related to study drug. A “possibly” assessment suggests 
that the association of the AE with the study medication is unknown; however, the AE is not 
reasonably supported by other conditions. 
Unlikely Related: The AE is doubtfully related to study drug. An “unlikely” assessment 
suggests other conditions, including chronic illness, progression or expression of the 
disease state, or reaction to concomitant medication, appear more likely to explain the 
reported AE. 
Not Related: The AE is clearly not related to the study drug. 
7.4.3 Recording of AEs and SAEs 
All AEs occurring during this clinical study will be recorded in the eCRF in precise medical 
terms, along with the date of onset and the date of resolution. To avoid vague, ambiguous, 
or colloquial expressions, the AE should be recorded in standard medical terminology 
rather than the subject’s own words. Whenever possible, the Investigator should group 
signs and symptoms together into a single term that constitutes a single diagnosis. Each AE 
is to be evaluated for duration, severity, seriousness, and relatedness to the study 
medication. The severity of the AE and its relationship to the study medication will be 
assessed by the Investigator.  
The action taken and the outcome must also be recorded. The possible actions concerning 
study medication are:  
 Drug withdrawn 
 Dose not changed 
 Unknown  
 Not applicable 
 Dose interrupted 
 
Recorded outcomes include: 
 
 Recovered/Resolved  
 Recovering/Resolving  
 Not recovered/Not resolved  
 Resolved with sequelae 
 Fatal 
 Unknown  


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7.5 
Reporting of Serious Adverse Events 
7.5.1 Serious Adverse Event Notification 
Serious adverse events must be reported within 24 hours of knowledge of the occurrence. 
This includes events that occur following completion of treatment with study drug. 
Additionally, if an Investigator learns of any SAEs that occurred after study completion for 
which there is a reasonable possibility of study drug relationship, that event should be 
reported to the Sponsor within 24 hours. 
The eCRF SAE Reporting Form will be completed with as much information as is available 
and must include information below within 24 hours of when the investigative site 
becomes aware of the event. 
Required SAE information: 
 Name of Reporter/Investigator 
 Subject identification  
 Adverse event term 
 Date of onset 
 Criteria of seriousness 
 Study drug relationship 
 
For assistance regarding SAE reporting, please contact the
 
 
 
7.5.2 SAE Expedited Reporting 
For each SAE, the Investigator should assess whether there is a reasonable possibility that 
the event may have been caused by the study drug (“drug related”) using the categories 
given in Section 7.4.2. The Sponsor or designee will notify all Investigators of an SAE. Those 
SAEs that meet reporting criteria will be submitted to the appropriate Regulatory 
Authorities as required by clinical trial regulations. The Investigator is responsible for 
notifying his/her respective IRB. 
7.6 
Procedures for Reporting Pregnancy Exposure and Birth Events 
Should a female subject become pregnant or be suspected of being pregnant while 
participating in this study, the event must be reported to 
 upon receipt 
of information by the study staff. While the pregnancy itself is not considered to be an AE 
or SAE, any pregnancy complications should be recorded as AEs or SAEs (if applicable). 
Pregnancy must be reported within 24 hours from first knowledge on the pregnancy eCRF. 
Any pregnancy will be followed through delivery for the observation of any SAEs including 
congenital abnormalities. Fatalities and spontaneous abortions must be reported as SAEs. 


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7.7 
Emergency Unblinding 
Unblinding should occur only when knowing the treatment assignment has a bearing on 
the medical treatment or evaluation of a subject. Whenever possible, the need to unblind 
should be discussed with the Medical Monitor prior to unblinding. In the event of an 
emergency, the Investigator, Pharmacist, or designated qualified individual may obtain the 
subject’s blinded treatment via IWRS. If an individual designated to perform emergency 
unblinding does not have access to the IWRS, Sponsor Designee may be contacted and can 
perform the unblinding for that individual. A subsequent written report, including all 
pertinent details, must be submitted to the Medical Monitor within 24 hours of the 
unblinding. Whenever possible, the blind of the subject should be maintained. 
7.8 
Follow-up of AEs and SAEs 
All AEs must be followed until they resolve (return to normal or baseline values), stabilize, 
or are judged by the Investigator to be no longer clinically significant. Serious adverse 
events observed during the study should be followed by the responsible Investigator at the 
clinical site until they resolve or stabilize, the subject is lost to follow-up, or the events are 
otherwise explained. 
8 
STUDY ADMINISTRATION 
8.1 
Quality Assurance/Quality Control 
8.1.1 Direct Access to Source/Data Documents 
The Investigator will permit study-related monitoring, audits, IRB review, and regulatory 
inspections by providing direct access to source data and documents. 
8.1.2 Periodic Monitoring 
The Sponsor or its designee will monitor all aspects of the study with respect to current 
Good Clinical Practice (GCP) and standard operating procedures for compliance with 
applicable regulations. These individuals must have access to all records necessary to 
ensure integrity of the data and will periodically review progress of the study with the 
Principal Investigator. 
Monitoring of the study progress and conduct will be ongoing. The Sponsor or its designee 
will be responsible for the following: 
 Monitoring study conduct to ensure that the rights of subjects are protected 
 Monitoring study conduct to ensure study compliance with GCP guidelines 
 Monitoring accuracy, completion, and verification of source documents for study 
data. 
8.1.3 Audit and Inspection 
All data recorded during the study will be made available by the site for audit against 
source data and for compliance with GCP and specific protocol requirements. 


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8.1.4 Confidentiality of Subject Data 
All information obtained during the conduct of the study that relates to an individual 
subject will be regarded as confidential. Throughout the study, participating subjects will 
be referenced using their allotted subject ID and initials. They will not be referred to by 
name in any document concerning the study or disclosed to any person not under the 
direct control of the Investigator. 
8.2 
Data Handling and Record Keeping 
8.2.1 Electronic Case Report Forms (eCRFs) 
Adequate and accurate case records will be maintained and all relevant observations and 
data related to the study will be recorded. This will include (but will not be limited to) 
medical history/physical examination, vital signs, medication history, pregnancy tests, a 
check of inclusion and exclusion criteria, drug administration, a record of sample collection, 
AEs, and final evaluation. 
The eCRFs will be signed electronically by the Principal Investigator after the review (date 
and time will be captured in the eCRF audit trail). After the completion of the study, 
completed eCRFs will be electronically transferred to the Sponsor and/or designee and 
stored in the archives according to the Data Management Plan for the study. 
Completed eCRFs will be reviewed by the study monitor against the source documentation 
for accuracy and completeness. Once eCRFs are signed by the Investigator, the data 
manager will lock the eCRFs for data analysis. 
8.2.2 Study Records Retention 
All primary data that are a result of the original observations and activities of the study that 
are necessary for the reconstruction and evaluation of any study report will be retained in 
a secure archive at the study site for a period of at least 2 years after the last approval of a 
marketing application for a specified drug indication being investigated or, if an application 
is not approved, until at least 2 years after the investigation is discontinued and regulatory 
authorities are notified. 
The Investigator must maintain adequate records for the study including completed CRFs, 
medical records, laboratory reports, signed ICFs, drug disposition records, adverse 
experience reports, information regarding subjects who discontinued, all correspondence 
with the IRB and the sponsor, and other pertinent data.   
The Investigator will notify Arbor in writing of the relocation of any study records away 
from the clinical site after study closure. The Investigator must contact Arbor in writing 
prior to the destruction of any study records, or in the event of loss of any study records.   
8.3 
Termination of the Study 
The Sponsor reserves the right to terminate the study in the interest of subject welfare. 


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9 
STATISTICAL ANALYSES 
9.1 
Determination of Sample Size 
The primary efficacy endpoint is change from Baseline in AISRS total score at Visit 7 
(Week 5). A Bonferroni adjustment will be utilized for the primary efficacy analysis where 
each AR19 dose will be tested against placebo separately using an alpha of 0.025 for each 
test. 
Eighty-seven (87) subjects per treatment group will provide approximately 90% power to 
detect a 7.0-point difference in mean change from Baseline to Visit 7 in the AISRS total 
score between one of the AR19 doses and placebo with a standard deviation of 13.0 and 
Type I error of 0.025 using a two-sample test. To account for an approximate 20% dropout 
rate, a total of 104 subjects will be randomized to each of the three treatment groups for a 
total of 312 randomized subjects. 
 
9.2 
General Methodology 
All continuous study assessments will be summarized by treatment and time point using 
descriptive statistics (n, mean, median, standard deviation, minimum, and maximum). All 
categorical study assessments will be summarized by treatment and time point using 
frequency counts and percentages. Hypothesis testing, unless otherwise indicated, will be 
two-sided and performed at the 5% significance level.  
A detailed statistical analysis plan (SAP) will be written and finalized prior to database 
unblinding. 
9.3 
Subject Populations for Statistical Analysis 
The three analysis populations for this study are defined below. Identification of the 
subjects to be included in each analysis population will be determined prior to database 
unblinding. 
9.3.1 Safety Population 
All patients who are randomized and receive at least one dose of study medication will be 
included in the Safety Population. The Safety Population is the primary analysis population 
for safety assessments. Results will be presented “as treated.” 
9.3.2 Full Analysis Set (FAS) Population  
All patients who are randomized, receive at least one dose of study medication, and had 
one or more post-Baseline on-treatment primary efficacy assessment(s) will be included in 
the FAS Population. The FAS Population is the primary analysis population for clinical 
efficacy. Results will be presented “as randomized.” 


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9.3.3 Per Protocol Population 
All patients who are in the FAS population and who do not have any major protocol 
deviations will be included in the PP Population. The PP Population will be used as a 
sensitivity analysis for clinical efficacy. 
9.4 
Primary Efficacy Analysis  
The primary efficacy analysis will be performed on the FAS population. 
For the primary efficacy endpoint, change from baseline in AISRS at Visit 7 (Week 5), the 
two AR19 dose levels (20 and 40 mg/day) will be compared with placebo. To account for 
these comparisons, a Bonferroni multiple comparison adjustment will be utilized. Both 
comparisons will be conducted at the 0.025 (0.05/2) alpha level. No other adjustments for 
multiplicity will be applied to any other endpoints or comparisons. 
Change from Baseline in AISRS at Visit 7 will be compared between each of the two 
different AR19 dose groups and the placebo group using a restricted maximum likelihood 
(REML)-based mixed model for repeated measures (MMRM). This model will include fixed 
effects for treatment, week, baseline AISRS, and the treatment-by-week interaction. Study 
week will be included in the model as a categorical variable. Within this model, pairwise 
comparisons (using least squares [LS] mean contrasts) will be made to compare AISRS at 
Visit 7 for each AR19 dose level with placebo separately (primary efficacy outcome). 
Treatments will also be compared at other weeks as secondary analyses. If differences 
between baseline characteristics exist between the three treatment groups in this 
comparison, it will be investigated whether adjustment for these characteristics is clinically 
relevant and necessary as a sensitivity analysis. 
All available data will be used; there will be no imputation of missing data. 
9.5 
Secondary Efficacy Analyses 
The primary analysis will be repeated on the PP population using the MMRM analysis 
described in Section 9.4. 
The secondary efficacy outcomes include: 
 AISRS hyperactivity/impulsivity subscale scores  
 CGI-S 
 CGI-I 
 BRIEF-A 
For the AISRS, the proportion of responders (defined as a subject who has a change from 
Baseline of 30% or greater in the AISRS) will also be presented. 
The number and percentage of subjects who have each category of the CGI-S and CGI-I at 
each time point will be presented by treatment group. Cochran-Mantel-Haenszel row mean 
score tests will be used to compare the treatment groups. CGI-S and CGI-I results will also 
be summarized treating the responses as continuous values. A MMRM will be utilized to 


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compare treatments at each time point. The model will include fixed effects for treatment, 
week, and the treatment-by-week interaction.   
BRIEF-A will be summarized descriptively over time utilizing observed and change from 
Baseline scores. Treatments will be compared at each time point utilizing MMRM models 
on change from Baseline scores. The model will include fixed effects for treatment, week, 
baseline value, and the treatment-by-week interaction. 
9.6 
Exploratory Endpoints 
Similar to the BRIEF-A, DERS and ASQ scale scores will be summarized descriptively over 
time utilizing observed and change from Baseline scores. Treatments will be compared at 
each time point utilizing MMRM models on change from Baseline scores. The model will 
include fixed effects for treatment, week, baseline value, and the treatment-by-week 
interaction. 
The pharmacokinetic analysis and reporting will be covered in a separate SAP and report. 
9.7 
Handling of Drop-Outs or Missing Data 
For subjects who discontinue prematurely, a MMRM approach will be used to address 
missing data. Other imputation methods (e.g., last observation carried forward [LOCF] or 
multiple imputation) may be used as sensitivity analyses. Full details will be described in 
the SAP. 
9.8 
Safety Analyses 
All safety data will be analyzed descriptively by treatment group using the Safety 
Population. 
9.8.1 Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. Treatment-emergent AEs will be defined as any event with a 
start date occurring on or after first dose of study medication. 
The incidence of treatment-emergent AEs will be summarized by body system, preferred 
term, and treatment group. If a subject reports the same AE more than once, then that 
subject will be counted only once for the summary of that AE, using the most severe 
intensity or highest relationship to study medication. 
Treatment-emergent AEs will be summarized as follows: 
 All treatment-emergent AEs; 
 All treatment-emergent AEs by intensity; 
 All treatment-emergent AEs by relationship to study drug; 
 All treatment-emergent SAEs; and 
 All treatment-emergent AEs that led to premature discontinuation from study. 


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9.8.2 Clinical Laboratory Assessments 
Hematology, blood chemistry, and urinalysis parameters will be summarized at Baseline 
and at Visit 7, as well as changes from Baseline to Visit 7. Laboratory values and changes 
from Baseline in laboratory values will be summarized descriptively overall and by 
treatment group. 
A summary of shifts from Baseline to final evaluation will be provided for each treatment 
group for each parameter. The normal range for each parameter will be used to create 
categories of low, normal, or high. Any result higher than the ULN or lower than the LLN 
will be categorized as high or low respectively, and any result within the lower and upper 
limits of normal will be categorized as normal. The number and percentage of subjects in 
each treatment group in each shift category from Baseline to final evaluation will be shown 
for each parameter. 
9.8.3 Vital Signs and ECGs 
Vital sign measurements will be summarized at Baseline and at each study visit. In 
addition, changes from Baseline to each study visit in vital sign and ECG measurements will 
be summarized.  
ECG measurements will be summarized at Baseline and at Visit 7. In addition, changes from 
Baseline to Visit 7 in vital sign and ECG measurements will be summarized.  
The incidence of sponsor-defined, potentially clinically significant, post-treatment vital sign 
values will also be presented by treatment group. 
9.8.4 Other Safety Variables 
Concomitant medications taken during study will be categorized by World Health 
Organization (WHO) classification for therapeutic class and drug name and summarized by 
number and percentage of subjects by treatment group. Prior medications will also be 
summarized. 
C-SSRS data will be listed. 
10 
ETHICS, LEGAL, AND ADMINISTRATIVE ASPECTS 
10.1 Institutional Review Board 
The Principal Investigator will provide the IRB with all requisite materials, including a copy 
of the protocol, ICF, and any subject information or advertising materials. The study will 
not be initiated until the IRB provides written approval of the protocol and the ICF and 
until approved documents have been obtained by the Principal Investigator and copies 
received by the Sponsor’s designee. All amendments will be sent to the IRB for information 
(minor amendment) or for submission (major amendment) before implementation. The 
Principal Investigator will supply the IRB and the Sponsor’s designee with appropriate 
reports on the progress of this study, including any necessary safety updates, in accordance 


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with the applicable government regulations and in agreement with policies established by 
the Sponsor. 
10.2 Ethical Conduct of the Study 
The study will be performed in accordance with Health Insurance Portability and 
Accountability Act (HIPAA) regulations, FDA GCP Regulations (21 Code of Federal 
Regulations parts 50, 56, and 312) and International Conference on Harmonisation (ICH) 
guidelines for GCP (E6) and clinical safety data management (E2A). 
10.3 Subject Information and Informed Consent 
In compliance with GCP guidelines, all subjects will be informed of the purpose of the 
research, possible risks of participation, and their rights to withdraw at any time from the 
study without prejudice and without jeopardy to the subject’s future medical care at the 
center. Each subject must give informed written acknowledgment (signed ICF) to the 
Investigator prior to participation in the study. Each subject residing in the US must also 
provide HIPAA authorization. Each subject will be given a copy of their signed ICF.  
No subject is to participate in study activities until written informed consent has been 
obtained. Documentation of the informed consent process and subject information 
discussion must appear in the subject’s medical record, and include a statement that 
informed consent was obtained prior to participation in the study. Signed ICF 
acknowledgments must remain in the subject’s file and be available for verification by 
monitors, auditors, and/or inspectors at any time. 


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11 
APPENDICES 
11.1 Appendix A   
Listing of Laboratory Assays 
 
Serum chemistry panel:  
 
Hematology complete blood count:  
Alanine aminotransferase (ALT)  
Albumin  
Alkaline phosphatase  
Aspartate aminotransferase (AST)  
Bicarbonate  
Bilirubin (total)  
Blood urea nitrogen (BUN)  
Calcium  
Chloride  
Creatinine  
Glucose (non-fasting) 
Potassium  
Sodium  
Total protein  
Uric acid  
White blood cell count (WBC)  
Red blood cell count (RBC)  
Hemoglobin  
Hematocrit (packed cell volume)  
Mean cell volume (MCV)  
Mean cell hemoglobin (MCH)  
Mean cell hemoglobin concentration 
(MCHC)  
Platelet count  
Differential WBC  
Other:  
Thyroid-stimulating hormone (TSH) 
Serum pregnancy test (females of child-bearing potential)  
Urine dipstick pregnancy test (onsite) 
Drugs of abuse screen (urine onsite) 
Blood alcohol level 
Glycosylated hemoglobin (HgA1C) 
Hepatitis C virus RNA (for subjects who report positive history of HCV 
infection that is now completely treated) 
CYP 2D6 (only samples from randomized subjects who opt in will be analyzed) 
Population pharmacokinetic samples  
 
 
 


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11.2 Appendix B   
Prohibited Concomitant Medications 
Subjects are not to use an investigational medication from another trial during the study or 
for the 60 days prior to study start. Prohibited concomitant medications can be resumed 
after Visit 8. 
Sedative hypnotics are excluded unless they have been on a stable dose at least one month 
prior to screening and will be continuing their use during the study. 
The table below shows examples of prohibited concomitant medication classes that are not 
allowed in the study; the list is not intended to be comprehensive. Some of the example 
medications listed are included more than once. 
Prohibited Medication Class 
Examples 
Any stimulant used for any indication or 
non-stimulant medications for ADHD 
Stimulants: 
methylphenidate, dexmethylphenidate, 
amphetamine, dextroamphetamine, 
lisdexamfetamine 
Non-stimulants: 
amoxetine, guanfacine, clonidine, 
bupropion 
Monoamine oxidase inhibitors 
selegiline, isocarboxazid, phenelzine, 
tranylcypromine 
Serotonergic drugs 
SSRIs, SNRIs, triptans, tricyclic 
antidepressants, fentanyl, lithium, 
tramadol, tryptophan, buspirone, St. 
John’s wort 
Mood stabilizers 
lithium, valproate, quetiapine 
Anticonvulsants 
phenobarbital, phenytoin, primidone 
Anticoagulants 
warfarin 
Antipsychotics 
risperidone, olanzapine, haloperidol 
Tricyclic antidepressants 
desipramine, protriptyline 
Medications with pressor effects  
phenylephrine, pseudoephedrine, 
ephedrine, midodrine, fludrocortisone 
Systemic corticosteroids 
prednisone, methylprednisolone, 
dexamethasone 


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Psychotropic medications or those with 
psychotropic properties (some are 
already noted above) 
Antidepressants, antipsychotics, mood 
stabilizers, antianxiety agents, certain 
non-prescription cold allergy 
medications (e.g., diphenhydramine, 
dextromethorphan) 
Acidifying agents 
Gastrointestinal acidifying agents (e.g.,  
glutamic acid HCl, ascorbic acid) 
 
Urinary acidifying agents (e.g., 
ammonium chloride, sodium 
acid phosphate, methenamine salts) 
Alkalinizing agents 
Gastrointestinal alkalinizing agents (e.g., 
sodium bicarbonate) 
 
Urinary alkalinizing agents (e.g., 
acetazolamide) 
CYP 2D6 inhibitors 
paroxetine, fluoxetine, quinidine, 
ritonavir 
Other medications 
halogenated anesthetics, phenylbutazone, 
chlorpromazine, ethosuximide 
ADHD = attention deficit hyperactivity disorder; CYP = cytochrome P450; SNRI = serotonin-norepinephrine 
reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor 
 
 


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12 
REFERENCES 
1. American Psychiatric Association. Diagnostic and statistical manual of mental 
disorders (5th ed.). Arlington, VA: American Psychiatric Association; 2013. 
2. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in 
the United States: results from the National Comorbidity Survey Replication. Am J 
Psychiatry. 2006;163(4):716-723. 
3. Bernardi S, Faraone SV, Cortese S, et al. The lifetime impact of attention deficit 
hyperactivity disorder: results from the National Epidemiologic Survey on Alcohol 
and Related Conditions (NESARC). Psychol Med. 2012;42(4):875-887. 
4. Barkley RA. Major life activity and health outcomes associated with attention-
deficit/hyperactivity disorder. J Clin Psychiatry. 2002;63 Suppl 12:10-15. 
5. Arnsten AF. Modulation of prefrontal cortical-striatal circuits: relevance to 
therapeutic treatments for Tourette syndrome and attention-deficit hyperactivity 
disorder. Adv Neurol. 2001;85:333-341. 
6. Faraone S, Rostain A, Blader, J, et.al.  Emotional Dysregulation in ADHD:  
Implications for Clinical Recognition and Intervention, accepted J Child Psychol 
Psychiat.  
7. Behaviour Rating Inventory of Executive Function - Adult Version [BRIEF-A].  
http://www.psychassessments.com.au/Category.aspx?cID=141. Accessed 
November 24, 2017. 
8. Gratz K and Roemer L.  Multidimensional Assessment of Emotion Regulation and 
Dysregulation: Development, Factor Structure, and Initial Validation of the 
Difficuties in Emotion Regulation Scale.  J Psychopathol Behav Assess. 2004;26:41-54. 
9. Hofmann S and Kasdan T.  The Affective Style Questionaire:  Development and 
Psychometric Properties.  J Psychopathol Behav Assess. 2010;32:255-63. 
10. Fredriksen M, Halmoy A, Faraone SV, Haavik J. Long-term efficacy and safety of 
treatment with stimulants and atomoxetine in adult ADHD: a review of controlled 
and naturalistic studies. Eur Neuropsychopharmacol. 2013;23(6):508-527. 
11. Coghill DR, Banaschewski T, Soutullo C, Cottingham MG, Zuddas A. Systematic 
review of quality of life and functional outcomes in randomized placebo controlled 
studies of medications for attention-deficit/hyperactivity disorder. Eur Child Adolesc 
Psychiatry. 2017. 
12. Faraone SV, Glatt SJ. A comparison of the efficacy of medications for adult attention-
deficit/hyperactivity disorder using meta-analysis of effect sizes. J Clin Psychiatry. 
2010;71(6):754-763. 
13. EVEKEO® (amphetamine sulfate tablets, USP) CII  Prescribing Information. 2016; 
https://www.evekeo.com/pdfs/evekeo-pi.pdf. Accessed November 5, 2017. 
14. Weyandt LL, Oster DR, Marraccini ME, et al. Prescription stimulant medication 
misuse: Where are we and where do we go from here? Exp Clin Psychopharmacol. 
2016;24(5):400-414. 
15. Lile JA, Babalonis S, Emurian C, Martin CA, Wermeling DP, Kelly TH. Comparison of 
the behavioral and cardiovascular effects of intranasal and oral d-amphetamine in 
healthy human subjects. J Clin Pharmacol. 2011;51(6):888-898. 
16. Strohl MP. Bradley's Benzedrine studies on children with behavioral disorders. The 
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18Ju12018 
 
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17. Childress AC, Brams M, Cutler AJ, et al. The Efficacy and Safety of Evekeo®, Racemic 
Amphetamine Sulfate, for Treatment of Attention-Deficit/Hyperactivity Disorder 
Symptoms: A Multicenter, Dose-Optimized, Double-Blind, Randomized, Placebo-
Controlled Crossover Laboratory Classroom Study. J Child Adolesc Psychopharmacol. 
2015;25(5):402-414. 
18. Heal DJ, Smith SL, Gosden J, Nutt DJ. Amphetamine, past and present--a 
pharmacological and clinical perspective. J Psychopharmacol. 2013;27(6):479-496. 
19. VYVANSE ® (lisdexamfetamine dimesylate) capsules, for oral use, CII  2017; 
https://www.accessdata.fda.gov/drugsatfda docs/label/2017/021977s034,208510
s002lbl.pdf. Accessed October 20, 2017. 
20. MYDAYIS® (mixed salts of a single-entity amphetamine product) 
dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine 
aspartate monohydrate, amphetamine sulfate capsules, CII 2017; 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022063s000lbl.pdf. 
Accessed January 4, 2017. 
21. Markowitz JS and Patrick KS.  The Clinical Pharmacokinetics of Amphetamine 
Utilized in the Treatment of Attention-Deficit/Hyperactivity Disorder.  J Child 
Adolesc Psychopharmacol.  2017;27(8):  678-689.     
22. Attention deficit hyperactivity disorder: diagnosis and management. National 
Institute for Health and Care Excellence 2016; 
https://www.nice.org.uk/guidance/cg72. Accessed October 20, 2017. 
23. Kooij SJ, Bejerot S, Blackwell A, et al. European consensus statement on diagnosis 
and treatment of adult ADHD: The European Network Adult ADHD. BMC Psychiatry. 
2010;10:67. 
24. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the 
FDA's pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 
2007;164(7):1035-1043. 
25. Spencer TJ, Adler LA, Meihua Q, et al. Validation of the adult ADHD investigator 
symptom rating scale (AISRS). J Atten Disord. 2010;14(1):57-68. 
26. Mini International Neuropsychiatric Interview (MINI) 7.0.2-4. 2017; 
http://harmresearch.org/index.php/product/mini-international-neuropsychiatric-
interview-mini-7-0-2-4/. Accessed November 12, 2017. 
27. Greenhill LL, Osman BB. Ritalin : theory and practice. 2nd ed. Larchmont, NY: M.A. 
Liebert Publishers; 2000. 
28. Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: 
initial validity and internal consistency findings from three multisite studies with 
adolescents and adults. Am J Psychiatry. 2011;168(12):1266-1277. 
 

SAP_001.pdf: 
Arbor Pharmaceuticals, LLC. 
CONFIDENTIAL
Statistical Analysis Plan
Protocol No. AR19.004
12 November 2018
STATISTICAL ANALYSIS PLAN
A Multicenter, Fixed-Dose, Double-Blind, Randomized Study to 
Evaluate the Efficacy and Safety of AR19 (Amphetamine Sulfate) in 
Adult Subjects (Ages 18-55) with Attention Deficit Hyperactivity 
Disorder (ADHD) 
Protocol AR19.004
SPONSORED BY
Arbor Pharmaceuticals, LLC. 
6 Concourse Parkway, Suite 1800
Atlanta, GA 30328
PREPARED BY
This document is confidential and proprietary to Arbor Pharmaceuticals.  Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be 
reproduced, published, or otherwise disclosed without the prior written approval of Arbor, except that this 
document may be disclosed to appropriate Institutional Review Boards under the condition that they keep 
the information confidential.
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Arbor Pharmaceuticals, LLC. 
CONFIDENTIAL
Statistical Analysis Plan
Protocol No. AR19.004
12 November 2018
DOCUMENT VERSION CONTROL
Version Number
Date
Comments/Changes
Final 1.0
12 November 2018
Original
Version:  Final 1.0
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Arbor Pharmaceuticals, LLC. 
CONFIDENTIAL
Statistical Analysis Plan
Protocol No. AR19.004
12 November 2018
TABLE OF CONTENTS
  
LIST OF ABBREVIATIONS...................................................................................... 6 
1. PURPOSE OF THE STATISTICAL ANALYSES ............................................. 8 
2. PROTOCOL SUMMARY.................................................................................... 8 
2.1 
Introduction............................................................................................... 8 
2.2 
Study Objectives ....................................................................................10 
2.3 
Overall Study Design and Plan .............................................................10 
2.4 
Study Population....................................................................................11 
2.5 
Method of Assigning Subjects to Treatment ........................................11 
2.6 
Treatment Regimens .............................................................................11 
2.7 
Sample Size Determination...................................................................13 
3. GENERAL ANALYSIS, REPORTING, AND PROGRAMMING CONVENTIONS
...........................................................................................................................13 
4. ANALYSIS POPULATIONS ............................................................................14 
4.1.1 
Safety Population..........................................................................14 
4.1.2 
Full Analysis Set (FAS) Population..............................................14 
4.1.3 
Per Protocol (PP) Population .......................................................14 
4.2 
Disposition of Subjects ..........................................................................15 
4.3 
Protocol Deviations................................................................................15 
5. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS...............16 
5.1 
Demographics and Baseline Characteristics .......................................16 
5.2 
Prior and Concomitant Medications......................................................16 
5.3 
Medical History ......................................................................................17 
6. MEASUREMENT OF TREATMENT COMPLIANCE .....................................17 
7. EFFICACY EVALUATION ...............................................................................17 
7.1 
Overview of Efficacy Analysis Issues ...................................................17 
7.1.1 
Handling of Dropouts or Missing Data.........................................17 
7.1.1.1 
Missing Individual Items in the AISRS Scale........................17 
7.1.1.2 
Missing AISRS Total Scores at Individual Study Visits.........18 
7.1.2 
Assessment Time Windows .........................................................20 
7.2 
Efficacy Measurements .........................................................................21 
7.2.1 
Adult ADHD Investigator Rating Scale (AISRS) .........................21 
7.2.2 
Clinical Global Impression Scale (CGI) .......................................21 
7.2.3 
Mini International Neuropsychiatric Interview 7.0.2 (MINI).........22 
7.2.4 
Conners’ Adult ADHD Diagnostic Interview for DSM-IVTM (CAADID)
.......................................................................................................22 
7.2.5 
Behavior Rating Inventory of Executive Function–Adult Version 
(BRIEF-A)......................................................................................23 
7.2.6 
Difficulties in Emotional Regulation Scale (DERS).....................24 
7.2.7 
Affective Style Questionnaire (ASQ)............................................24 
7.3 
Efficacy Outcomes.................................................................................25 
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Arbor Pharmaceuticals, LLC. 
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Statistical Analysis Plan
Protocol No. AR19.004
12 November 2018
7.3.1 
Primary Efficacy Outcome – AISRS total score..........................25 
7.3.2 
Secondary Efficacy Outcomes.....................................................25 
7.3.3 
Additional Efficacy Outcomes ......................................................25 
7.4 
Analysis Methods...................................................................................26 
7.4.1 
Primary Efficacy Analyses – AISRS Total Scores ......................26 
7.4.2 
Secondary Efficacy Analyses.......................................................27 
7.5 
Other Efficacy Analyses ........................................................................28 
7.6 
Examination of Subgroups ....................................................................28 
8. SAFETY EVALUATION ...................................................................................28 
8.1 
Overview of Safety Analysis Issues......................................................28 
8.2 
Overview of Safety Analysis Methods ..................................................29 
8.3 
Extent of Exposure ................................................................................29 
8.4 
Adverse Events......................................................................................29 
8.5 
Clinical Laboratory Evaluations.............................................................31 
8.6 
Physical Examinations...........................................................................32 
8.7 
Vital Signs ..............................................................................................32 
8.8 
Electrocardiogram..................................................................................33 
8.9 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................33 
9. PHARMACOKINETIC EVALUATION.............................................................34 
10. OTHER ANALYSES.........................................................................................34 
11. INTERIM ANALYSES AND DATA MONITORING ........................................34 
12. CHANGES TO STUDY CONDUCT OR ANALYSES PLANNED IN THE 
PROTOCOL......................................................................................................34 
12.1 
Changes in the Conduct of the Study...................................................34 
12.2 
Changes in the Analysis Planned in the Protocol ................................34 
13. REFERENCES..................................................................................................34 
14. APPENDICES ...................................................................................................36 
14.1 
Schedule of Events................................................................................36 
14.2 
Adult ADHD Investigator Symptom Rating Scale (AISRS) and Subscales
................................................................................................................37 
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Arbor Pharmaceuticals, LLC. 
CONFIDENTIAL
Statistical Analysis Plan
Protocol No. AR19.004
12 November 2018
LIST OF ABBREVIATIONS
Commonly used abbreviations (such as units and abbreviations used for 
electrocardiogram assessments) are not included in this list.
ADHD
Attention Deficit Hyperactivity Disorder
AISRS
Adult ADHD Investigator Rating Scale
AE(s) 
Adverse event(s)
ASQ
Affective Style Questionnaire
ATC
Anatomical Therapeutic Chemical
BRIEF-A 
Behavior Rating Inventory of Executive Function – Adult Version
CAADID
Conners' Adult ADHD Diagnostic Interview for DSM-IV™
CBC 
Complete Blood Count
CGI-I 
Clinical Global Impression - Improvement
CGI-S
Clinical Global Impression - Severity
CSR 
Clinical Study Report
C-SSRS 
Columbia Suicide Severity Rating Scale
DERS
Difficulties in Emotional Regulation Scale
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition.
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, Fourth Ed.
ECG 
Electrocardiogram 
FAS
Full Analysis Set
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
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Arbor Pharmaceuticals, LLC. 
CONFIDENTIAL
Statistical Analysis Plan
Protocol No. AR19.004
12 November 2018
IR
Immediate Release
IWRS   
Interactive Web Response System 
LS Mean
Least-Squares Mean
MINI
Mini International Neuropsychiatric Interview for Adults
MMRM
Mixed Model for Repeated Measures
PFC
Prefrontal Cortex
PP
Per Protocol
SAE(s) 
Serious Adverse Event(s)
SAP
Statistical Analysis Plan
SE
Standard Error
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Arbor Pharmaceuticals, LLC. 
CONFIDENTIAL
Statistical Analysis Plan
Protocol No. AR19.004
12 November 2018
1. PURPOSE OF THE STATISTICAL ANALYSES 
The purpose of the analyses described in this document is to compare the safety and 
effectiveness of AR19 (Amphetamine Sulfate) compared to placebo in adult subjects
with Attention Deficit Hyperactivity Disorder (ADHD). 
The statistical analysis plan (SAP) is written with due consideration of the 
recommendations outlined in the most recent International Conference on 
Harmonization (ICH) E9 Guideline entitled Guidance for Industry: Statistical Principles 
for Clinical Trials [1] and the most recent ICH E3 Guideline, entitled Guidance for 
Industry: Structure and Content of Clinical Study Reports [2]. 
2. PROTOCOL SUMMARY
2.1
Introduction
Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder which 
typically presents in childhood. As defined in the Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition (DSM-5™), ADHD is characterized by pervasive and 
impairing symptoms of inattention, hyperactivity, and impulsivity which begin in 
childhood. ADHD often persists into adulthood with one-half to two-thirds of child 
patients continuing to be symptomatic adults. The estimated prevalence of ADHD in 
adults in the United States is 4.4%. ADHD causes significant impairment in patients 
throughout the lifespan. Adults with ADHD are more likely to quit a job or be fired, have 
auto accidents, experience sudden changes in personal or career goals, and have
higher perceived social and emotional stress.
Specific etiology of this disorder is unknown, and there is no single diagnostic test. It is 
apparent that the prefrontal cortex (PFC) plays a significant role in maintaining 
executive function, and that patients with ADHD appear to have less-than-adequate
PFC activity, resulting in an overall inability to regulate impulsive behavior. Adequate 
diagnosis requires the use not only of medical but also of special psychological, 
educational, and social resources. Learning may or may not be impaired. The diagnosis
must be based upon a complete history and evaluation of the patient and not solely on 
the presence of the required number of DSM-5™ characteristics.
The core symptoms used to diagnose ADHD in adults are inattention and hyperactivity-
impulsivity. It has, however, been recognized for decades that many adult ADHD 
patients experience clinically significant levels of emotional dysregulation. Items 
pertaining to emotional dysregulation are contained in certain domains of several 
existing tools, including the Behavior Rating Inventory of Executive Function—Adult 
Version (BRIEF-A), Difficulties in Emotion Regulation Scale (DERS), and Affective Style 
Questionnaire (ASQ).
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Arbor Pharmaceuticals, LLC. 
CONFIDENTIAL
Statistical Analysis Plan
Protocol No. AR19.004
12 November 2018
composition (AR19) in adult subjects 18 through 55 years old with ADHD.
2.2
Study Objectives
The primary objective of this study is to assess the efficacy of AR19 compared to 
placebo using the Adult ADHD Investigator Rating Scale (AISRS). 
2.3
Overall Study Design and Plan
This randomized, fixed-dose, double-blind, multi-center trial investigates the 
safety and efficacy of AR19 in the treatment of ADHD in adults from 18 through 55 
years of age.
Safety parameters and therapeutic effect will be evaluated throughout the trial.
Subjects will be randomized to 20 or 40 mg AR19 daily or placebo in a 1:1:1 ratio 
in this fixed dose study. The expected drop-out rate is projected at 20%.
The study will consist of:
x
A 30-day Screening period and Baseline evaluation
x
Titration with AR19 for 4 weeks to 20 or 40 mg daily dose or placebo
x
At least two weeks at a stable dose of AR19 or placebo
x
Post Withdrawal Follow-Up phone call at Visit 8
Study visits will be conducted according to the Schedule of Events (Appendix
14.1).
Subjects who have signed an informed consent form (ICF) and who satisfy the 
inclusion/exclusion criteria will receive study drug twice daily, once in the morning 
and again four to six hours later. Study medication dosing will start at 10 mg/day 
and will be titrated in weekly intervals in 10-mg increments to 20 or 40 mg/day, 
depending on randomization.
It is anticipated that approximately 30 sites will participate in the study. Subject 
enrollment will continue until approximately 312 subjects are enrolled. 
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Arbor Pharmaceuticals, LLC. 
CONFIDENTIAL
Statistical Analysis Plan
Protocol No. AR19.004
12 November 2018
2.4
Study Population
Approximately 312 adult subjects (male or female) with a diagnosis of ADHD per DSM-
5™criteria will be enrolled. Subjects must be 18 to 55 years old, inclusive, at the time of 
Screening. 
2.5
Method of Assigning Subjects to Treatment
Subjects who satisfy the inclusion/exclusion criteria will undergo a 7-day washout of 
previous ADHD stimulant medications, and AR19 or placebo will then be initiated at 10 
mg/day the morning after Visit 2. Depending on treatment group, the daily dose will be 
increased in 10-mg increments every week to 20 or 40 mg/day. The study duration from 
first dose of study drug to the follow-up visit is expected to be approximately 6 weeks.
Subjects will be monitored for safety and for therapeutic response to AR19 treatment. 
Safety and clinical response assessments will be performed at each visit or more 
frequently if clinically indicated. 
Each subject must meet all the inclusion criteria and none of the exclusion criteria to be 
eligible for enrollment in the study. Waivers to inclusion/exclusion criteria will NOT be 
granted. 
Randomization will occur via Interactive Web Response System (IWRS) at Visit 2, if a 
subject meets all inclusion and no exclusion criteria. Subjects will be randomized 1:1:1 
to placebo or 20 or 40 mg AR19/day. Randomization will take place according to a fixed 
schedule using a permuted block design with no stratification by clinical site. 
2.6
Treatment Regimens 
The following dosing procedures will be followed:  
x
The dosing regimen will be two capsules twice daily. All subjects will be 
instructed to take their first dose (two different colored capsules) of study 
medication in the morning. The second dose (two different colored capsules) 
should be taken four to six hours later.
x
Study medication will be administered orally by swallowing the capsules. 
x
Study drug can be taken with or without food.
This study is a fixed dose regimen. Dose adjustments are not allowed during the study. 
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Arbor Pharmaceuticals, LLC. 
CONFIDENTIAL
Statistical Analysis Plan
Protocol No. AR19.004
12 November 2018
After Screening and Baseline evaluations are complete, eligible subjects will be 
randomized 1:1:1 to one of two fixed-dose groups (AR19 10 mg p.o. b.i.d. or AR19 20 
mg p.o. b.i.d.) or placebo. 
Subjects unable to tolerate their AR19 dose at any time during study drug administration 
will be withdrawn from the trial.
Subjects will begin dosing with double-blind study drug the morning following the 
Baseline visit. The first dose will be taken in the morning (2 capsules) and the second 
dose (2 capsules) will be taken 4 to 6 hours later. 
Table 2.6.1 Titration Scheme for 20 mg Daily Dose
 
 
 
 
 
 
Table 2.6.2 Titration Scheme for 40 mg Daily Dose
 
 
 
 
 
 
 
 
 
 
 
 
Subjects randomized to placebo will receive the 10 mg and 20 mg placebo capsules for 
the first and second dose (4 capsules/day) during the trial.
Kit Assigned on Visit/Day
First Dose
Second Dose
Visit 2, Day 1 
20 mg 
Placebo
10 mg 
20 mg
Placebo
10 mg
Placebo
Visit 3, Day 8
20 mg 
Placebo
10 mg
20 mg 
Placebo
10 mg
Visit 4, Day 15
20 mg
Placebo
10 mg
20 mg
Placebo
10 mg
Visit 5, Day 22
20 mg
Placebo
10 mg
20 mg
Placebo
10 mg
Visit 6, Day 29
20 mg
Placebo
10 mg
20 mg
Placebo
10 mg
Kit Assigned on Visit/Day
First Dose
Second Dose
Visit 2, Day 1 
20 mg
Placebo
10 mg 
20 mg
Placebo
10 mg
Placebo
Visit 3, Day 8
20 mg 
Placebo
10 mg
20 mg 
Placebo
10 mg
Visit 4, Day 15
20 mg
10 mg
Placebo
20 mg 
Placebo
10 mg
Visit 5, Day 22
20 mg
10 mg
Placebo
20 mg
10 mg
Placebo
Visit 6, Day 29
20 mg
10 mg
Placebo
20 mg
10 mg
Placebo
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Arbor Pharmaceuticals, LLC. 
CONFIDENTIAL
Statistical Analysis Plan
Protocol No. AR19.004
12 November 2018
2.7
Sample Size Determination
The primary efficacy endpoint is change from Baseline in AISRS total score at Visit 7 
(Week 5). A Bonferroni adjustment will be utilized for the primary efficacy analysis 
where each AR19 dose will be tested against placebo separately using an alpha of 
0.025 for each test.
Eighty-seven (87) subjects per treatment group will provide approximately 90% power to 
detect a 7.0-point difference in mean change from Baseline to Visit 7 in the AISRS total 
score between one of the AR19 doses and placebo with a standard deviation of 13.0 
and Type I error of 0.025 using a two-sample test. To account for an approximate 20% 
dropout rate, a total of 104 subjects will be randomized to each of the three treatment 
groups for a total of 312 randomized subjects. 
3. GENERAL ANALYSIS, REPORTING, AND PROGRAMMING CONVENTIONS
This section discusses general policies to be employed in the analysis and reporting of 
the data from the study.  Departures from these general policies may be given in the 
specific detailed sections of this SAP.  When this situation occurs, the rules set forth in 
the specific section take precedence over the general policies.
Descriptive statistics for continuous parameters will include number of observations (n),
mean, median, standard deviation, minimum, and maximum values. Descriptive 
statistics for categorical parameters will include frequency counts and percentages.  All 
study data will be listed by subject, treatment group, sequence (as applicable), and time 
point (as applicable).
Hypothesis testing, unless otherwise indicated, will be two-sided and performed at the 
2.5% significance level.  When confidence intervals are presented, they will be two-
sided with a confidence coefficient of 97.5%.   P-values will be reported to 3 decimal 
places if greater than 0.001.  If less than 0.001, report ‘<0.001’.  P-values and significant 
levels will be reported as 0.025 rather than .025.  
Data will be summarized based on the recorded visit; no visit windowing will be 
performed. 
No preliminary rounding will be performed; rounding will only occur after analysis.  To 
round, the digit to right of last significant digit will be considered:  if < 5 then round down, 
LIWKHQURXQGXS0HDQVDQGPHGLDQVZLOOEHSUHVHQWHGZLWKRQHPRUHGHFLPDO
place than the precision of the data.  Standard deviations will be presented with two 
more decimal places than the precision of the data.  Percentages will be presented with 
one decimal place.  Minimums and maximums will be presented with the same 
precision as the original data.
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Arbor Pharmaceuticals, LLC. 
CONFIDENTIAL
Statistical Analysis Plan
Protocol No. AR19.004
12 November 2018
All analyses will be performed using the SAS System® version 9.3 or higher.
The following general programming conventions will apply:
Exposure Days: (Last dosing date – first dosing date + 1) 
Compliance: [(Number of doses taken)/(number of doses planned) ]*100
Duration days: (End/resolution date – start/onset date +1)
Study day: (Date of interest – first dosing date +1) if date of interest is on or after the 
first dosing date:  (Date of interest – first dosing date) if date of interest is before the first 
dosing date.
4. ANALYSIS POPULATIONS
The three analysis populations for this study are defined below. Identification of the 
subjects to be included in each analysis population will be determined prior to database 
unblinding. The database will be locked and unblinded after the SAP is signed and 
authorized, there are no outstanding data issues, and the final analysis populations are 
imported into the study database.
4.1.1 
Safety Population
All subjects who are randomized and receive at least one dose of study medication will 
be included in the Safety Population. The Safety Population is the primary analysis 
population for safety assessments. Results will be presented “as treated.” 
4.1.2
Full Analysis Set (FAS) Population
All subjects who are randomized, receive at least one dose of study medication, and 
had one or more post-Baseline on-treatment primary efficacy assessment(s) will be 
included in the FAS Population. The FAS Population is the primary analysis population 
for clinical efficacy. Results will be presented “as randomized.”
4.1.3
Per Protocol (PP) Population
All subjects who are in the FAS population and who do not have any major protocol 
deviations will be included in the PP Population. The PP Population will be used as a 
sensitivity analysis for clinical efficacy.
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Arbor Pharmaceuticals, LLC. 
CONFIDENTIAL
Statistical Analysis Plan
Protocol No. AR19.004
12 November 2018
4.2
Disposition of Subjects
Subject accountability will be summarized based on all subjects enrolled into the study
by treatment sequence.  The following patient accountability information will be 
presented:
x
The number and percentage of subjects who enrolled in the study, who were 
randomized, who completed the study, and who prematurely discontinued from 
the study
x
The number and percentage of subjects who discontinued prematurely, by 
reason for premature discontinuation
x
The number and percentage of subjects in the Safety, FAS, and PP populations
In addition to these summaries, a listing by patient will be provided that shows 
treatment, subject number, sex, age, race, reason for discontinuation, and any specific 
comments related to discontinuation.
4.3
Protocol Deviations
Protocol deviations will be jointly assessed by the sponsor and Rho and summarized by 
treatment sequence and overall.  The final protocol deviation listing for the study (prior 
to unblinding) will be approved by the sponsor.
Protocol deviations will be categorized into, but not limited to, the following protocol 
deviation categories and will be classified as major or minor: 
x
Prohibited Medication/Therapy
x
Dosing or Randomization Error
x
ICF/Consent Process
x
Eligibility Criteria Not Met
x
Missed Study Procedure: Efficacy or Safety Assessment
x
Unreported AEs/SAEs
x
Other Protocol Deviation (not otherwise defined)
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Arbor Pharmaceuticals, LLC. 
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Statistical Analysis Plan
Protocol No. AR19.004
12 November 2018
5. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
5.1
Demographics and Baseline Characteristics
Demographics and baseline characteristics including age, sex, race, weight and height
will be summarized by treatment sequence and overall on the safety, FAS, and PP
populations.
5.2 
Prior and Concomitant Medications
Prior medications are medications that were taken prior to the first dose of study 
medication. Concomitant medications are medications that were taken during the 
treatment period.
Medications with partial start dates will be determined as concomitant medications by 
using available non-missing information. Completely missing start dates (i.e. missing 
information for medication start day, month, and year) are assumed to be concomitant 
medications.
Missing end dates for prior and concomitant medication will be imputed based on the 
following rules: 
x If only the year is known, the date will be set to 31 December of that year. If the 
year is the same as the treatment start date, the date will be set to the treatment 
end date. 
x If the year and month are known the date will be set to the end of the specified
month.
x If the end date is completely missing it will be assumed that the medication is 
ongoing for the duration of the study, and as such regarded as concomitant.
x If these rules are followed and the completed end date is after the last visit date, 
the end date will be set to the last visit date.
The frequency of subjects using prior and concomitant medications at any stage of the 
study will be summarized according to WHO-DD Version 2018.01 Anatomical 
Therapeutic Chemical (ATC) level 2 and level 4, by treatment on the Safety Population. 
The ATC levels will be presented in decreasing order of the total number of subjects
(frequency) who used each medication. The ATC levels with the same frequency will be 
presented alphabetically.
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5.3
Medical History
Medical history findings will be coded using MedDRA 21.0 and will be summarized 
descriptively by treatment on the Safety Population. 
6. MEASUREMENT OF TREATMENT COMPLIANCE
Compliance rates will be calculated by dividing the number of doses taken by the 
number of doses that should have been taken during the treatment period and will be 
summarized by treatment group.
Compliance will be further categorized and summarized by treatment group as follows:
x 
<80%.
x 
80% to 100%.
x 
>100%.
7. EFFICACY EVALUATION
7.1
Overview of Efficacy Analysis Issues
7.1.1
Handling of Dropouts or Missing Data
Missing data could occur under either or both of the following scenarios: (1) missing or 
invalid data for individual questions in the AISRS; and (2) missing AISRS total scores at 
individual visits.  The approach to handling missing data under these scenarios is 
described below.   
7.1.1.1
Missing Individual Items in the AISRS Scale
The AISRS is a validated 18-item scale that corresponds directly to the 18 ADHD items 
in the Diagnostic and Statistical Manual of Mental Disorders. It includes adult prompts 
for each item. The AISRS will be used to determine trial eligibility. An AISRS 
assessment will be completed at Study Visits 1 through 7. The Investigator or other 
designated, qualified individual from the study research team will complete the 
assessment.
Missing or invalid data for individual questions will be handled by rules specified as 
follows:
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x
If 4 or more individual items in the AISRS have missing or invalid data, the 
AISRS total score will be set to missing.
x
If 3 or less individual items in the AISRS are missing or invalid, the values for the 
missing individual items will be imputed using the mean of the non-missing 
individual items for the particular subject at that visit, rounded up to the nearest 
integer.
x
If any item within an AISRS subscale is missing or invalid, the entire subscale 
score will be set to missing.
7.1.1.2
Missing AISRS Total Scores at Individual Study Visits
Primary Analysis
No imputation of missing AISRS total scores at individual visits will be done for the 
primary efficacy analysis.  The mixed model repeated measures methods used to 
analyze the primary endpoint has been designed to utilize all available data and 
provides valid estimates under the assumption of data which are missing completely at 
random or missing at random.  Accordingly, all subjects with one dose of study 
medication and at least one post-baseline on-treatment assessment of the primary 
efficacy variable will be included in the model.
Sensitivity Analyses
To explore the sensitivity of the primary analysis results, analyses using two imputation 
methods may be performed: a placebo-based multiple imputation (MI) pattern-mixture 
model (PMM) analysis and a tipping point analysis using the PMM. If the dropout rate in 
this study is <2%, these sensitivity analyses will not be performed. This decision will be 
made prior to database unblinding.
Sensitivity analysis one: Placebo-based MI PMM
To explore the robustness of the primary analysis results, a sensitivity analysis will 
be carried out that assesses the situation where the data are not missing at 
random (NMAR).  More specifically, all subjects taking AR19 who discontinue for 
any reason will be assumed to behave like placebo subjects.
A controlled, multiple imputation approach based on PMM will be applied for those 
subjects on AR19 using the ‘Copy Reference’ approach [3].  More specifically, 
missing data for those subjects taking AR19 who discontinued early will be 
imputed based on the posterior distribution of the placebo group.  Missing data for 
placebo subjects who discontinue early will also be imputed using the observed 
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values of the placebo group.
Data will be imputed using SAS PROC MI (v9.3 or later) using the full conditional 
specification method (FCS).  Twenty burn-in iterations will be performed prior to 
each imputation.  The imputation model will include observed non-missing AISRS 
scores, baseline AISRS score, age, and sex.  One hundred imputed datasets will 
be generated for analysis.
The same model used in the primary analyses will be fit to each of the 100 
datasets.  The parameter estimates and standard errors will be combined using 
PROC MIANALYZE in SAS v 9.3 or higher.
Sensitivity analysis two: Tipping Point Analysis using PMM
The goal of the tipping point analysis is to determine how robust the results of the 
primary analysis are to varying its assumption that the change from baseline at 
Visit 7 AISRS total scores for subjects that discontinue early from the AR19 group 
is the same as the completers in the AR19 group.  In particular, this analysis 
examines how altering this assumption to allow the discontinued subjects to have 
better and worse outcomes will impact the resulting estimates of the treatment 
effect.  This will quantify the range of values which the assumptions can take on 
and still provide the same conclusions as the primary analysis, giving a very direct 
measure of the sensitivity of the primary analysis to deviations from the 
assumptions using an approach that has missing values for AR19 discontinuation 
subjects imputed.  Missing AISRS total score data in the AR19 group will be 
imputed based on observed values in the AR19 group and likewise, missing 
AISRS total score values in the placebo group will be imputed based on observed 
values in the placebo group.
In this analysis, the estimate of the effect in the AR19 subjects may be viewed as 
a weighted average of the observed average for AR19 completers and the 
average MAR estimate for AR19 subjects.  Shift values of .05 (treated subjects 
have 5% of the change from baseline AISRS total score as assumed in the 
primary methodology) through 1 (treated subjects have 100% of the change from 
baseline AISRS total score as assumed via the primary methodology) will be 
applied at increments of .05 and reported.  The primary analysis will be rerun for 
all shift values and the resulting treatment difference, 97.5% CI and p-value for 
each shift value will be reported; the wider the range of values that result in no 
change in interpretation, the more robust the analysis results may be considered 
to be.
Subjects receiving placebo who discontinue prior to the end of the treatment 
period will have their change from baseline AISRS total score value imputed 
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based on the assumption that they respond to treatment in a similar manner to the 
placebo subjects who completed the study.  For subjects receiving AR19 who 
discontinue prior to the end of the treatment period, the assumed response to 
treatment will be examined in increments from worst (subjects respond in a similar 
manner to the placebo subjects who completed the study) to best (subjects 
respond in a similar manner to the AR19 subjects who completed the study).
The steps to implement the tipping point analysis are as follows:
1) A mixed model repeated measures (MMRM) model will be run using all 
observed data and the LS mean in the AR19 group (20 and 40 mg/day 
separately) of change from baseline at Week 7 in AISRS total score will be 
calculated.
2) Missing data will be imputed based on the MAR assumption using multiple 
imputation procedure (PROC MI) to create 100 complete datasets with 20
burn-in iterations. 
3) For subjects in the AR19 dose groups, the imputed values from Step 2 will 
be “penalized” by adding a percentage (i.e. 5%, 10%, 15%, 20%, etc. of the 
LS mean treatment difference) of the absolute value of the mean change 
calculated from Step 1; for the placebo group, no “penalty” will be taken for 
the imputed values. 
4) Each newly generated complete dataset from Step 3 will be analyzed using 
the primary analysis MMRM model and results from all 100 datasets will be 
combined (PROC MIANALYZE) to generate inferences. 
5) This analysis (Steps 3-4) will be repeated for a range of values (i.e. 5%, 10%, 
15%, 20%, etc. of the treatment difference) until either the tipping point (where 
statistical significance of the treatment effect is lost) is identified or the 100% 
penalty is applied.
7.1.2
Assessment Time Windows
Data will be summarized based on the recorded visit; no visit windowing will be 
conducted. Visit 7 must be performed as scheduled based on the protocol, allowing for 
consistent and reliable efficacy measurements.
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7.2
Efficacy Measurements
7.2.1
Adult ADHD Investigator Rating Scale (AISRS)
The AISRS is a validated 18-item scale that corresponds directly to the 18 ADHD items 
in the Diagnostic and Statistical Manual of Mental Disorders. It includes adult prompts 
for each item. The AISRS will be used to determine trial eligibility. An AISRS 
assessment will be completed at Study Visits 1 through 7. The Investigator or other 
designated, qualified individual from the study research team will complete the 
assessment.
Each item is scored from a range of zero (reflecting no symptoms) to 3 (reflecting 
severe symptoms) with total scores ranging from zero to 54. Higher AISRS total scores 
signify greater severity of ADHD symptoms.
The following AISRS scores will be assessed:
x
AISRS Hyperactivity/Impulsivity subscale score (sum of even numbered items 2 
through 18)
x
AISRS Inattentiveness subscale score (sum of odd numbered items 1 through 
17)
x
AISRS total score (sum of all items)
See Appendix 14.2 for more details on these items. Missing or invalid data for individual 
questions will be handled by rules described in Section 7.1.1.1.
7.2.2
Clinical Global Impression Scale (CGI)
The Clinical Global Impression Scales are used to measure features associated 
with ADHD. A global assessment of disease severity (CGI-S) will be completed at 
Study Visits 1 through 7. A global assessment of disease improvement (CGI-I) 
relative to baseline will be completed at Study Visits 3 through 7. The Investigator 
or designated, qualified individual from the study site will perform the assessment.
The severity of a subject’s ADHD symptoms will be rated on a 7-point scale 
ranging from 1 (normal) to 7 (among the most extremely ill subjects). 
The subject’s current disease status will be classified as follows:   
1 = Normal, not at all ill.
2 = Borderline ill.
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3 = Mildly ill.
4 = Moderately ill.
5 = Markedly ill.
6 = Severely ill.
7 = Among the most extremely ill subjects.
The subject’s disease improvement relative to Baseline (Visit 2) will be classified as 
follows:  
1 = Very much improved.
2 = Much improved.
3 = Minimally improved.
4 = No change.
5 = Minimally worse.
6 = Much worse.
7 = Very much worse.
7.2.3
Mini International Neuropsychiatric Interview 7.0.2 (MINI)
The MINI is a short, structured diagnostic interview developed for DSM-5™. It assesses 
the 15 most common psychiatric diagnoses and can be completed in about 15 minutes.
The MINI will be completed at Screening. 
7.2.4
Conners’ Adult ADHD Diagnostic Interview for DSM-IVTM (CAADID)
The CAADID is a structured interview that assesses childhood and adult ADHD 
symptoms. Although the version used was designed for DSM-IVTM, it can be adapted to 
make an ADHD diagnosis using DSM-5™ criteria. The CAADID will be completed at 
Screening.
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7.2.5
Behavior Rating Inventory of Executive Function–Adult Version (BRIEF-
A)
The BRIEF-A is a standardized measure designed to assess adult executive functioning 
and self-regulation. It is composed of 75 items and 9 clinical scales which include: 
Inhibit, Self-Monitor, Plan/Organize, Shift, Initiate, Task Monitor, Emotional Control, 
Working Memory, and Organization of Materials. The clinical scales compose two 
indexes: Behavioral Regulation Index (BRI) and Metacognition (MI), and these indexes 
form the overall summary score, the Global Executive Composite (GEC). The BRIEF-A
will be completed at Baseline (Visit 2) and Visit 7.
The BRIEF-A subscales, indices and overall summary score are scored as follows: 
x BRIEF-A Inhibit subscale score (sum of items 5,16, 29, 36, 43, 55, 58, 73)
x BRIEF-A Self-Monitor subscale score (sum of items 13, 23, 37, 50, 64, 70)
x BRIEF-A Plan/Organize subscale score (sum of items 9, 15, 21, 34, 39, 47, 54, 
63, 66, 71)
x BRIEF-A Shift subscale score (sum of items 8, 22, 32, 44, 61, 67)
x BRIEF-A Initiate subscale score (sum of items 6, 14, 20, 25, 45, 49, 53 62)
x BRIEF-A Task Monitor subscale score (sum of items 2, 18, 24, 41, 52, 75)
x BRIEF-A Emotional Control subscale score (sum of items 1, 12, 19, 28, 33, 42, 
51, 57, 69, 72)
x BRIEF-A Working Memory subscale score (sum of items 4, 11, 17, 26, 35, 46, 
56, 68)
x BRIEF-A Organization of Materials Subscale Score (sum of items 3, 7, 30, 31, 
40, 60, 65, 74)
x BRIEF-A Behavioral Regulation Index (BRI) (sum of Inhibit, Shift, Emotional
Control, Self-Monitor subscale scores)
x BRIEF-A Metacognition Index (MI) (sum of Initiate, Working Memory, 
Plan/Organize, Task Monitor, Organization of Materials subscale scores)
x BRIEF-A Global Executive Composite (GEC) Score (sum of BRI and MI scores)
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7.2.6
Difficulties in Emotional Regulation Scale (DERS)
The DERS is a validated non-disease state scale consisting of 36 items scored on a
range of 1 (almost never) to 5 (almost always). These items are grouped to reflect 
difficulties in: a) awareness and understanding of emotions; b) acceptance of emotions; 
c) ability to engage in goal directed behavior and refrain from impulsive behavior while 
experiencing negative emotions; and d) access to emotional regulation strategies 
perceived as effective. The DERS will be completed at Baseline (Visit 2) and Visit 7.
The following DERS scores will be assessed:
x
DERS Non-acceptance subscale score (sum of items 11, 12, 21, 23, 25, 29)
x
DERS Goals subscale score (sum of items 13, 18, 20R, 26, 33)
x
DERS Impulse subscale score (sum of items 3, 14, 19, 24R, 27, 32)
x
DERS Awareness subscale score (sum of items 2R, 6R, 8R, 10R, 17R, 34R)
x
DERS Strategies subscale score (sum of items 15, 16, 22R, 28, 30, 31, 35, 36)
x
DERS Clarity subscale score (sum of items 1R, 4, 5, 7R, 9)
x
DERS total score (sum of all subscale scores)
Note: “R” indicates a reverse-scored item which is calculated by subtracting the item 
score rather than adding.
7.2.7
Affective Style Questionnaire (ASQ)
The ASQ is a 20-item questionnaire used to measure individual styles in emotional 
regulation scored on a range of 1 (not true of me at all) to 5 (extremely true of me). The 
styles assessed in this instrument are: a) suppression and other strategies to conceal or 
avoid emotion; b) more able to access emotional information in adaptive problem 
solving (i.e., to be better able to modulate emotional experience and expression 
according to contextual demands); and c) reflecting comfort and non-defensiveness in 
response to arousing emotional responses, thus tolerating the aroused emotional 
response. The ASQ will be completed at Baseline (Visit 2) and Visit 7.
The following ASQ scores will be assessed:
x
ASQ Concealing subscale score (sum of items 1, 5, 9, 10, 13, 15, 18, 20)
x
ASQ Adjusting subscale score (sum of items 2, 4, 7, 8, 12, 16, 19)
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x
ASQ Tolerating subscale score (sum of items 3, 6, 11, 14, 17)
x
ASQ Total score (sum of all items)
7.3
Efficacy Outcomes
7.3.1
Primary Efficacy Outcome – AISRS total score
The primary efficacy analysis will be performed on the FAS population. The primary 
efficacy outcome is the change in AISRS total score from Visit 2 (Baseline) to Visit 7 
(End of Study) in AR19 treated subjects compared to placebo.
7.3.2
Secondary Efficacy Outcomes
The primary analysis will be repeated on the PP population using the MMRM analysis 
described in Section 7.4.1. 
The secondary efficacy outcomes include:
x
CGI-S at Visit 7 compared to Baseline
x
CGI-I at Visit 7
x
Changes from Baseline of AISRS subscale scores compared to Visit 7
x
Changes from Baseline of the BRIEF-A, subscales, indices, and composites 
compared to Visit 7
7.3.3
Additional Efficacy Outcomes
Items pertaining to emotional dysregulation are contained in certain domains of several 
existing tools, including the BRIEF-A, DERS, and ASQ, which will be used in this study.  
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7.4
Analysis Methods
7.4.1 
Primary Efficacy Analyses – AISRS Total Scores
The primary efficacy analysis will be performed on the FAS population.  The primary 
efficacy outcome is the change from baseline in AISRS total score at Visit 7 (Week 5) in 
AR19 (20 and 40 mg/day) versus placebo. To account for these comparisons, a 
Bonferroni multiple comparison adjustment will be utilized. Both comparisons will be 
conducted at the 0.025 (0.05/2) alpha level. No other adjustments for multiplicity will be 
applied to any other endpoints or comparisons. Change from Baseline in AISRS at Visit 
7 will be compared between each of the two different AR19 dose groups and the 
placebo group. 
The key elements of the primary efficacy analysis are as follows:
Data: AISRS total scores measured at Baseline through Visit 7.  All available data will 
be used; there will be no imputation of missing data.
Model: Restricted maximum likelihood (REML)-based MMRM analysis
Fixed effects:  The following fixed effects are planned:
x
Treatment (class effect: AR19 20 mg/day, AR19 40 mg/day, placebo)
x
Week (class effect: Weeks 1, 2, 3, 4, 5)
x
Baseline AISRS total score
x
Treatment-by-week interaction
Residual Variance-Covariance Matrix: An unstructured correlation matrix will be used 
to model the within-patient errors and restricted maximum likelihood estimation will be 
used. The Kenward-Roger method will be used for the denominator degrees of 
freedom. Should the model fail to converge with an unstructured covariance matrix, 
alternative covariance structures will be applied, in the following order, until the model 
converges: heterogeneous Toeplitz, heterogeneous compound symmetry, then 
heterogeneous autoregressive(1).
The null hypothesis: 
H0: Change from baseline AISRS total scores at Visit 7 are the same for AR19 and
placebo 
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will be tested against the two-sided alternative hypothesis
H1: Change from baseline AISRS totals scores at Visit 7 are not the same for AR19 and
placebo. 
Within this model, pairwise comparisons (using least squares [LS] mean contrasts) will 
be made to compare AISRS at Visit 7 for each AR19 dose level with placebo separately 
(primary efficacy outcome). Treatments will also be compared at other weeks as 
secondary analyses. If differences between baseline characteristics exist between the 
three treatment groups in this comparison, it will be investigated whether adjustment for 
these characteristics is clinically relevant and necessary as a sensitivity analysis.
The estimand of this primary efficacy analysis is the mean treatment difference, AR19 
(20 mg/day and 40 mg/day) vs. placebo, of change from baseline in AISRS total scores 
among all randomized subjects who remain in the study for the duration of the blind 
treatment period, regardless of treatment adherence.
7.4.2
Secondary Efficacy Analyses 
The primary analysis will be repeated on the FAS population using the mixed model 
repeated measures analysis described in Section 7.4.1.
The secondary efficacy outcomes include:
x
Changes from Baseline of AISRS hyperactivity/impulsivity and inattentive 
subscale scores compared to Visit 7
x
CGI-S at Visit 7 compared to Baseline
x
CGI-I at Visit 7  
x
Changes from Baseline of the BRIEF-A, subscales, indices, and composites 
compared to Visit 7
For the AISRS, the proportion of responders (defined as a subject who has a 
change from Baseline of 30% or greater in the AISRS) will also be presented.
The number and percentage of subjects who have each category of the CGI-S
and CGI-I at each time point will be presented by treatment group. Cochran-
Mantel-Haenszel row mean score tests will be used to compare the treatment 
groups. CGI-S and CGI-I results will also be summarized treating the responses 
as continuous values. A MMRM will be utilized to compare treatments at each 
time point. The model will include fixed effects for treatment, week, and the 
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treatment-by-week interaction.  
BRIEF-A will be summarized descriptively over time utilizing observed and change from 
Baseline scores. Treatments will be compared at each time point utilizing MMRM 
models on change from Baseline scores. The model will include fixed effects for 
treatment, week, baseline value, and the treatment-by-week interaction.
7.5
Other Efficacy Analyses
Similar to the BRIEF-A, DERS and ASQ scale scores will be summarized descriptively 
over time utilizing observed and change from Baseline scores. Treatments will be 
compared at each time point utilizing MMRM models on change from Baseline scores. 
The model will include fixed effects for treatment, week, baseline value, and the
treatment-by-week interaction. 
7.6
Examination of Subgroups
The primary and secondary efficacy analyses (CGI and BRIEF-A composite scores 
only) will be repeated on the FAS population based on the following subgroups:
x
Sex (Male, Female)
x
Race (White, Black or African American, Other)
x
ADHD type (Hyperactive-Impulsive, Inattentive, Combined)
8. SAFETY EVALUATION
All subjects who enter the study will be assessed for safety.  Safety will be monitored by 
AEs assessed at each post-dose visit, physical examination, vital signs,
electrocardiogram and clinical laboratory tests.  In addition, the Columbia Suicide 
Severity Rating Scale (C-SSRS) will be administered at Screening, Baseline and all 
subsequent scheduled visits to assess emergent suicidal thoughts or behaviors.  
8.1
Overview of Safety Analysis Issues
Missing end dates for AEs will not be imputed. If end date information is not available, it 
will be assumed that the finding or event is ongoing.
Missing AE start dates will be imputed based on the following rules: 
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x If only the year is known, the date will be set to 01 January of that year. If the 
year is the same as the year of the first dose of study medication, the date will be 
set to the date of the first dose of study medication. 
x If the year and month are known the date will be set to first day of the month. If 
the year and month are the same as the year and month of the first dose of study 
medication, the date will be set to the date of the first dose of study medication.
x If the start date is completely missing it will be set to the date of the first dose of 
study medication.
8.2
Overview of Safety Analysis Methods
All safety data will be analyzed descriptively using the Safety population described in
Section 4.1.1.
8.3
Extent of Exposure
The length of exposure (in days) of study medication will be calculated based on the 
dates of first and last dosing of study medication (last dosing date - first dosing date +
1), by treatment and overall. Length of exposure will be summarized by treatment group 
on the Safety population as continuous values and for the following categories (which 
correspond to scheduled study visit timing): 1-7 days, 8-14 days, 15-21 days, 22-28
days, and >=29 days. 
8.4
Adverse Events
All AEs will be coded using MedDRA Version 21.0. 
An AE is considered treatment-emergent, if it started on or after the first dose of study 
medication is administered. If a subject terminates early from the study and has an AE 
after his/her last dosing date, the AE will be deemed as treatment-emergent if it occurs 
24 hours after the last dose and not as treatment-emergent if it occurs > 24 hours 
after the last dose of study medication. AEs with partial start dates will be imputed as 
outlined in Section 8.1. 
Summary Tabulations
An overview of the frequency, i.e., the number and percentage of subjects with at least 
one of the following AEs will be presented by treatment group: 
x Treatment-emergent adverse events (TEAEs).
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x TEAEs related to study medication.
x Severe TEAEs.
x Serious treatment emergent AEs (SAEs).
x SAEs related to study medication.
x AEs leading to death.
x AEs leading to premature withdrawal of study medication.
System Organ Class/Preferred Term Tabulations
The frequency of subjects reporting TEAEs will be summarized within each system 
organ class (SOC), preferred term (PT), and treatment group. The SOC terms and PTs 
will be presented in decreasing order of the total number of subjects (frequency) who 
experienced each adverse event. System organ class terms and PTs with the same 
frequency will be presented alphabetically.
If a single subject experiences the same AE more than once, the subject will be counted 
once per SOC and PT for that AE, using the most severe intensity or highest 
relationship to study medication.
The frequency of subjects reporting the following TEAEs will be presented:
x
All TEAEs. 
x
All TEAEs by intensity.
x
All TEAEs by relationship to study drug. 
x
All treatment-emergent SAEs. 
x
All TEAEs leading to premature discontinuation from study.
By-Subject Listings
By-subject listings including relevant information (i.e. treatment, age, sex, race, duration 
of AE, severity, relationship, outcome, action taken, etc.) will be presented for:
x
All AEs.
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x SAEs.
x AEs leading to death.
x AEs leading to premature discontinuation of study medication.
The onset of AEs will be calculated relative to the first dose of study medication. The 
duration of AEs in days will be calculated as the difference between the onset and 
resolution dates of the AE. If the AE is ongoing at the end of the study, or the resolution 
date is unknown, the duration will be presented as ‘Unknown’.
8.5
Clinical Laboratory Evaluations 
The following laboratory tests will be performed: 
x
At Screening (Visit 1), End of Study (Visit 7) and at an Early Termination Visit (if 
necessary), laboratory tests will include a non-fasting serum chemistry panel, 
hematology (complete blood count), and urinalysis. Laboratory assessments are 
optional at Unscheduled Visits.
x
CYP 2D6 genetic testing will be performed only at Baseline (Visit 2) for those 
randomized subjects who opt in. Subjects who opt out are still eligible for the 
study. During the trial, CYP 2D6 testing results will be blinded to the subject and 
investigative site in order to ensure protocol efficacy and safety assessments 
remain unbiased.      
x
At the Screening Visit (Visit 1), a serum pregnancy test will be performed for all 
female subjects of child-bearing potential. Urine dipstick pregnancy tests will be 
performed onsite at Visit 2 (Baseline) and Visits 4, 6, and 7 (End of Study) or 
early termination visit (if necessary) and may be performed at any time during 
study participation, if pregnancy is suspected. If positive, confirmation should be 
performed via a serum pregnancy test.
x
A urine test for drugs of abuse will be performed at the site during Visit 1 
(Screening) and Visit 2 (Baseline). The following drugs will be included: 
amphetamine, barbituates, benzodiazepenes, cocaine, opiates, methadone, 
methamphetamine, tetrahydrocannabinol (THC)/cannabis, and phencyclidine 
(PCP).
All laboratory values will be presented in data listings indicating abnormal values for 
non-fasting serum chemistry, CBC, genetic testing, and tests for drugs of abuse; and 
positive values for pregnancy tests.
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8.6
Physical Examinations
A full physical examination will be performed at Visits 1 (Screening), 7 (End of Study), 
and at an Early Termination Visit, if necessary. Although not scheduled, a full physical 
examination may be performed at any time (post-screening) for safety reasons.   The
following body areas and systems will be examined: head and neck, abdominal, chest, 
cardiovascular, heart, respiratory, musculoskeletal, skin, neurological and endocrine.
Body weight will be measured at Screening (Visit 1), Baseline (Visit 2), and at the end of 
Study (Visit 7) or at the Early Termination Visit, if necessary.
Abnormal physical examination results performed prior to first dose of study drug will be 
summarized descriptively in the medical history table by treatment group. Abnormal 
results obtained on or after the first dose of study drug will be presented in the 
applicable adverse event table(s).   
8.7
Vital Signs
Blood pressure and pulse will be assessed at all study visits and will be taken using 
automated machines programmed to take 3 consecutive readings (at least 2 minutes 
apart). Respiratory rate, height for BMI, and temperature will be measured at Screening
(Visit 1) only. 
Systolic blood pressure, diastolic blood pressure, pulse, respiratory rate, and 
temperature will be summarized descriptively for each visit, including change from 
Baseline (where applicable). 
In addition, the incidence of sponsor defined potentially clinically significant (PCS) post-
treatment vital sign values will be presented by treatment group and visit to examine the 
frequency and percentage of subjects that meet the PCS criteria outlined below:
x
Heart Rate
o
ESPLQFUHDVH
o
ESPGHFUHDVH
x
Systolic Blood Pressure
o
mmHg increase
o
PP+JGHFUHDVH
x
Diastolic Blood Pressure
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Statistical Analysis Plan
Protocol No. AR19.004
12 November 2018
o
PP+JLQFUHDVH
o
PP+JGHFUHDVH
x
Weight
o
LQFUHDVH
o
GHFUHDVH
8.8
Electrocardiogram
A 12-lead ECG will be recorded at Screening (Visit 1), End of Study (Visit 7) and at an 
Early Termination Visit (if necessary) by the Investigator or other designated, qualified 
individual from the study site. The ECGs will be read by a central reader(s).  Although 
not scheduled, an ECG assessment may be performed at any time (post-screening) for 
safety reasons.  Final assessment of normal, abnormal results and clinical significance 
of the ECG, including the central reader’s report, will be made by the investigator.   
Screening ECG measurements, overall interpretation, and individual diagnoses will be 
summarized descriptively on the Safety population. All ECG measurements (including 
safety-related post-screening values) will be presented in data listings. 
8.9
Columbia Suicide Severity Rating Scale (C-SSRS) 
The Columbia Suicide Severity Rating Scale (C-SSRS) is a brief Investigator-
administered questionnaire that provides for the identification, quantification and
standardized assessment of the occurrences and severity of suicidal ideation and 
behavior.  
The “Baseline/Screening” version of the C-SSRS will be administered to all subjects at 
the Screening Visit. The “Since Last Visit” version will be used at all subsequent study 
visits (and Early Termination, if necessary). The Investigator or other designated, 
qualified individual at the clinical site will perform these assessments).  
The frequency of suicidality using the C-SSRS will be summarized for each visit for 
each of the following outcomes: 
x Number of subjects reporting at least one occurrence of suicidal ideation or 
behavior.
x Number of subjects reporting any type of suicidal behavior.
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Statistical Analysis Plan
Protocol No. AR19.004
12 November 2018
x Number of subjects reporting any type of suicidal ideation.
9. PHARMACOKINETIC EVALUATION
Exposure-response relationships using population pharmacokinetics will be explored. 
To aid the population pharmacokinetic analysis, two blood plasma samples will be 
collected from all subjects. The samples collected will include pre-dose up to 
approximately 6 hours following drug administration on planned subject visit days (Visit 
6 and Visit 7). Covariates such as age, weight, liver function (AST and ALT), CYP 2D6 
metabolizer status, and race and their effect on AR19 pharmacokinetic parameters will 
be explored. The pharmacokinetic analysis and reporting will be covered in a separate 
SAP and report.
10. OTHER ANALYSES
No other analyses are planned for this study.  However, any additional analyses 
performed after finalization of the SAP will be considered exploratory and will be 
identified as such in the clinical study report (CSR). 
11. INTERIM ANALYSES AND DATA MONITORING
No interim analyses or official data monitoring are planned for this study.
12. CHANGES TO STUDY CONDUCT OR ANALYSES PLANNED IN THE 
PROTOCOL
12.1
Changes in the Conduct of the Study
This SAP is based on Version 3.0 of the AR19.004 clinical study protocol dated August 
20, 2018.  No changes in the conduct of the study are planned from this version of the 
protocol.  
12.2
Changes in the Analysis Planned in the Protocol
This SAP is based on Version 3.0 of the AR19.004 clinical study protocol dated August 
20, 2018. No changes in the analyses of the study are planned from this version of the 
protocol.
13. REFERENCES 
1. US Federal Register. (1998) International Conference on Harmonization; Guidance 
for Industry: Statistical Principles for Clinical Trials. Department of Health and 
Human Services: Food and Drug Administration.  Federal Register, Vol. 63, No. 179, 
September 16, 1998, page 49583.
2. US Federal Register. (1996) International Conference on Harmonization; Guidance 
for Industry: Structure and Content of Clinical Study Reports. Department of Health 
and Human Services: Food and Drug Administration.  Federal Register Vol. 61, July 
17, 1996, page 37320.
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Statistical Analysis Plan
Protocol No. AR19.004
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3. Carpenter JR, Roger JH, Kenward MG.  Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via 
multiple imputation.  J Biopharm Stat.  2013;23(6):1352-71.
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Statistical Analysis Plan
Protocol No. AR19.004
12 November 2018
15. Find yourself being distracted by activity
17. Problems remembering appointments
Version:  Final 1.0
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